Immediate effects of acute Mars mission equivalent doses of SEP and GCR radiation on the murine gastrointestinal system-protective effects of curcumin-loaded nanolipoprotein particles (cNLPs).

Introduction: Missions beyond low Earth orbit (LEO) will expose astronauts to ionizing radiation (IR) in the form of solar energetic particles (SEP) and galactic cosmic rays (GCR) including high atomic number and energy (HZE) nuclei. The gastrointestinal (GI) system is documented to be highly radiosensitive with even relatively low dose IR exposures capable of inducing mucosal lesions and disrupting epithelial barrier function. IR is also an established risk factor for colorectal cancer (CRC) with several studies examining long-term GI effects of SEP/GCR exposure using tumor-prone APC mouse models. Studies of acute short-term effects of modeled space radiation exposures in wildtype mouse models are more limited and necessary to better define charged particle-induced GI pathologies and test novel medical countermeasures (MCMs) to promote astronaut safety. Methods: In this study, we performed ground-based studies where male and female C57BL/6J mice were exposed to γ-rays, 50 MeV protons, or 1 GeV/n Fe-56 ions at the NASA Space Radiation Laboratory (NSRL) with histology and immunohistochemistry endpoints measured in the first 24 h post-irradiation to define immediate SEP/GCR-induced GI alterations. Results: Our data show that unlike matched γ-ray controls, acute exposures to protons and iron ions disrupts intestinal function and induces mucosal lesions, vascular congestion, epithelial barrier breakdown, and marked enlargement of mucosa-associated lymphoid tissue. We also measured kinetics of DNA double-strand break (DSB) repair using gamma-H2AX- specific antibodies and apoptosis via TUNEL labeling, noting the induction and disappearance of extranuclear cytoplasmic DNA marked by gamma-H2AX only in the charged particle-irradiated samples. We show that 18 h pre-treatment with curcumin-loaded nanolipoprotein particles (cNLPs) delivered via IV injection reduces DSB-associated foci levels and apoptosis and restore crypt villi lengths. Discussion: These data improve our understanding of physiological alterations in the GI tract immediately following exposures to modeled space radiations and demonstrates effectiveness of a promising space radiation MCM.

Effects of Dehumidification on the Survivorship of Four Psocid Species.

Psocids are damaging stored-product pests. In this study, eggs and early-instar nymphs, adults, and all life stages of Liposcelis entomophila, L. decolor, L. bostrychophila, and L. paeta were subjected to 43, 50, or 75% (Control) relative humidity (RH) for 2, 4, 6, 8, 10, 12, 14, or 16 d at 30.0°C. All adults of these species died within 8 d at both 43 and 50% RH, except for L. bostrychophila, which required 12 d at 50% RH for 100% mortality to occur. For all life stages and eggs and early-instar nymphs, maximum survival times (times to 100% mortality) at 43 or 50% RH for L. entomophila, L. decolor, L. bostrychophila, and L. paeta, were 8 and 10 d, 8 and 12 d, 12 and 14 d, and 12 and 16 d, respectively. During this study, numbers of nymphs and adults of all species 14 d after the RH treatments increased within the 75% RH Control arenas. Different species and life stages responded differently to 43 and 50% RH, as time to kill all stages of the four psocid species was 8-12 and 10-16 d, respectively. Results indicate that using a specific RH environment may be effective in psocid management.

Gene delivery of a modified antibody to Aß reduces progression of murine Alzheimer's disease.

Antibody therapies for Alzheimer's Disease (AD) hold promise but have been limited by the inability of these proteins to migrate efficiently across the blood brain barrier (BBB). Central nervous system (CNS) gene transfer by vectors like adeno-associated virus (AAV) overcome this barrier by allowing the bodies' own cells to produce the therapeutic protein, but previous studies using this method to target amyloid-ß have shown success only with truncated single chain antibodies (Abs) lacking an Fc domain. The Fc region mediates effector function and enhances antigen clearance from the brain by neonatal Fc receptor (FcRn)-mediated reverse transcytosis and is therefore desirable to include for such treatments. Here, we show that single chain Abs fused to an Fc domain retaining FcRn binding, but lacking Fc gamma receptor (FcγR) binding, termed a silent scFv-IgG, can be expressed and released into the CNS following gene transfer with AAV. While expression of canonical IgG in the brain led to signs of neurotoxicity, this modified Ab was efficiently secreted from neuronal cells and retained target specificity. Steady state levels in the brain exceeded peak levels obtained by intravenous injection of IgG. AAV-mediated expression of this scFv-IgG reduced cortical and hippocampal plaque load in a transgenic mouse model of progressive ß-amyloid plaque accumulation. These findings suggest that CNS gene delivery of a silent anti-Aß scFv-IgG was well-tolerated, durably expressed and functional in a relevant disease model, demonstrating the potential of this modality for the treatment of Alzheimer's disease.

