On the nature and cause of Specific Language Impairment: a view from sentence processing and infant research

This paper addresses the nature and cause of Specific Language Impairment (SLI) by reviewing recent research in sentence processing of children with SLI compared to typically developing (TD) children and research in infant speech perception. These studies have revealed that children with SLI are sensitive to syntactic, semantic, and real-world information, but do not show sensitivity to grammatical morphemes with low phonetic saliency, and they show longer reaction times than age-matched controls. TD children from the age of 4 show trace reactivation, but some children with SLI fail to show this effect, which resembles the pattern of adults and TD children with low working memory. Finally, findings from the German Language Development (GLAD) Project have revealed that a group of children at risk for SLI had a history of an auditory delay and impaired processing of prosodic information in the first months of their life, which is not detectable later in life. Although this is a single project that needs to be replicated with a larger group of children, it provides preliminary support for accounts of SLI which make an explicit link between an early deficit in the processing of phonology and later language deficits, and the Computational Complexity Hypothesis that argues that the language deficit in children with SLI lies in difficulties integrating different types of information at the interfaces.

Iron Uptake and Homeostasis in Microorganisms

Preface. Iron is considered to be a minor element employed, in a variety of forms, by nearly all living organisms. In some cases, it is utilised in large quantities, for instance for the formation of magnetosomes within magnetotactic bacteria or during use of iron as a respiratory donor or acceptor by iron oxidising or reducing bacteria. However, in most cases the role of iron is restricted to its use as a cofactor or prosthetic group assisting the biological activity of many different types of protein. The key metabolic processes that are dependent on iron as a cofactor are numerous; they include respiration, light harvesting, nitrogen fixation, the Krebs cycle, redox stress resistance, amino acid synthesis and oxygen transport. Indeed, it is clear that Life in its current form would be impossible in the absence of iron. One of the main reasons for the reliance of Life upon this metal is the ability of iron to exist in multiple redox states, in particular the relatively stable ferrous (Fe2+) and ferric (Fe3+) forms. The availability of these stable oxidation states allows iron to engage in redox reactions over a wide range of midpoint potentials, depending on the coordination environment, making it an extremely adaptable mediator of electron exchange processes. Iron is also one of the most common elements within the Earth’s crust (5% abundance) and thus is considered to have been readily available when Life evolved on our early, anaerobic planet. However, as oxygen accumulated (the ‘Great oxidation event’) within the atmosphere some 2.4 billion years ago, and as the oceans became less acidic, the iron within primordial oceans was converted from its soluble reduced form to its weakly-soluble oxidised ferric form, which precipitated (~1.8 billion years ago) to form the ‘banded iron formations’ (BIFs) observed today in Precambrian sedimentary rocks around the world. These BIFs provide a geological record marking a transition point away from the ancient anaerobic world towards modern aerobic Earth. They also indicate a period over which the bio-availability of iron shifted from abundance to limitation, a condition that extends to the modern day. Thus, it is considered likely that the vast majority of extant organisms face the common problem of securing sufficient iron from their environment – a problem that Life on Earth has had to cope with for some 2 billion years. This struggle for iron is exemplified by the competition for this metal amongst co-habiting microorganisms who resort to stealing (pirating) each others iron supplies! The reliance of micro-organisms upon iron can be disadvantageous to them, and to our innate immune system it represents a chink in the microbial armour, offering an opportunity that can be exploited to ward off pathogenic invaders. In order to infect body tissues and cause disease, pathogens must secure all their iron from the host. To fight such infections, the host specifically withdraws available iron through the action of various iron depleting processes (e.g. the release of lactoferrin and lipocalin-2) – this represents an important strategy in our defence against disease. However, pathogens are frequently able to deploy iron acquisition systems that target host iron sources such as transferrin, lactoferrin and hemoproteins, and thus counteract the iron-withdrawal approaches of the host. Inactivation of such host-targeting iron-uptake systems often attenuates the pathogenicity of the invading microbe, illustrating the importance of ‘the battle for iron’ in the infection process. The role of iron sequestration systems in facilitating microbial infections has been a major driving force in research aimed at unravelling the complexities of microbial iron transport processes. But also, the intricacy of such systems offers a challenge that stimulates the curiosity. One such challenge is to understand how balanced levels of free iron within the cytosol are achieved in a way that avoids toxicity whilst providing sufficient levels for metabolic purposes – this is a requirement that all organisms have to meet. Although the systems involved in achieving this balance can be highly variable amongst different microorganisms, the overall strategy is common. On a coarse level, the homeostatic control of cellular iron is maintained through strict control of the uptake, storage and utilisation of available iron, and is co-ordinated by integrated iron-regulatory networks. However, much yet remains to be discovered concerning the fine details of these different iron regulatory processes. As already indicated, perhaps the most difficult task in maintaining iron homeostasis is simply the procurement of sufficient iron from external sources. The importance of this problem is demonstrated by the plethora of distinct iron transporters often found within a single bacterium, each targeting different forms (complex or redox state) of iron or a different environmental condition. Thus, microbes devote considerable cellular resource to securing iron from their surroundings, reflecting how successful acquisition of iron can be crucial in the competition for survival. The aim of this book is provide the reader with an overview of iron transport processes within a range of microorganisms and to provide an indication of how microbial iron levels are controlled. This aim is promoted through the inclusion of expert reviews on several well studied examples that illustrate the current state of play concerning our comprehension of how iron is translocated into the bacterial (or fungal) cell and how iron homeostasis is controlled within microbes. The first two chapters (1-2) consider the general properties of microbial iron-chelating compounds (known as ‘siderophores’), and the mechanisms used by bacteria to acquire haem and utilise it as an iron source. The following twelve chapters (3-14) focus on specific types of microorganism that are of key interest, covering both an array of pathogens for humans, animals and plants (e.g. species of Bordetella, Shigella, , Erwinia, Vibrio, Aeromonas, Francisella, Campylobacter and Staphylococci, and EHEC) as well as a number of prominent non-pathogens (e.g. the rhizobia, E. coli K-12, Bacteroides spp., cyanobacteria, Bacillus spp. and yeasts). The chapters relay the common themes in microbial iron uptake approaches (e.g. the use of siderophores, TonB-dependent transporters, and ABC transport systems), but also highlight many distinctions (such as use of different types iron regulator and the impact of the presence/absence of a cell wall) in the strategies employed. We hope that those both within and outside the field will find this book useful, stimulating and interesting. We intend that it will provide a source for reference that will assist relevant researchers and provide an entry point for those initiating their studies within this subject. Finally, it is important that we acknowledge and thank wholeheartedly the many contributors who have provided the 14 excellent chapters from which this book is composed. Without their considerable efforts, this book, and the understanding that it relays, would not have been possible. Simon C Andrews and Pierre Cornelis

