Alkylresorcinol, a biomarker for whole grain intake, and its association with osteoarthritis: the MOST study.

INTRODUCTION: Higher intake of fiber has been associated with lower risk of incident symptomatic osteoarthritis (OA). We examined whether levels of alkylresorcinol (AR), a marker of whole grain intake, were associated with OA in subjects in The Multicenter Osteoarthritis (MOST) Study. METHOD: Knee x-rays and knee pain were assessed at baseline and through 60-months. Stored baseline fasting plasma samples were analyzed for AR homologues (C17:0, C19:0, C21:0, C23:0, C25:0) and total AR levels (AR sum). Two nested case-control studies, one for incident radiographic OA and one for incident symptomatic OA were performed with participants re-assessed at 15, 30 and 60 months. Multivariable conditional logistic regression with baseline covariates including age, sex, BMI, physical activity, quadriceps strength, race, smoking, depressive symptoms, diabetes and knee injury tested the association of log transformed AR levels with OA outcomes. RESULTS: Seven hundred seventy-seven subjects were, on average, in their 60's, and most were women. For 60-month cumulative incidence, there was no significant association between quartiles of AR concentration and incident radiographic (e.g., for incident radiographic OA, highest vs lowest quartile of AR sum showed RR = 0.93 (95% CI 0.59, 1.47), and for symptomatic OA RR was 1.22 (95% CI 0.76, 1.94). In secondary analyses examining 30-month incidence, high AR levels were associated with a reduced risk of X-ray OA (RR = 0.31 (95% CI 0.15, 0.64). CONCLUSION: In primary analyses, AR levels were not associated with risk of OA, but secondary analyses left open the possibility that high AR levels may protect against OA.

Fatty acids and osteoarthritis: the MOST study.

OBJECTIVE: Inflammation worsens joint destruction in osteoarthritis (OA) and aggravates pain. Saturated and n-6 fatty acids (FAs) increase, whereas n-3 FAs reduce inflammation. We examined whether FA levels affected the development of OA. DESIGN: We studied participants from the Multicenter Osteoarthritis study (MOST) at risk of developing knee OA. After baseline, repeated knee x-rays and MRIs were obtained and knee symptoms queried through 60 month follow-up. Using baseline fasting samples, serum FAs were analyzed with standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of MRI cartilage loss and synovitis and of knee pain using WOMAC and evaluated the number of hand joints affected by nodules. In regression models, we tested the association of each OA outcome with levels of saturated, n-3 and n-6 FAs adjusting for age, sex, BMI, education, race, baseline pain and depressive symptoms. RESULTS: We studied 260 cases with incident symptomatic and 259 with incident radiographic OA. Mean age was 61 years (61% women). We found no signficant nor suggestive associations of FA levels with incident OA (e.g., for incident symptomatic OA, OR per s.d. increase in n-3 FA 1.00 (0.85, 1.18) nor with any OA outcome in knee or hand. CONCLUSION: Despite previously described effects on systemic inflammation, blood levels of FAs were not associated with risk of later knee OA or other OA outcomes.

Serum non-esterified fatty acid levels and hip fracture risk: The Cardiovascular Health Study.

Among elderly participants from the Cardiovascular Health Study, we found that non-esterified trans fatty acid levels had a significant prospective association with hip fracture risk. Other non-esterified fatty acid classes were not associated with hip fracture risk. INTRODUCTION: Serum non-esterified fatty acids (NEFAs) are bioactive metabolic intermediates that can be taken up by bone tissue. Their associations with hip fracture risk have not been previously examined. METHODS: Thirty-five individual NEFAs in five classes (saturated [SFA], mono-un-saturated [MUFA], poly-unsaturated n-6 and n-3 [PUFA], and trans-FA) were measured in Cardiovascular Health Study participants (n = 2139, mean age 77.8 years) without known diabetes. The multivariable associations of NEFA levels with hip fracture risk were evaluated in Cox hazards models. RESULTS: We documented 303 incident hip fractures during 11.1 years of follow-up. Among the five NEFA classes, total trans FA levels were positively associated with higher hip fracture risk (HR 1.17 [95% CI, 1.04, 1.31; p = 0.01] per one standard deviation higher level). The SFA lignoceric acid (24:0) was positively associated with higher risk (HR 1.09 [1.04, 1.1]; p < 0.001), while behenic (22:0) and docosatetraenoic (22:4 n6) acids were associated with lower risk (HR 0.76 [0.61, 0.94]; p = 0.01; 0.84 [0.70, 1.00]; p = 0.05, respectively). CONCLUSION: Total plasma trans NEFA levels are related to hip fracture risk, suggesting an unrecognized benefit of their systematic removal from food. Novel associations of individual NEFAs with hip fracture risk require confirmation in other cohort studies.

