Arriving late and lean at a stopover site is selected against in a declining migratory bird population.

Loss and/or deterioration of refuelling habitats have caused population declines in many migratory bird species but whether this results from unequal mortality among individuals varying in migration traits remains to be shown. Based on 13 years of body mass and size data of great knots (Calidris tenuirostris) at a stopover site of the Yellow Sea, combined with resightings of individuals marked at this stopover site along the East Asian-Australasian Flyway, we assessed year to year changes in annual apparent survival rates, and how apparent survival differed between migration phenotypes (i.e. migration timing and fuel stores). The measurements occurred over a period of habitat loss and/or deterioration in this flyway. We found that the annual apparent survival rates of great knots rapidly declined from 2006 to 2018, late-arriving individuals with small fuel stores exhibiting the lowest apparent survival rate. There was an advancement in mean arrival date and an increase in the mean fuel load of stopping birds over the study period. Our results suggest that late-arriving individuals with small fuel loads were selected against. Thus, habitat loss and/or deterioration at staging sites may cause changes in the composition of migratory phenotypes at the population-level.

Far eastern curlew and whimbrel prefer flying low - wind support and good visibility appear only secondary factors in determining migratory flight altitude.

BACKGROUND: In-flight conditions are hypothesized to influence the timing and success of long-distance migration. Wind assistance and thermal uplift are thought to reduce the energetic costs of flight, humidity, air pressure and temperature may affect the migrants' water balance, and clouds may impede navigation. Recent advances in animal-borne long-distance tracking enable evaluating the importance of these factors in determining animals' flight altitude. METHODS: Here we determine the effects of wind, humidity, temperature, cloud cover, and altitude (as proxy for climbing costs and air pressure) on flight altitude selection of two long-distance migratory shorebirds, far eastern curlew (Numenius madagascariensis) and whimbrel (Numenius phaeopus). To reveal the predominant drivers of flight altitude selection during migration we compared the atmospheric conditions at the altitude the birds were found flying with conditions elsewhere in the air column using conditional logistic mixed effect models. RESULTS: Our results demonstrate that despite occasional high-altitude migrations (up to 5550 m above ground level), our study species typically forego flying at high altitudes, limiting climbing costs and potentially alleviating water loss and facilitating navigation. While mainly preferring migrating at low altitude, notably in combination with low air temperature, the birds also preferred flying with wind support to likely reduce flight costs. They avoided clouds, perhaps to help navigation or to reduce the risks from adverse weather. CONCLUSIONS: We conclude that the primary determinant of avian migrant's flight altitude selection is a preference for low altitude, with wind support as an important secondary factor. Our approach and findings can assist in predicting climate change effects on migration and in mitigating bird strikes with air traffic, wind farms, power lines, and other human-made structures.

Prenatal Alcohol Exposure and Chorioamnionitis Results in Microstructural Brain Injury in a Preclinical Investigation.

BACKGROUND: Prenatal Alcohol Exposure (PAE) impacts 2% to 5% of infants born in the United States yearly. Women who consume alcohol during pregnancy have a five-fold increased rate of Chorioamnionitis (CHORIO). Both PAE and CHORIO cause microstructural injury to multiple brain regions including major white matter tracts. OBJECTIVE: Utilizing two previously established animal models, we hypothesized that the combination of PAE+CHORIO would result in greater deficits in myelination and structural integrity than PAE alone. MATERIAL AND METHODS: Pregnant Long-Evans rats voluntarily drank 5% ethanol or saccharin until Gestational Day 19 (GD). On GD19, CHORIO was induced in one group of PAE dams by a 30 min uterine artery occlusion and injection of Lipopolysaccharide (LPS) into each amniotic sac. The remaining PAE dams and saccharin controls underwent sham surgery. Pups were born on GD22 and weaned on Postnatal Day 24 (PD). On PD28, offspring were sacrificed, and their brains examined using ex-vivo Diffusion Tensor Imaging (DTI). RESULTS: Compared to control, PAE alone did not affect offspring birth weights, mortality or any DTI measures. In contrast, PAE+CHORIO significantly reduced offspring survival and, in surviving pups, increased Radial Diffusivity (RD) in medial frontal cortex and decreased Fractional Anisotropy (FA) in medial and ventral frontal cortex and within capsular regions. CONCLUSION: The combination of moderate PAE+CHORIO results in an increased mortality, concomitant with diffuse microstructural brain injury noted in young adolescent offspring at PD28. Future studies should examine the extent to which PAE exacerbates the damage caused by CHORIO alone and whether these deficits persist into adulthood.

Rapid population decline in migratory shorebirds relying on Yellow Sea tidal mudflats as stopover sites.