Role of temperature, moisture and Trichoderma species on the survival of Fusarium oxysporum ciceri in the rainfed areas of Pakistan

It has been observed in the present study that when spores of Trichoderma harzianum (Th-2) isolate were applied in the sandy clay loam soil and continuously incubated for 4 months at 25 degrees C and 35 degrees C and at three water potentials, -0.03 MPa, -0.3 MPa and <-50 MPa, it has resulted in significantly reduced (P<0.05), growth of Fusarium oxysporum ciceri (Foc) on branches of chickpea plant. The pathogen population was greatly reduced in the moist soil (43 MPa) when compared with the wet soil (-0.03 MPa) at both temperatures which was indicated by greater colonization and growth of T. harzanum-2 on the branch pieces of chickpea plants. The pathogen was completely eradicated from the chickpea branch pieces, after 6 months at 35 degrees C in the moist soil. In air-dry soil (<-50 MPa), Foc survived in 100% of the branch pieces even after 6 months at both temperatures. When chickpea plant branch pieces having pathogen was sprayed with Th-2 antagonistic isolates of Trichoderma spp., the Th-2 isolate killed the pathogen up to minimum level (10-12%) after 5 months at 35 degrees C in the sandy clay loam soil. It can be concluded that in chickpea growing rainfed areas of Pakistan having sandy clay loam soil, Foc can be controlled by using specific Trichoderma spp., especially in the summer season as after harvest of the crop the temperature increased up and there is rainfall during this period which makes the soil moist. This practice will be able to reduce the inoculum of Foc during this hot period as field remain fallow till next crop is sown in most of the chickpea growing rainfed areas of Pakistan.

Comparison of survival rates of captive-reared and wild-bred Mauritius kestrels (Falco punctatus) in a re-introduced population

Re-introduction is a technique widely used in the conservation of threatened bird species. With advances in aviculture the use of captive-produced individuals as the release stock is becoming more commonplace, and ideally, survival of captive-produced, released individuals should be no different from their wild-bred counterparts. During the late 1980s the Critically Endangered Mauritius kestrel (Falco punctatus) was successfully re-introduced into the Bambous mountain range, Mauritius, some 30 years after its local extinction. Between 1987 and 2001 the developing population was closely monitored enabling us to construct re-sighting histories for 88 released and 284 wild-bred kestrels. We used age-structured models in the survival analysis software program MARK to determine if an individual's origin influenced its subsequent survival. Our analysis indicated no compelling evidence for reduced survival among juvenile captive-reared and released individuals, relative to their wild-bred counterparts, across the majority of cohorts and only limited evidence of a cohort-specific effect. This study illustrates that despite the lack of a formal experimental approach it is still feasible to conduct an assessment of re-introduction outcomes and techniques.