Temperature-Induced Lifshitz Transition and Possible Excitonic Instability in ZrSiSe.

The nodal-line semimetals have attracted immense interest due to the unique electronic structures such as the linear dispersion and the vanishing density of states as the Fermi energy approaching the nodes. Here, we report temperature-dependent transport and scanning tunneling microscopy (spectroscopy) [STM(S)] measurements on nodal-line semimetal ZrSiSe. Our experimental results and theoretical analyses consistently demonstrate that the temperature induces Lifshitz transitions at 80 and 106 K in ZrSiSe, which results in the transport anomalies at the same temperatures. More strikingly, we observe a V-shaped dip structure around Fermi energy from the STS spectrum at low temperature, which can be attributed to co-effect of the spin-orbit coupling and excitonic instability. Our observations indicate the correlation interaction may play an important role in ZrSiSe, which owns the quasi-two-dimensional electronic structures.

Effective Heisenberg Model and Exchange Interaction for Strongly Correlated Systems.

We consider the extended Hubbard model and introduce a corresponding Heisenberg-like problem written in terms of spin operators. The derived formalism is reminiscent of Anderson's idea of the effective exchange interaction and takes into account nonlocal correlation effects. The results for the exchange interaction and spin susceptibility in the magnetic phase are expressed in terms of single-particle quantities. This fact not only can be used for realistic calculations of multiband systems but also allows us to reconsider a general description of many-body effects in the most interesting physical regimes, where the physical properties of the system are dominated by collective (bosonic) fluctuations. In the strongly spin-polarized limit, when the local magnetic moment is well defined, the exchange interaction reduces to a standard expression of the density functional theory that has been successfully used in practical calculations of magnetic properties of real materials.

Excitonic Instability and Pseudogap Formation in Nodal Line Semimetal ZrSiS.

Electron correlation effects are studied in ZrSiS using a combination of first-principles and model approaches. We show that basic electronic properties of ZrSiS can be described within a two-dimensional lattice model of two nested square lattices. A high degree of electron-hole symmetry characteristic for ZrSiS is one of the key features of this model. Having determined model parameters from first-principles calculations, we then explicitly take electron-electron interactions into account and show that, at moderately low temperatures, ZrSiS exhibits excitonic instability, leading to the formation of a pseudogap in the electronic spectrum. The results can be understood in terms of Coulomb-interaction-assisted pairing of electrons and holes reminiscent of that of an excitonic insulator. Our finding allows us to provide a physical interpretation of the unusual mass enhancement of charge carriers in ZrSiS recently observed experimentally.

Dietary fat modulation of hepatic lipase variant -514 C/T for lipids: a crossover randomized dietary intervention trial in Caribbean Hispanics.

The hepatic lipase (LIPC) locus is a well-established determinant of high-density lipoprotein cholesterol (HDL-C) concentrations, an association that is modified by dietary fat in observational studies. Dietary interventions are lacking. We investigated dietary modulation of LIPC rs1800588 (-514 C/T) for lipids and glucose using a randomized crossover design comparing a high-fat Western diet and a low-fat traditional Hispanic diet in individuals of Caribbean Hispanic descent (n = 42, 4 wk/phase). No significant gene-diet interactions were observed for HDL-C. However, differences in dietary response according to LIPC genotype were observed. In major allele carriers (CC/CT), HDL-C (mmol/l) was higher following the Western diet compared with the Hispanic diet: phase 1 (Western: 1.3 ± 0.03; Hispanic: 1.1 ± 0.04; P = 0.0004); phase 2 (Western: 1.4 ± 0.03; Hispanic: 1.2 ± 0.03; P = 0.0003). In contrast, HDL-C in TT individuals did not differ by diet. Only major allele carriers benefited from the higher-fat diet for HDL-C. Secondarily, we explored dietary fat quality and rs1800588 for HDL-C and triglycerides (TG) in a Boston Puerto Rican Health Study (BPRHS) subset matched for diabetes and obesity status (subset n = 384). In the BPRHS, saturated fat was unfavorably associated with HDL-C and TG in rs1800588 TT carriers. LIPC rs1800588 appears to modify plasma lipids in the context of dietary fat. This new evidence of genetic modulation of dietary responses may inform optimal and personalized dietary fat advice and reinforces the importance of studying genetic markers in diet and cardiometabolic health.