Leaf:wood allometry and functional traits together explain substantial growth rate variation in rainforest trees.

Plant growth rates drive ecosystem productivity and are a central element of plant ecological strategies. For seedlings grown under controlled conditions, a large literature has firmly identified the functional traits that drive interspecific variation in growth rate. For adult plants, the corresponding knowledge is surprisingly poorly understood. Until recently it was widely assumed that the key trait drivers would be the same (e.g. specific leaf area, or SLA), but an increasing number of papers has demonstrated this not to be the case, or not generally so. New theory has provided a prospective basis for understanding these discrepancies. Here we quantified relationships between stem diameter growth rates and functional traits of adult woody plants for 41 species in an Australian tropical rainforest. From various cost-benefit considerations, core predictions included that: (i) photosynthetic rate would be positively related to growth rate; (ii) SLA would be unrelated to growth rate (unlike in seedlings where it is positively related to growth); (iii) wood density would be negatively related to growth rate; and (iv) leaf mass:sapwood mass ratio (LM:SM) in branches (analogous to a benefit:cost ratio) would be positively related to growth rate. All our predictions found support, particularly those for LM:SM and wood density; photosynthetic rate was more weakly related to stem diameter growth rates. Specific leaf area was convincingly correlated to growth rate, in fact negatively. Together, SLA, wood density and LM:SM accounted for 52 % of variation in growth rate among these 41 species, with each trait contributing roughly similar explanatory power. That low SLA species can achieve faster growth rates than high SLA species was an unexpected result but, as it turns out, not without precedent, and easily understood via cost-benefit theory that considers whole-plant allocation to different tissue types. Branch-scale leaf:sapwood ratio holds promise as an easily measurable variable that may help to understand growth rate variation. Using cost-benefit approaches teamed with combinations of leaf, wood and allometric variables may provide a path towards a more complete understanding of growth rates under field conditions.

Author Correction: Crowther et al. reply.

In this Brief Communications Arising Reply, the affiliation for author P. H. Templer was incorrectly listed as 'Department of Ecology & Evolutionary Biology, University of California Irvine, Irvine, California 92697, USA' instead of 'Department of Biology, Boston University, Boston, Massachusetts 02215, USA'. This has been corrected online.

The Effect of Signal to Noise Ratio on Cortical Auditory-Evoked Potentials Elicited to Speech Stimuli in Infants and Adults With Normal Hearing.

OBJECTIVES: Identification and discrimination of speech sounds in noisy environments is challenging for adults and even more so for infants and children. Behavioral studies consistently report maturational differences in the influence that signal to noise ratio (SNR) and masker type have on speech processing; however, few studies have investigated the neural mechanisms underlying these differences at the level of the auditory cortex. In the present study, we investigated the effect of different SNRs on speech-evoked cortical auditory-evoked potentials (CAEPs) in infants and adults with normal hearing. DESIGN: A total of 10 adults (mean age 24.1 years) and 15 infants (mean age 30.7 weeks), all with normal hearing, were included in the data analyses. CAEPs were evoked to /m/ and /t/ speech stimuli (duration: 79 ms) presented at 75 dB SPL in the sound field with a jittered interstimulus interval of 1000-1200 ms. Each of the stimuli were presented in quiet and in the presence of white noise (SNRs of 10, 15, and 20 dB). Amplitude and latency measures were compared for P1, N1, and P2 for adults and for the large positivity (P) and following negativity (N: N250 and/or N450) for infants elicited in quiet and across SNR conditions. RESULTS: Infant P-N responses to /t/ showed no statistically significant amplitude and latency effects across SNR conditions; in contrast, infant CAEPs to /m/ were greatly reduced in amplitude and delayed in latency. Responses were more frequently absent for SNRs of 20 dB or less. Adult P1-N1-P2 responses were present for all SNRs for /t/ and most SNRs for /m/ (two adults had no responses to /m/ for SNR 10); significant effects of SNR were found for P1, N1, and P2 amplitude and latencies. CONCLUSIONS: The findings of the present study support that SNR effects on CAEP amplitudes and latencies in infants cannot be generalized across different types of speech stimuli and cannot be predicted from adult data. These findings also suggest that factors other than energetic masking are contributing to the immaturities in the SNR effects for infants. How these CAEP findings relate to an infant's capacity to process speech-in-noise perceptually has yet to be established; however, we can be confident that the presence of CAEPs to a speech stimulus in noise means that the stimulus is detected at the level of the auditory cortex. The absence of a response should be interpreted with caution as further studies are needed to investigate a range of different speech stimuli and SNRs, in conjunction with behavioral measures, to confirm that infant CAEPs do indeed reflect functional auditory capacity to process speech stimuli in noise.