Migratory animals are threatened by human-induced global change. However, little is known about how stopover habitat, essential for refuelling during migration, affects the population dynamics of migratory species. Using 20 years of continent-wide citizen science data, we assess population trends of ten shorebird taxa that refuel on Yellow Sea tidal mudflats, a threatened ecosystem that has shrunk by >65% in recent decades. Seven of the taxa declined at rates of up to 8% per year. Taxa with the greatest reliance on the Yellow Sea as a stopover site showed the greatest declines, whereas those that stop primarily in other regions had slowly declining or stable populations. Decline rate was unaffected by shared evolutionary history among taxa and was not predicted by migration distance, breeding range size, non-breeding location, generation time or body size. These results suggest that changes in stopover habitat can severely limit migratory populations.

Prenatal Hypoxia-Ischemia Induces Abnormalities in CA3 Microstructure, Potassium Chloride Co-Transporter 2 Expression and Inhibitory Tone.

Infants who suffer perinatal brain injury, including those with encephalopathy of prematurity, are prone to chronic neurological deficits, including epilepsy, cognitive impairment, and behavioral problems, such as anxiety, inattention, and poor social interaction. These deficits, especially in combination, pose the greatest hindrance to these children becoming independent adults. Cerebral function depends on adequate development of essential inhibitory neural circuits and the appropriate amount of excitation and inhibition at specific stages of maturation. Early neuronal synaptic responses to γ-amino butyric acid (GABA) are initially excitatory. During the early postnatal period, GABAAR responses switch to inhibitory with the upregulation of potassium-chloride co-transporter KCC2. With extrusion of chloride by KCC2, the Cl(-) reversal potential shifts and GABA and glycine responses become inhibitory. We hypothesized that prenatal hypoxic-ischemic brain injury chronically impairs the developmental upregulation of KCC2 that is essential for cerebral circuit formation. Following late gestation hypoxia-ischemia (HI), diffusion tensor imaging in juvenile rats shows poor microstructural integrity in the hippocampal CA3 subfield, with reduced fractional anisotropy and elevated radial diffusivity. The loss of microstructure correlates with early reduced KCC2 expression on NeuN-positive pyramidal neurons, and decreased monomeric and oligomeric KCC2 protein expression in the CA3 subfield. Together with decreased inhibitory post-synaptic currents during a critical window of development, we document for the first time that prenatal transient systemic HI in rats impairs hippocampal CA3 inhibitory tone. Failure of timely development of inhibitory tone likely contributes to a lower seizure threshold and impaired cognitive function in children who suffer perinatal brain injury.

Kidins220/ARMS is expressed in neuroblastoma tumors and stabilizes neurotrophic signaling in a human neuroblastoma cell line.

BACKGROUND: Neurotrophic signaling is an important factor in the survival of developing neurons, and the expression of neurotrophic receptors correlates with prognosis in neuroblastoma. Kinase D-interacting substrate of 220 kDa (Kidins220) associates with neurotrophic receptors and stabilizes them, but the expression and function of Kidins220 in neuroblastoma are unknown. METHODS: We study Kidins220 expression in human neuroblastoma cell lines and tumor samples by western blotting and microarray analyses. We determine the functional consequences of downregulation of Kidins220 for response of cell lines to oxidative stress, chemotherapeutic treatment, and neurotrophins using small interfering RNA silencing and by measuring cell survival, signaling, and migration. RESULTS: Kidins220 is expressed in all neuroblastoma tumors and cell lines studied. Downregulation of Kidins220 leads to attenuation of nerve growth factor (NGF)-induced, but not brain-derived neurotrophic factor (BDNF)-induced, MAPK signaling. However, downregulation of Kidins220 does not alter the response to chemotherapeutic drugs or oxidative stress or affect cellular motility. CONCLUSION: Kidins220 is expressed in neuroblastoma tumors and stabilizes NGF-induced, but not BDNF-induced, survival signaling in neuroblastoma cell lines.

Migratory connectivity magnifies the consequences of habitat loss from sea-level rise for shorebird populations.

Sea-level rise (SLR) will greatly alter littoral ecosystems, causing habitat change and loss for coastal species. Habitat loss is widely used as a measurement of the risk of extinction, but because many coastal species are migratory, the impact of habitat loss will depend not only on its extent, but also on where it occurs. Here, we develop a novel graph-theoretic approach to measure the vulnerability of a migratory network to the impact of habitat loss from SLR based on population flow through the network. We show that reductions in population flow far exceed the proportion of habitat lost for 10 long-distance migrant shorebirds using the East Asian-Australasian Flyway. We estimate that SLR will inundate 23-40% of intertidal habitat area along their migration routes, but cause a reduction in population flow of up to 72 per cent across the taxa. This magnifying effect was particularly strong for taxa whose migration routes contain bottlenecks-sites through which a large fraction of the population travels. We develop the bottleneck index, a new network metric that positively correlates with the predicted impacts of habitat loss on overall population flow. Our results indicate that migratory species are at greater risk than previously realized.

