Phototropins do not alter accumulation of evening-phased circadian transcripts under blue light.

The circadian system induces rhythmic variation in a suite of biochemical and physiological processes that serves to optimise plant growth in diel cycles. To be of greatest utility, these rhythmic behaviours are coordinated with regular environmental changes such as the rising and setting of the sun. Photoreceptors, and metabolites produced during photosynthesis, act to synchronise the internal timing mechanism with lighting cues. We have recently shown that phototropins help maintain robust rhythms of photosynthetic operating efficiency (?PSII or Fq'/Fm') under blue light, although rhythmic accumulation of morning-phased circadian transcripts in the nucleus was unaffected. Here we report that evening-phased nuclear clock transcripts were also unaffected. We also observe that rhythms of nuclear clock transcript accumulation are maintained in phototropin mutant plants under a fluctuating lighting regime that induced a loss of Fq'/Fm' rhythms

Caspase 8 activation independent of Fas (CD95/APO-1) signaling may mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic drugs or gamma radiation.

Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or agonistic anti-Fas monoclonal antibodies results in the cleavage and activation of the cysteine protease procaspase 8 followed by the activation of procaspase 3 and by apoptosis. In some leukemia cell lines, cytotoxic drugs induce expression of Fas-L, which may contribute to cell killing through the ligation of Fas. The involvement of Fas, Fas-L, and caspase 8 was studied in the killing of B-cell chronic lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or gamma radiation. Spontaneous apoptosis was observed at 24-hour incubation, with additional apoptosis induced by each of the cytotoxic treatments. Although Fas mRNA expression was elevated after exposure to chlorambucil, fludarabine, or gamma radiation, Fas protein levels only increased after irradiation. Therefore, Fas expression may be regulated by multiple mechanisms that allow the translation of Fas mRNA only in response to restricted cytotoxic stimuli. None of the cytotoxic stimuli studied here induced Fas-L expression. An agonistic anti-Fas monoclonal antibody (CH-11) did not significantly augment apoptosis induction by any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit spontaneous, chlorambucil-, fludarabine-, or radiation-induced apoptosis. However, procaspase 8 processing was induced by all cytotoxic stimuli. These data suggest that the Fas/Fas-L signaling system does not play a major role in the induction of apoptosis in B-CLL cells treated with cytotoxic drugs or radiation. However, Fas-independent activation of caspase 8 may play a crucial role in the regulation of apoptosis in these cells

Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.

We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL

How alliteration enhances conceptual–attentional interactions in reading

In linguistics, the relationship between phonological word form and meaning is mostly considered arbitrary. Why, then, do literary authors traditionally craft sound relationships between words? We set out to characterise how dynamic interactions between word form and meaning may account for this literary practice. Here, we show that alliteration influences both meaning integration and attentional engagement during reading. We presented participants with adjective-noun phrases, having manipulated semantic relatedness (congruent, incongruent) and form repetition (alliterating, non-alliterating) orthogonally, as in "dazzling-diamond"; "sparkling-diamond"; "dangerous-diamond"; and "creepy-diamond". Using simultaneous recording of event-related brain potentials and pupil dilation (PD), we establish that, whilst semantic incongruency increased N400 amplitude as expected, it reduced PD, an index of attentional engagement. Second, alliteration affected semantic evaluation of word pairs, since it reduced N400 amplitude even in the case of unrelated items (e.g., "dangerous-diamond"). Third, alliteration specifically boosted attentional engagement for related words (e.g., "dazzling-diamond"), as shown by a sustained negative correlation between N400 amplitudes and PD change after the window of lexical integration. Thus, alliteration strategically arouses attention during reading and when comprehension is challenged, phonological information helps readers link concepts beyond the level of literal semantics. Overall, our findings provide a tentative mechanism for the empowering effect of sound repetition in literary constructs

Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia.

This is the peer reviewed version of the article, which has been published in final form at DOI: 10.1113/jphysiol.2014.282889. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.Neurons within the CA1 region of the hippocampus are co-activated during high frequency (100-250 Hz) sharp wave ripple (SWR) activity in a manner that likely drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice) which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7-8 month old wild-type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off-line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and points to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia. This article is protected by copyright. All rights reserved.Alzheimer’s Research UKMedical Research Counci

Solution structure of a repeated unit of the ABA-1 nematode polyprotein allergen of ascaris reveals a novel fold and two discrete lipid-binding sites

Parasitic nematode worms cause serious health problems in humans and other animals. They can induce allergic-type immune responses, which can be harmful but may at the same time protect against the infections. Allergens are proteins that trigger allergic reactions and these parasites produce a type that is confined to nematodes, the nematode polyprotein allergens (NPAs). These are synthesized as large precursor proteins comprising repeating units of similar amino acid sequence that are subsequently cleaved into multiple copies of the allergen protein. NPAs bind small lipids such as fatty acids and retinol (Vitamin A) and probably transport these sensitive and insoluble compounds between the tissues of the worms. Nematodes cannot synthesize these lipids, so NPAs may also be crucial for extracting nutrients from their hosts. They may also be involved in altering immune responses by controlling the lipids by which the immune and inflammatory cells communicate. We describe the molecular structure of one unit of an NPA, the well-known ABA-1 allergen of Ascaris and find its structure to be of a type not previously found for lipid-binding proteins, and we describe the unusual sites where lipids bind within this structur

Source attribution of air pollution by spatial scale separation using high spatial density networks of low cost air quality sensors

To carry out detailed source attribution for air quality assessment it is necessary to distinguish pollutant contributions that arise from local emissions from those attributable to non-local or regional emission sources. Frequently this requires the use of complex models and inversion methods, prior knowledge or assumptions regarding the pollution environment. In this paper we demonstrate how high spatial density and fast response measurements from low-cost sensor networks may facilitate this separation. A purely measurement-based approach to extract underlying pollution levels (baselines) from the measurements is presented exploiting the different relative frequencies of local and background pollution variations. This paper shows that if high spatial and temporal coverage of air quality measurements are available, the different contributions to the total pollution levels, namely the regional signal as well as near and far field local sources, can be quantified. The advantage of using high spatial resolution observations, as can be provided by low-cost sensor networks, lies in the fact that no prior assumptions about pollution levels at individual deployment sites are required. The methodology we present here, utilising measurements of carbon monoxide (CO), has wide applicability, including additional gas phase species and measurements obtained using reference networks. While similar studies have been performed, this is the first study using networks at this density, or using low cost sensor networks.The authors thank EPSRC (EP/E001912/1) for funding for the Message project. IH thanks the German National Academic Foundation for funding of MPhil degree.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S1352231015300583#

Altered intrinsic pyramidal neuron properties and pathway-specific synaptic dysfunction underlie aberrant hippocampal network function in a mouse model of Tauopathy.

Final published version of article. This article is freely available online through the J Neurosci Author Open Choice option.The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.Medical Research Council (MRC)Royal SocietyAlzheimer's Research United Kingdo