Novel high-resolution characterization of ancient DNA reveals C > U-type base modification events as the sole cause of post mortem miscoding lesions

Ancient DNA (aDNA) research has long depended on the power of PCR to amplify trace amounts of surviving genetic material from preserved specimens. While PCR permits specific loci to be targeted and amplified, in many ways it can be intrinsically unsuited to damaged and degraded aDNA templates. PCR amplification of aDNA can produce highly-skewed distributions with significant contributions from miscoding lesion damage and non-authentic sequence artefacts. As traditional PCR-based approaches have been unable to fully resolve the molecular nature of aDNA damage over many years, we have developed a novel single primer extension (SPEX)-based approach to generate more accurate sequence information. SPEX targets selected template strands at defined loci and can generate a quantifiable redundancy of coverage; providing new insights into the molecular nature of aDNA damage and fragmentation. SPEX sequence data reveals inherent limitations in both traditional and metagenomic PCR-based approaches to aDNA, which can make current damage analyses and correct genotyping of ancient specimens problematic. In contrast to previous aDNA studies, SPEX provides strong quantitative evidence that C U-type base modifications are the sole cause of authentic endogenous damage-derived miscoding lesions. This new approach could allow ancient specimens to be genotyped with unprecedented accuracy.

Comparison of survival rates of captive-reared and wild-bred Mauritius kestrels (falco punctatus) in a re-introduced population

Re-introduction is a technique widely used in the conservation of threatened bird species. With advances in aviculture the use of captive-produced individuals as the release stock is becoming more commonplace, and ideally, survival of captive-produced, released individuals should be no different from their wild-bred counterparts. During the late 1980s the Critically Endangered Mauritius kestrel (Falco punctatus) was successfully re-introduced into the Bambous mountain range, Mauritius, some 30 years after its local extinction. Between 1987 and 2001 the developing population was closely monitored enabling us to construct re-sighting histories for 88 released and 284 wild-bred kestrels. We used age-structured models in the survival analysis software program MARK to determine if an individual's origin influenced its subsequent survival. Our analysis indicated no compelling evidence for reduced survival among juvenile captive-reared and released individuals, relative to their wild-bred counterparts, across the majority of cohorts and only limited evidence of a cohort-specific effect. This study illustrates that despite the lack of a formal experimental approach it is still feasible to conduct an assessment of re-introduction outcomes and techniques. (C) 2003 Elsevier Ltd. All rights reserved.

Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability

Much recent interest has focused on the potential of flavonoids to interact with intracellular signaling pathways such as with the mitogen-activated protein kinase cascade. We have investigated whether the observed strong neurotoxic potential of quercetin in primary cortical neurons may occur via specific and sensitive interactions within neuronal mitogen-activated protein kinase and Akt/protein kinase B (PKB) signaling cascades, both implicated in neuronal apoptosis. Quercetin induced potent inhibition of both Akt/PKB and ERK phosphorylation, resulting in reduced phosphorylation of BAD and a strong activation of caspase-3. High quercetin concentrations (30 microM) led to sustained loss of Akt phosphorylation and subsequent Akt cleavage by caspase-3, whereas at lower concentrations (<10 microM) the inhibition of Akt phosphorylation was transient and eventually returned to basal levels. Lower levels of quercetin also induced strong activation of the pro-survival transcription factor cAMP-responsive element-binding protein, although this did not prevent neuronal damage. O-Methylated quercetin metabolites inhibited Akt/PKB to lesser extent and did not induce such strong activation of caspase-3, which was reflected in the lower amount of damage they inflicted on neurons. In contrast, neither quercetin nor its O-methylated metabolites had any measurable effect on c-Jun N-terminal kinase phosphorylation. The glucuronide of quercetin was not toxic and did not evoke any alterations in neuronal signaling, probably reflecting its inability to enter neurons. Together these data suggest that quercetin and to a lesser extent its O-methylated metabolites may induce neuronal death via a mechanism involving an inhibition of neuronal survival signaling through the inhibition of both Akt/PKB and ERK rather than by an activation of the c-Jun N-terminal kinase-mediated death pathway.