Kidins220/ARMS depletion is associated with the neural-to Schwann-like transition in a human neuroblastoma cell line model.

Peripheral neuroblastic tumors exist as a heterogeneous mixture of neuroblastic (N-type) cells and Schwannian stromal (S-type) cells. These stromal cells not only represent a differentiated and less aggressive fraction of the tumor, but also have properties that can influence the further differentiation of nearby malignant cells. In vitro neuroblastoma cultures exhibit similar heterogeneity with N-type and S-type cells representing the neuroblastic and stromal portions of the tumor, respectively, in behavior, morphology, and molecular expression patterns. In this study, we deplete kinase D-interacting substrate of 220kD (Kidins220) with an shRNA construct and thereby cause morphologic transition of the human SH-SY5Y neuroblastoma cell line from N-type to S-type. The resulting cells have similar morphology and expression profile to SH-EP1 cells, a native S-type cell line from the same parent cell line, and to SH-SY5Y cells treated with BrdU, a treatment that induces S-type morphology. Specifically, both Kidins220-deficient SH-SY5Y cells and native SH-EP1 cells demonstrate down-regulation of the genes DCX and STMN2, markers for the neuronal lineage. We further show that Kidins220, DCX and STMN2 are co-down-regulated in cells of S-type morphology generated by methods other than Kidins220 depletion. Finally, we report that the association of low Kidins220 expression with S-type morphology and low DCX and STMN2 expression is demonstrated in spontaneously occurring human peripheral neuroblastic tumors. We propose that Kidins220 is critical in N- to S-type transition of neural crest tumor cells.

The child is father to the man: developmental roles for proteins of importance for neurodegenerative disease.

Although Alzheimer's and Parkinson's diseases predominately affect elderly adults, the proteins that play a role in the pathogenesis of these diseases are expressed throughout life. In fact, many of the proteins hypothesized to be important in the progression of neurodegeneration play direct or indirect roles in the development of the central nervous system. The systems affected by these proteins include neural stem cell fate decisions, neuronal differentiation, cellular migration, protection from oxidative stress, and programmed cell death. Insights into the developmental roles of these proteins may ultimately impact the understanding of neurodegenerative diseases and lead to the discovery of novel treatments.

p75NTR-dependent modulation of cellular handling of reactive oxygen species.

Our previous studies demonstrated that p75NTR confers protection against oxidative stress-induced apoptosis upon PC12 cells; however, the mechanisms responsible for this effect are not known. The present studies reveal decreased mitochondrion membrane potential and increased generation of reactive oxygen species (ROS) in p75NTR-deficient PC12 cells as well as diminution of ROS generation after transfection of a full-length p75NTR construct into these cells. They also show that p75NTR deficiency attenuates activation of the phosphatidylinositol 3-kinase --> phospho-Akt/protein kinase B pathway in PC12 cells by oxidative stress or neurotrophic ligands and inhibition of Akt phosphorylation decreases the glutathione (GSH) content in PC12 cells. In addition, decreased de novo GSH synthesis and increased GSH consumption are observed in p75NTR-deficient cells. These findings indicate that p75NTR regulates cellular handling of ROS to effect a survival response to oxidative stress.

Molecular predictors of human nervous system cancer responsiveness to enediyne chemotherapy.

PURPOSE: To identify and mathematically model molecular predictors of response to the enediyne chemotherapeutic agent, neocarzinostatin, in nervous system cancer cell lines. METHODS: Human neuroblastoma, breast cancer, glioma, and medulloblastoma cell lines were maintained in culture. Content of caspase-3 and Bcl-2, respectively, was determined relative to actin content for each cell line by Western blotting and optical densitometry. For each cell line, sensitivity to neocarzinostatin was determined. Brain tumor cell lines were stably transfected with human Bcl-2 cDNA cloned into the pcDNA3 plasmid vector. RESULTS: In human tumor cell lines of different tissue origins, sensitivity to neocarzinostatin is proportional to the product of the relative contents of Bcl-2 and caspase-3 (r (2) = 0.9; P < 0.01). Neuroblastoma and brain tumor cell lines are particularly sensitive to neocarzinostatin; the sensitivity of brain tumor lines to neocarzinostatin is enhanced by transfection with an expression construct for Bcl-2 and is proportional in transfected cells to the product of the relative contents of Bcl-2 and caspase-3 (r (2) = 0.7). CONCLUSION: These studies underscore the potential of molecular profiling in identifying effective chemotherapeutic paradigms for cancer in general and tumors of the nervous system in particular.

Intake rates and the functional response in shorebirds (Charadriiformes) eating macro-invertebrates.