Epstein-Barr virus biomarkers for nasopharyngeal carcinoma in non-endemic regions.

The Epstein-Barr virus (EBV) plays a key role in the development of undifferentiated nasopharyngeal carcinoma (uNPC). In uNPC endemic regions EBV-specific antibodies and plasma EBV DNA load are used as markers for the early detection of uNPC and monitoring of the disease. In non-endemic regions, such studies were practically not conducted. The aim of this study was to compare the clinical significance of EBV serological markers and plasma EBV DNA levels for uNPC patients in a non-endemic region, Russia. The results obtained indicate that both viral capsid antigen/immunoglobulin A (VCA/IgA) antibodies and plasma EBV DNA copies can effectively be used for nasopharyngeal carcinoma (NPC) diagnosis. Besides, plasma EBV DNA load was found to be a more sensitive marker of uNPC than VCA/IgA antibody titres, as it reflected the effect of the therapy in stages of remission and relapse of the disease more precisely. Our study, for the first time, demonstrates that the simultaneous use of plasma EBV DNA loads and VCA/IgA antibody levels are indispensable markers for uNPC in non-endemic regions: a serological marker can be more effectively used for NPC screening, but EBV DNA copies are better for monitoring the disease. However, both markers turned out to be practically unsuitable for assessing the clinical status of patients. Serological markers did not correlate with any signs of the tumour process estimated by tumour, node and metastasis (TNM) classification and the plasma EBV DNA loads correlated only with the size of the pathologically altered lymph nodes (N). Additional study is required to confirm these findings.

Band Filling Control of the Dzyaloshinskii-Moriya Interaction in Weakly Ferromagnetic Insulators.

We observe and explain theoretically a dramatic evolution of the Dzyaloshinskii-Moriya interaction (DMI) in the series of isostructural weak ferromagnets, MnCO_{3}, FeBO_{3}, CoCO_{3}, and NiCO_{3}. The sign of the interaction is encoded in the phase of the x-ray magnetic diffraction amplitude, observed through interference with resonant quadrupole scattering. We find very good quantitative agreement with first-principles electronic structure calculations, reproducing both sign and magnitude through the series, and propose a simplified "toy model" to explain the change in sign with 3d shell filling. The model gives insight into the evolution of the DMI in Mott and charge transfer insulators.

Cancer: Bad Luck or Punishment?

Contrasting opinions on the role of extrinsic and intrinsic factors in cancer etiology (Tomasetti, C., and Vogelstein, B. (2015) Science, 347, 78-81; Wu, S., et al. (2016) Nature, 529, 43-47) variously define priorities in the war on cancer. The correlation between the lifetime risk of several types of cancer and the total number of divisions of normal self-renewing cells revealed by the authors has given them grounds to put forward the "bad luck" hypothesis. It assumes that ~70% of cancer variability is attributed to random errors arising during DNA replication in normal, noncancerous stem cells, i.e. to internal factors, which is impossible either to expect or to prevent. This assumption caused many critical responses that emphasize, on the contrary, the defining role of extrinsic factors in cancer etiology. The analysis of epidemiological and genetic data presented in this work testifies in favor of the "bad luck" hypothesis.

Response to Comments by V. N. Manskikh: "Do External or Internal Factors Lead to Tumor Development? It Is Still Unknown".

The opinion is presented according to which the "bad luck" hypothesis (Tomasetti, C., and Vogelstein, B. (2015) Science, 347, 78-81), which has recently received experimental confirmation, has the right to exist, and its criticisms are largely unfounded.