Layer-by-layer coating of alginate matrices with chitosan–alginate for the improved survival and targeted delivery of probiotic bacteria after oral administration

The oral administration of probiotic bacteria has shown potential in clinical trials for the alleviation of specific disorders of the gastrointestinal tract. However, cells must be alive in order to exert these benefits. The low pH of the stomach can greatly reduce the number of viable microorganisms that reach the intestine, thereby reducing the efficacy of the administration. Herein, a model probiotic, Bifidobacterium breve, has been encapsulated into an alginate matrix before coating in multilayers of alternating alginate and chitosan. The intention of this formulation was to improve the survival of B. breve during exposure to low pH and to target the delivery of the cells to the intestine. The material properties were first characterized before in vitro testing. Biacore™ experiments allowed for the polymer interactions to be confirmed; additionally, the stability of these multilayers to buffers simulating the pH of the gastrointestinal tract was demonstrated. Texture analysis was used to monitor changes in the gel strength during preparation, showing a weakening of the matrices during coating as a result of calcium ion sequestration. The build-up of multilayers was confirmed by confocal laser-scanning microscopy, which also showed the increase in the thickness of coat over time. During exposure to in vitro gastric conditions, an increase in viability from <3 log(CFU) per mL, seen in free cells, up to a maximum of 8.84 ± 0.17 log(CFU) per mL was noted in a 3-layer coated matrix. Multilayer-coated alginate matrices also showed a targeting of delivery to the intestine, with a gradual release of their loads over 240 min.

The rulB gene of plasmid pWW0 is a hotspot for the site-specific insertion of integron-like elements found in the chromosomes of environmental Pseudomonas fluorescens group bacteria

The rulAB operon of Pseudomonas spp. confers fitness traits on the host and has been suggested to be a hotspot for insertion of mobile elements that carry avirulence genes. Here, for the first time, we show that rulB on plasmid pWW0 is a hotspot for the active site-specific integration of related integron-like elements (ILEs) found in six environmental pseudomonads (strains FH1–FH6). Integration into rulB on pWW0 occurred at position 6488 generating a 3 bp direct repeat. ILEs from FH1 and FH5 were 9403 bp in length and contained eight open reading frames (ORFs), while the ILE from FH4 was 16 233 bp in length and contained 16 ORFs. In all three ILEs, the first 5.1 kb (containing ORFs 1–4) were structurally conserved and contained three predicted site-specific recombinases/integrases and a tetR homologue. Downstream of these resided ORFs of the ‘variable side’ with structural and sequence similarity to those encoding survival traits on the fitness enhancing plasmid pGRT1 (ILEFH1 and ILEFH5) and the NR-II virulence region of genomic island PAGI-5 (ILEFH4). Collectively, these ILEs share features with the previously described type III protein secretion system effector ILEs and are considered important to host survival and transfer of fitness enhancing and (a)virulence genes between bacteria.

Walking in a winter wonderland? Strategies for Early and Middle Pleistocene survival in mid-latitude Europe

Any occupation of northern Europe by Lower Palaeolithic hominins, even those occurring during full interglacials, must have addressed the challenges of marked seasonality and cold winters. These would have included the problems of: wind-chill and frostbite; duration, distribution and depth of snow-cover; reduced daylight hours; and distribution and availability of animal and plant foods. Solutions can essentially be characterised as a ‘stick or twist’ choice: i.e. year-round presence on a local scale vs. extensive annual mobility. However these options, and the ‘interim’ strategies that lie between them, present various problems, including maintaining core body temperature, meeting the energetic demands of mobility, coping with reduced resource availability and increasing patchiness, and meeting nutritional requirements. The feasibility of different winter survival strategies are explored with reference to Lower Palaeolithic palaeoenvironmental reconstructions and on-site behavioural evidence. Emphasis is placed upon possible strategies for (i) avoiding the excessive lean meat protein problem of ‘rabbit starvation’ (e.g. through exploitation of ‘residential’ species with significant winter body fat and/or by targeting specific body parts, following modern ethnographic examples, supplemented by the exploitation of winter plants); and (ii) maintaining body temperatures (e.g. through managed pyrotechnology, and/or other forms of cultural insulation). The paper concludes with a suggested winter strategy.

Endothelial cell-specific ROS production increases susceptibility to aortic dissection

Background—Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. Methods and Results—A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II–mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45+ inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II–induced vascular smooth muscle cell ROS production. Conclusions—These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II–mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.