Мовні реалії іншого часу і простору (про особливості слововживання у творах Івана Багряного)

The structure of Earthʼs deep inner core has important implications for core evolution, since it is thought to be related to the early stages of core formation. Previous studies have suggested that there exists an innermost inner core with distinct anisotropy relative to the rest of the inner core. Using an extensive new data set of handpicked absolute travel time observations of the inner core phase PKIKP, we find that the data are best explained by variations in anisotropy between two hemispheres and do not require an innermost inner core. We demonstrate that observations of an innermost inner core are an artifact from averaging over lateral anisotropy variations. More significantly we show that hemispherical variations in anisotropy, previously only imaged in the upper inner core, continue to its centre. The eastern region has 0.5–1.5% anisotropy, whereas the western region has 3.5–8.8% anisotropy increasing with depth, with a slow direction at 57–61° to the Earthʼs rotation axis at all depths. Such anisotropy is consistent with models of aligned hcp or bcc iron aggregates

Neoadjuvant chemotherapy and trastuzumab versus neoadjuvant chemotherapy followed by post-operative trastuzumab for patients with HER2-positive breast cancer

Neoadjuvant chemotherapy plus trastuzumab (NCT) increases the rate of pathological complete response (pCR) and event-free survival (EFS) compared to neoadjuvant chemotherapy (NC) alone in women with HER2 positive breast cancer (BC). pCR in this setting is associated with improved EFS. Whether NCT preferentially improves EFS in comparison to NC followed by adjuvant trastuzumab initiated postoperatively (NCAT) has not been addressed. Using clinical data from women with HER2 positive BC treated at 7 European institutions between 2007 and 2010 we sought to investigate the impact on breast cancer outcomes of concomitant (NCT) versus sequential (NCAT) treatment in HER2 positive early BC. The unadjusted hazard ratio (HR) for event free survival with NCT compared with NCAT was 0.63 (95% CI 0.37–1.08; p = 0.091). Multivariable analysis revealed that treatment group, tumour size and ER status were significantly associated with EFS from diagnosis. In the whole group NCT was associated with a reduced risk of an event relative to NCAT, an effect that was confined to ER negative (HR: 0.25; 95% CI, 0.10–0.62; p = 0.003) as opposed to ER positive tumours (HR: 1.07; 95% CI, 0.46–2.52; p = 0.869). HER2 positive/ER negative BC treated with NC gain greatest survival benefit when trastuzumab is administered in both the neoadjuvant and adjuvant period rather than in the adjuvant period alone. These data support the early introduction of targeted combination therapy in HER2 positive/ER negative BC

A de novo approach to inferring within-host fitness effects during untreated HIV-1 infection

Funder: Isaac Newton Trust; funder-id: http://dx.doi.org/10.13039/501100004815Funder: Li Ka Shing Foundation; funder-id: http://dx.doi.org/10.13039/100007421Funder: Division of Intramural Research, National Institute of Allergy and Infectious Diseases; funder-id: http://dx.doi.org/10.13039/100006492Funder: Helsingin Yliopisto; funder-id: http://dx.doi.org/10.13039/100007797In the absence of effective antiviral therapy, HIV-1 evolves in response to the within-host environment, of which the immune system is an important aspect. During the earliest stages of infection, this process of evolution is very rapid, driven by a small number of CTL escape mutations. As the infection progresses, immune escape variants evolve under reduced magnitudes of selection, while competition between an increasing number of polymorphic alleles (i.e., clonal interference) makes it difficult to quantify the magnitude of selection acting upon specific variant alleles. To tackle this complex problem, we developed a novel multi-locus inference method to evaluate the role of selection during the chronic stage of within-host infection. We applied this method to targeted sequence data from the p24 and gp41 regions of HIV-1 collected from 34 patients with long-term untreated HIV-1 infection. We identify a broad distribution of beneficial fitness effects during infection, with a small number of variants evolving under strong selection and very many variants evolving under weaker selection. The uniquely large number of infections analysed granted a previously unparalleled statistical power to identify loci at which selection could be inferred to act with statistical confidence. Our model makes no prior assumptions about the nature of alleles under selection, such that any synonymous or non-synonymous variant may be inferred to evolve under selection. However, the majority of variants inferred with confidence to be under selection were non-synonymous in nature, and in most cases were have previously been associated with either CTL escape in p24 or neutralising antibody escape in gp41. We also identified a putative new CTL escape site (residue 286 in gag), and a region of gp41 (including residues 644, 648, 655 in env) likely to be associated with immune escape. Sites inferred to be under selection in multiple hosts have high within-host and between-host diversity although not all sites with high between-host diversity were inferred to be under selection at the within-host level. Our identification of selection at sites associated with resistance to broadly neutralising antibodies (bNAbs) highlights the need to fully understand the role of selection in untreated individuals when designing bNAb based therapies

Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis:Relationship to Gray Matter Volume

Background: The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia. Here we determine whether changes in brain glutamate are present in subjects at ultra high risk of developing psychosis and whether these changes are related to reductions in cortical gray matter volume. Methods: Twenty-seven individuals with an at-risk mental state and a group of 27 healthy volunteers underwent proton magnetic resonance spectroscopy and volumetric proton magnetic resonance imaging using a 3-Tesla scanner. Glutamate and glutamine levels were measured in anterior cingulate, left hippocampus, and left thalamus. These measures were then related to cortical gray matter volume. Results: At-risk mental state (ARMS) subjects had significantly lower levels of glutamate than control subjects in the thalamus (p < .05) but higher glutamine in the anterior cingulate (p < .05). Within the ARMS group, the level of thalamic glutamate was directly correlated with gray matter volume in the medial temporal cortex and insula (p < .01). Conclusions: This study provides the first evidence that brain glutamate function is perturbed in people with prodromal signs of schizophrenia and that glutamatergic dysfunction is associated with a reduction in gray matter volume in brain regions thought to be critical to the pathogenesis of the disorder. These findings support the hypothesis that drugs affecting the glutamate system may be of benefit in the early stages of psychotic illness. © 2009 Society of Biological Psychiatry

Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus

Anti-inflammatory therapies are the current most plausible drug candidates for anti-epileptogenesis and neuroprotection following prolonged seizures. Given that vasogenic edema is widely considered to be detrimental for outcome following status epilepticus, the anti-inflammatory agent dexamethasone is sometimes used in clinic for alleviating cerebral edema. In this study we perform longitudinal magnetic resonance imaging in order to assess the contribution of dexamethasone on cerebral edema and subsequent neuroprotection following status epilepticus. Lithium-pilocarpine was used to induce status epilepticus in rats. Following status epilepticus, rats were either post-treated with saline or with dexamethasone sodium phosphate (10mg/kg or 2mg/kg). Brain edema was assessed by means of magnetic resonance imaging (T2 relaxometry) and hippocampal volumetry was used as a marker of neuronal injury. T2 relaxometry was performed prior to, 48h and 96h following status epilepticus. Volume measurements were performed between 18 and 21days after status epilepticus. Unexpectedly, cerebral edema was worse in rats that were treated with dexamethasone compared to controls. Furthermore, dexamethasone treated rats had lower hippocampal volumes compared to controls 3weeks after the initial insult. The T2 measurements at 2days and 4days in the hippocampus correlated with hippocampal volumes at 3weeks. Finally, the mortality rate in the first week following status epilepticus increased from 14% in untreated rats to 33% and 46% in rats treated with 2mg/kg and 10mg/kg dexamethasone respectively. These findings suggest that dexamethasone can exacerbate the acute cerebral edema and brain injury associated with status epilepticus. © 2013