[Scanning for KRAS, NRAS, BRAF, and PIK3CA mutations by DNA melting analysis with TaqMan probes].

Scanning for mutations by DNA melting analysis (DMA) is based on asymmetric PCR followed by the melting of duplexes formed by single-stranded amplicons with TaqMan probes. The method is optimally suited for clinical genetic testing; it is easy to perform, high-throughput, and sensitive. The detection limit of mutant alleles by the DMA method is about 3%, which is much higher than the sensitivity of Sanger sequencing. In addition, the DMA method is realized in a closed-tube format, while 2-h assay is carried out in a single tube without any intermediate or additional procedures thereby minimizing the risk of cross contamination of the samples. The validation of the DMA method was performed by scanning for mutations of clinically significant genes KRAS, NRAS, BRAF, and   PIK3CA in 324 DNA samples from tumors of patients with melanoma, colorectal and lung cancer. DNA was isolated either directly from tumor tissues, or from formalin-fixed paraffin-embedded tumor tissues. The detected mutations were verified by Sanger sequencing. The spectra of mutations identified in each tumor type correspond to the literature data and, thus, validate the use of DMA.

Microscopic Origin of Heisenberg and Non-Heisenberg Exchange Interactions in Ferromagnetic bcc Fe.

By means of first principles calculations, we investigate the nature of exchange coupling in ferromagnetic bcc Fe on a microscopic level. Analyzing the basic electronic structure reveals a drastic difference between the 3d orbitals of E_{g} and T_{2g} symmetries. The latter ones define the shape of the Fermi surface, while the former ones form weakly interacting impurity levels. We demonstrate that, as a result of this, in Fe the T_{2g} orbitals participate in exchange interactions, which are only weakly dependent on the configuration of the spin moments and thus can be classified as Heisenberg-like. These couplings are shown to be driven by Fermi surface nesting. In contrast, for the E_{g} states, the Heisenberg picture breaks down since the corresponding contribution to the exchange interactions is shown to strongly depend on the reference state they are extracted from. Our analysis of the nearest-neighbor coupling indicates that the interactions among E_{g} states are mainly proportional to the corresponding hopping integral and thus can be attributed to be of double-exchange origin. By making a comparison to other magnetic transition metals, we put the results of bcc Fe into context and argue that iron has a unique behavior when it comes to magnetic exchange interactions.

Correlation-Driven Charge and Spin Fluctuations in LaCoO_{3}.

The spin transition in LaCoO_{3} has been investigated using density-functional theory in combination with dynamical mean-field theory employing continuous time quantum Monte Carlo and exact diagonalization impurity solvers. Calculations on the experimental rhombohedral atomic structure with two Co sites per unit cell show that an independent treatment of the Co atoms results in a ground state with strong charge fluctuations induced by electronic correlations. Each atom shows a contribution from either a d^{5} or a d^{7} state in addition to the main d^{6} state. These states play a relevant role in the spin transition which can be understood as a low spin-high spin (LS-HS) transition with significant contributions (~10%) to the LS and HS states of d^{5} and d^{7} states, respectively. We report spectra as well as optical conductivity data for all cases. A thermodynamic analysis reveals a significant kinetic energy gain through introduction of charge fluctuations, which in addition to the potential energy reduction lowers the total energy of the system.

Plasmons in strongly correlated systems: spectral weight transfer and renormalized dispersion.

We study the charge-density dynamics within the two-dimensional extended Hubbard model in the presence of long-range Coulomb interaction across the metal-insulator transition point. To take into account strong correlations we start from self-consistent extended dynamical mean-field theory and include nonlocal dynamical vertex corrections through a ladder approximation to the polarization operator. This is necessary to fulfill charge conservation and to describe plasmons in the correlated state. The calculated plasmon spectra are qualitatively different from those in the random-phase approximation: they exhibit a spectral density transfer and a renormalized dispersion with enhanced deviation from the canonical √q behavior. Both features are reminiscent of interaction induced changes found in single-electron spectra of strongly correlated systems.

Cancer research: a hurdle race.