As field determinations take much effort, it would be useful to be able to predict easily the coefficients describing the functional response of free-living predators, the function relating food intake rate to the abundance of food organisms in the environment. As a means easily to parameterise an individual-based model of shorebird Charadriiformes populations, we attempted this for shorebirds eating macro-invertebrates. Intake rate is measured as the ash-free dry mass (AFDM) per second of active foraging; i.e. excluding time spent on digestive pauses and other activities, such as preening. The present and previous studies show that the general shape of the functional response in shorebirds eating approximately the same size of prey across the full range of prey density is a decelerating rise to a plateau, thus approximating the Holling type II ('disc equation') formulation. But field studies confirmed that the asymptote was not set by handling time, as assumed by the disc equation, because only about half the foraging time was spent in successfully or unsuccessfully attacking and handling prey, the rest being devoted to searching.A review of 30 functional responses showed that intake rate in free-living shorebirds varied independently of prey density over a wide range, with the asymptote being reached at very low prey densities (<150/m-2). Accordingly, most of the many studies of shorebird intake rate have probably been conducted at or near the asymptote of the functional response, suggesting that equations that predict intake rate should also predict the asymptote.A multivariate analysis of 468 'spot' estimates of intake rates from 26 shorebirds identified ten variables, representing prey and shorebird characteristics, that accounted for 81% of the variance in logarithm-transformed intake rate. But four-variables accounted for almost as much (77.3%), these being bird size, prey size, whether the bird was an oystercatcher Haematopus ostralegus eating mussels Mytilus edulis, or breeding. The four variable equation under-predicted, on average, the observed 30 estimates of the asymptote by 11.6%, but this discrepancy was reduced to 0.2% when two suspect estimates from one early study in the 1960s were removed. The equation therefore predicted the observed asymptote very successfully in 93% of cases. We conclude that the asymptote can be reliably predicted from just four easily measured variables. Indeed, if the birds are not breeding and are not oystercatchers eating mussels, reliable predictions can be obtained using just two variables, bird and prey sizes. A multivariate analysis of 23 estimates of the half-asymptote constant suggested they were smaller when prey were small but greater when the birds were large, especially in oystercatchers. The resulting equation could be used to predict the half-asymptote constant, but its predictive power has yet to be tested. As well as predicting the asymptote of the functional response, the equations will enable research workers engaged in many areas of shorebird ecology and behaviour to estimate intake rate without the need for conventional time-consuming field studies, including species for which it has not yet proved possible to measure intake rate in the field.

ERPs and behavioural indices of long-term preattentive and attentive deficits after closed head injury.

Attentional deficits are often reported even years after sustaining a closed head injury (CHI). Disturbance of cognitive attentional functions following CHI has been documented in both behavioural and event-related brain potential (ERP) studies. Recently, the possibility that the sequelae of CHI extend to preattentive processes of attention has been pointed out. We used a paradigm that makes it possible to assess simultaneously the processing of relevant information and involuntary mechanisms of attention to gain further insight in this matter. Eleven patients with CHI greater than 1 year post-trauma and 14 age-matched control subjects were engaged in the performance of a continuous visual reaction time (RT) discrimination task while ignoring streams of auditory task-irrelevant stimuli. The main characteristic in the paradigm was that all visual stimuli were shortly preceded by an auditory stimulus, which could be a repeated (90%) or a different (deviant) tone. We measured performance on the discrimination task, and ERP indices of preattentive (mismatch negativity MMN) and attentive information processing (P1, N165, P3b). In relation to control subjects, CHI patients showed an attenuation of the MMN evoked by the deviant-tone. In response to the visual stimuli, CHI patients showed a delay of P1, and a reduction of the N165 and P3b components. Moreover, they had slower RT and missed more responses in a visual discrimination task. These results indicate both preattentive and attentive deficits, which is consistent with the typical diffuse axonal injury (DAI) resulting after CHI.

Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease.

Huntington's disease (HD) results from polyglutamine expansion in huntingtin (htt), a protein with several consensus caspase cleavage sites. Despite the identification of htt fragments in the brain, it has not been shown conclusively that htt is cleaved by caspases in vivo. Furthermore, no study has addressed when htt cleavage occurs with respect to the onset of neurodegeneration. Using antibodies that detect only caspase-cleaved htt, we demonstrate that htt is cleaved in vivo specifically at the caspase consensus site at amino acid 552. We detect caspase-cleaved htt in control human brain as well as in HD brains with early grade neuropathology, including one homozygote. Cleaved htt is also seen in wild-type and HD transgenic mouse brains before the onset of neurodegeneration. These results suggest that caspase cleavage of htt may be a normal physiological event. However, in HD, cleavage of mutant htt would release N-terminal fragments with the potential for increased toxicity and accumulation caused by the presence of the expanded polyglutamine tract. Furthermore, htt fragments were detected most abundantly in cortical projection neurons, suggesting that accumulation of expanded htt fragments in these neurons may lead to corticostriatal dysfunction as an early event in the pathogenesis of HD.