Loss of Prox1

Correct regulation of troponin and myosin contractile protein gene isoforms is a critical determinant of cardiac and skeletal striated muscle development and function, with misexpression frequently associated with impaired contractility or disease. Here we reveal a novel requirement for Prospero-related homeobox factor 1 (Prox1) during mouse heart development in the direct transcriptional repression of the fast-twitch skeletal muscle genes troponin T3, troponin I2, and myosin light chain 1. A proportion of cardiac-specific Prox1 knockout mice survive beyond birth with hearts characterized by marked overexpression of fast-twitch genes and postnatal development of a fatal dilated cardiomyopathy. Through conditional knockout of Prox1 from skeletal muscle, we demonstrate a conserved requirement for Prox1 in the repression of troponin T3, troponin I2, and myosin light chain 1 between cardiac and slow-twitch skeletal muscle and establish Prox1 ablation as sufficient to cause a switch from a slow- to fast-twitch muscle phenotype. Our study identifies conserved roles for Prox1 between cardiac and skeletal muscle, specifically implicated in slow-twitch fiber-type specification, function, and cardiomyopathic disease

Characterization of white matter damage in ischemic leukoaraiosis with diffusion tensor MRI

BACKGROUND AND PURPOSE: Information on the neuropathological changes underlying ischemic leukoaraiosis is only available postmortem, and there are limited data on histological appearances early in the disease. Diffusion tensor imaging allows determination of the directionality of diffusion, which is greater in the direction of white matter bundles. Therefore, the technique might be expected to show loss of anisotropy (directional diffusion) in leukoaraiosis. METHODS: Nine patients with ischemic leukoaraiosis (radiological leukoaraiosis and clinical lacunar stroke) and 10 age-matched controls were studied. Diffusion tensor imaging was performed, and maps of diffusion trace and fractional anisotropy were constructed. Mean values of trace and fractional anisotropy were determined in standard regions of the anterior and posterior white matter in both hemispheres. RESULTS: In all patients with ischemic leukoaraiosis, a characteristic abnormal pattern was found, with loss of anisotropy and increased trace in the white matter. For example, in the right anterior white matter mean (SD) trace/3 was 1.12 (0.33) x10(-3) mm2 s-1 in patients and 0.75 (0.11) in controls (P=0.001). In the same region, fractional anisotropy was 0.53 (0.11) in patients and 0.78 (0.09) in controls (P<0.001). Within the white matter regions, there was a strong negative correlation between mean diffusivity and anisotropy (r=-0.92, P<0.0001). CONCLUSIONS: The characteristic pattern found on diffusion tensor imaging in this patient group is consistent with axonal loss and gliosis leading to impairment to and loss of directional diffusion. The "in vivo histological" information obtained may be useful in monitoring disease progression and in investigating the pathogenesis of the cognitive impairment that may be present

Maternally inherited piRNAs direct transient heterochromatin formation at active transposons during early Drosophila embryogenesis

The PIWI-interacting RNA (piRNA) pathway controls transposon expression in animal germ cells, thereby ensuring genome stability over generations. In Drosophila, piRNAs are intergenerationally inherited through the maternal lineage, and this has demonstrated importance in the specification of piRNA source loci and in silencing of I- and P-elements in the germ cells of daughters. Maternally inherited Piwi protein enters somatic nuclei in early embryos prior to zygotic genome activation and persists therein for roughly half of the time required to complete embryonic development. To investigate the role of the piRNA pathway in the embryonic soma, we created a conditionally unstable Piwi protein. This enabled maternally deposited Piwi to be cleared from newly laid embryos within 30 min and well ahead of the activation of zygotic transcription. Examination of RNA and protein profiles over time, and correlation with patterns of H3K9me3 deposition, suggests a role for maternally deposited Piwi in attenuating zygotic transposon expression in somatic cells of the developing embryo. In particular, robust deposition of piRNAs targeting roo, an element whose expression is mainly restricted to embryonic development, results in the deposition of transient heterochromatic marks at active roo insertions. We hypothesize that roo, an extremely successful mobile element, may have adopted a lifestyle of expression in the embryonic soma to evade silencing in germ cells