Intrinsic non-uniqueness of the acoustic full waveform inverse problem

SUMMARY In the context of seismic imaging, full waveform inversion (FWI) is increasingly popular. Because of its lower numerical cost, the acoustic approximation is often used, especially at the exploration geophysics scale, both for tests and for real data. Moreover, some research domains such as helioseismology face true acoustic media for which FWI can be useful. In this work, an argument that combines particle relabelling and homogenization is used to show that the general acoustic inverse problem based on band-limited data is intrinsically non-unique. It follows that the results of such inversions should be interpreted with caution. To illustrate these ideas, we consider 2-D numerical FWI examples based on a Gauss–Newton iterative inversion scheme and demonstrate effects of this non-uniqueness in the local optimization context.</jats:p

The prognostic and predictive power of redox rotein expression for anthracycline-based chemotherapy response in locally advanced breast cancer

Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P¼0.05) and catalase (P¼0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P¼0.017) and thioredoxin reductase (P¼0.022) were independent prognostic factors for distant metastasis free survival and TxNIP for overall survival (P¼0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P¼0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments

Chromatin and epigenetics: current biophysical views

Recent advances in high-throughput sequencing experiments and their theoretical descriptions have determined fast dynamics of the "chromatin and epigenetics" field, with new concepts appearing at high rate. This field includes but is not limited to the study of DNA-protein-RNA interactions, chromatin packing properties at different scales, regulation of gene expression and protein trafficking in the cell nucleus, binding site search in the crowded chromatin environment and modulation of physical interactions by covalent chemical modifications of the binding partners. The current special issue does not pretend for the full coverage of the field, but it rather aims to capture its development and provide a snapshot of the most recent concepts and approaches. Eighteen open-access articles comprising this issue provide a delicate balance between current theoretical and experimental biophysical approaches to uncover chromatin structure and understand epigenetic regulation, allowing free flow of new ideas and preliminary results

DIAGNOSIS OF BOVINE ANAPLASMA MARGINALE IN NORTH WESTERN LIBYA USING SEROLOGY AND BLOOD FILM EXAMINATION: A COMPARATIVE STUDY

Anaplasmamarginale (A. marginale) is an obligate intra-erythrocytic rickettsia;it is the cause of anaplasmosis, an important tick-borne disease of cattle. Recovered and vaccinated cattle in endemic areas are apparently normal but remain persistently infected and serve as reservoirs for the parasite.This study intended to detect A. marginale in infected and apparently healthy subclinically infected cattle in North Western Libya. During the period extended from March-2006 till September-2007, blood samples and blood smears were collected from totally 119 adult cow (group – I). These cows were raised at some governmental and private farms in Tripoli, Al-Zawiya and Imssallata districts. Blood smears were stained with May-Grunewald- Giemsa stain and examined under Light microscope to detect the presence of intraerythrocytic bacteria. Indirect- ELISA (IELISA) using a 19 KD A. marginale recombinant antigen was used to detect serologically positive reactors.During the study period, 20 cases of acute anaplasmosis were diagnosed in these farms (Group-II); where, three cows died and two aborted. The Seroprevalence for A. marginale by IELISAwas 64% and 100% in group I and II, respectively. Stained thin blood smears failed to detect infective RBCs in group I, however, variable degrees of parasitaemia were detected in group II. In conclusion, this study approved that serological test (IELISA) was more reliable than direct microscopic examination of stained blood smear in detection of chronic persistent anaplasma-infected cows in endemic areas

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges

Balancing repair and tolerance of DNA damage caused by alkylating agents

Alkylating agents constitute a major class of frontline chemotherapeutic drugs that inflict cytotoxic DNA damage as their main mode of action, in addition to collateral mutagenic damage. Numerous cellular pathways, including direct DNA damage reversal, base excision repair (BER) and mismatch repair (MMR), respond to alkylation damage to defend against alkylation-induced cell death or mutation. However, maintaining a proper balance of activity both within and between these pathways is crucial for a favourable response of an organism to alkylating agents. Furthermore, the response of an individual to alkylating agents can vary considerably from tissue to tissue and from person to person, pointing to genetic and epigenetic mechanisms that modulate alkylating agent toxicity

Regulation and Function of FTO mRNA Expression in Human Skeletal Muscle and Subcutaneous Adipose Tissue

OBJECTIVE-Common variants in FTO (the fat mass- and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62-83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25-32 years) and elderly (58-66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158). RESULTS-Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1 alpha. CONCLUSIONS-The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism. Diabetes 58:2402-2408, 200

Human Body Composition and Immunity: Visceral Adipose Tissue Produces IL-15 and Muscle Strength Inversely Correlates with NK Cell Function in Elderly Humans

Natural killer (NK) lymphocyte-mediated cytotoxicity and cytokine secretion control infections and cancers, but these crucial activities decline with age. NK cell development, homeostasis, and function require IL-15 and its chaperone, IL-15 receptor alpha (IL-15Rα). Macrophages and dendritic cells (DC) are major sources of these proteins. We had previously postulated that additional IL-15 and IL-15Rα is made by skeletal muscle and adipose tissue. These sources may be important in aging, when IL-15-producing immune cells decline. NK cells circulate through adipose tissue, where they may be exposed to local IL-15. The objectives of this work were to determine (1) if human muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) are sources of IL-15 and IL-15 Rα, and (2) whether any of these tissues correlate with NK cell activity in elderly humans. We first investigated IL-15 and IL-15Rα RNA expression in paired muscle and SAT biopsies from healthy human subjects. Both tissues expressed these transcripts, but IL-15Rα RNA levels were higher in SAT than in skeletal muscle. We also investigated tissue obtained from surgeries and found that SAT and VAT expressed equivalent amounts of IL-15 and IL-15Rα RNA, respectively. Furthermore, stromal vascular fraction cells expressed more IL-15 RNA than did adipocytes. To test if these findings related to circulating IL-15 protein and NK cell function, we tested 50 healthy adults aged \u3e 70 years old. Plasma IL-15 levels significantly correlated with abdominal VAT mass in the entire cohort and in non-obese subjects. However, plasma IL-15 levels did not correlate with skeletal muscle cross-sectional area and correlated inversely with muscle strength. Plasma IL-15 did correlate with NK cell cytotoxic granule exocytosis and with CCL4 (MIP-1β) production in response to NKp46-crosslinking. Additionally, NK cell responses to K562 leukemia cells correlated inversely with muscle strength. With aging, immune function declines while infections, cancers, and deaths increase. We propose that VAT-derived IL-15 and IL-15Rα is a compensatory NK cell support mechanism in elderly humans