Cancer research has shifted in recent years from studying intracellular processes (identification of damaged genes and signaling pathways) to extracellular (hierarchy of tumor cells, cell transitions, clone competition) and tissue (interactions of a tumor with its environment) research. But then the next step seems to be logical: studying biochemistry of tumor-bearing organisms (namely, cancer-induced changes in cellular and tissue metabolism leading to the organism's death). These data can help to develop new methods of cancer treatment. This article discusses some of the challenges of contemporary oncology and possible ways to overcome them.

Optimal Hubbard models for materials with nonlocal Coulomb interactions: graphene, silicene, and benzene.

To understand how nonlocal Coulomb interactions affect the phase diagram of correlated electron materials, we report on a method to approximate a correlated lattice model with nonlocal interactions by an effective Hubbard model with on-site interactions U(*) only. The effective model is defined by the Peierls-Feynman-Bogoliubov variational principle. We find that the local part of the interaction U is reduced according to U(*)=U-V[over ¯], where V[over ¯] is a weighted average of nonlocal interactions. For graphene, silicene, and benzene we show that the nonlocal Coulomb interaction can decrease the effective local interaction by more than a factor of 2 in a wide doping range.

Adatoms and clusters of 3d transition metals on graphene: electronic and magnetic configurations.

We investigate the electronic and magnetic properties of single Fe, Co, and Ni atoms and clusters on monolayer graphene (MLG) on SiC(0001) by means of scanning tunneling microscopy (STM), x-ray absorption spectroscopy, x-ray magnetic circular dichroism (XMCD), and ab initio calculations. STM reveals different adsorption sites for Ni and Co adatoms. XMCD proves Fe and Co adatoms to be paramagnetic and to exhibit an out-of-plane easy axis in agreement with theory. In contrast, we experimentally find a nonmagnetic ground state for Ni monomers while an increasing cluster size leads to sizeable magnetic moments. These observations are well reproduced by our calculations and reveal the importance of hybridization effects and intra-atomic charge transfer for the properties of adatoms and clusters on MLG.

Excitation spectra of transition-metal atoms on the Ag (100) surface controlled by Hund's exchange.

We report photoemission experiments revealing the valence electron spectral function of Mn, Fe, Co, and Ni atoms on the Ag (100) surface. The series of spectra shows splittings of higher energy features which decrease with the filling of the 3d shell and a highly nonmonotonic evolution of spectral weight near the Fermi edge. First principles calculations demonstrate that two manifestations of Hund's exchange J are responsible for this evolution. First, there is a monotonic reduction of the effective exchange splittings with increasing filling of the 3d shell. Second, the amount of charge fluctuations and, thus, the weight of quasiparticle peaks at the Fermi level varies nonmonotonically through this 3d series due to a distinct occupancy dependence of effective charging energies U(eff).

[The LMP1 oncogene sequence variations in patients with oral tumours associated or not associated with the Epstein Barr].

The role of the Epstein-Barr virus (EBV), a ubiquitous lymphotropic human herpesvirus type 4, in the etiology of nasopharyngeal carcinoma (NPC) is not fully understood. The mechanism of NPC carcinogenesis, associated with the virus, is also not clear. The objective of present investigation was to carry out comparative analysis of the structure of an LMP1 oncogene of EBV in viral isolates obtained from patients with two types of tumors of the oral cavity: (a) associated (i.e., NPC) and (b) not associated (other tumors of the same anatomical region, OTOC) with EBV. Comparative analysis of C-terminal regions of LMP1 variants that was based on a sequence analysis of LMP1 from tumor, blood and throat washing samples of NPC and OTOC patients showed that all structural characteristics of LMP1 in both groups of patients were genetically similar, and differences found between compared parameters were statistically insignificant. Thus, for the first time it has been revealed that in NPC and OTOC patients in Russia genetically related EBV strains with structurally similar LMP1 variants are persisting that are likely to reflect a polymorphism of the virus circulating in population. The findings allow us to suggest that in non-NPC-endemic regions of the world, which include Russia, the risk of NPC development does not depend on the EBVstrain and its variant of LMP1 so much, but mostly from the genetic predisposition of infected persons to the disease and the exposure to other, as yet unknown agents.