Quantifying global soil carbon losses in response to warming.

The majority of the Earth's terrestrial carbon is stored in the soil. If anthropogenic warming stimulates the loss of this carbon to the atmosphere, it could drive further planetary warming. Despite evidence that warming enhances carbon fluxes to and from the soil, the net global balance between these responses remains uncertain. Here we present a comprehensive analysis of warming-induced changes in soil carbon stocks by assembling data from 49 field experiments located across North America, Europe and Asia. We find that the effects of warming are contingent on the size of the initial soil carbon stock, with considerable losses occurring in high-latitude areas. By extrapolating this empirical relationship to the global scale, we provide estimates of soil carbon sensitivity to warming that may help to constrain Earth system model projections. Our empirical relationship suggests that global soil carbon stocks in the upper soil horizons will fall by 30 ± 30 petagrams of carbon to 203 ± 161 petagrams of carbon under one degree of warming, depending on the rate at which the effects of warming are realized. Under the conservative assumption that the response of soil carbon to warming occurs within a year, a business-as-usual climate scenario would drive the loss of 55 ± 50 petagrams of carbon from the upper soil horizons by 2050. This value is around 12-17 per cent of the expected anthropogenic emissions over this period. Despite the considerable uncertainty in our estimates, the direction of the global soil carbon response is consistent across all scenarios. This provides strong empirical support for the idea that rising temperatures will stimulate the net loss of soil carbon to the atmosphere, driving a positive land carbon-climate feedback that could accelerate climate change.

Light-induced depigmentation in planarians models the pathophysiology of acute porphyrias.

Porphyrias are disorders of heme metabolism frequently characterized by extreme photosensitivity. This symptom results from accumulation of porphyrins, tetrapyrrole intermediates in heme biosynthesis that generate reactive oxygen species when exposed to light, in the skin of affected individuals. Here we report that in addition to producing an ommochrome body pigment, the planarian flatworm Schmidtea mediterranea generates porphyrins in its subepithelial pigment cells under physiological conditions, and that this leads to pigment cell loss when animals are exposed to intense visible light. Remarkably, porphyrin biosynthesis and light-induced depigmentation are enhanced by starvation, recapitulating a common feature of some porphyrias - decreased nutrient intake precipitates an acute manifestation of the disease. Our results establish planarians as an experimentally tractable animal model for research into the pathophysiology of acute porphyrias, and potentially for the identification of novel pharmacological interventions capable of alleviating porphyrin-mediated photosensitivity or decoupling dieting and fasting from disease pathogenesis.

Mapping tree density at a global scale.

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

Heterogeneity and disparities in the use of exception scores in pediatric liver allocation.

Physicians apply for Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease exception points on a case-by-case basis to improve an individual patient's chances of receiving a liver transplant. This retrospective cohort study describes trends in the use of exceptions among the pediatric liver waitlist population with chronic liver disease. The cohort (n = 3728) included all children with a diagnosis of chronic liver disease listed in the United Network for Organ Sharing transplant database for first isolated liver transplant between February 27, 2002 and March 31, 2013. Exception score requests were common (34%); 90% of requests were approved. The rate of exception score requests in 2013 was five times that of 2002 (incident rate ratios [IRR] 5.25, 95% confidence interval [CI] 3.19-8.63, p < 0.01). Patients of non-White race had exception score request rates 13% lower than patients of White race (IRR 0.87, 95% CI 0.77-0.98, p = 0.02). Older patients had lower rates of exception score requests than younger patients (p = 0.03). Request rates varied by region. Time spent at an active exception status nearly tripled the hazard rate for transplantation (hazard ratio = 2.90, 95% CI 2.62-3.21, p < 0.01). There is disparity in use of exceptions by race that is not explained by clinical disease severity, diagnosis, geography or other demographic factors.

IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas.

OBJECTIVE: The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas. METHODS: Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software. RESULTS: The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04). SIGNIFICANCE: Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.

Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas.

Tumour associated epilepsy (TAE) is common, debilitating and often not successfully controlled by surgical resection of the tumour and administration of multiple anti-epileptic drugs. It represents a cause of significant lost quality of life in an incurable disease and is therefore an important subject for ongoing research. The pathogenesis of TAE is likely to be multifactorial and involve, on the microscopic level, the interaction of genetic factors, changes in the peritumoural microenvironment, alterations in synaptic neurotransmitter release and re-uptake, and the excitotoxic effects of glutamate. On a macroscopic level, the occurrence of TAE is likely to be influenced by tumour size, location and interaction with environmental factors. The optimal treatment of TAE requires a multi-disciplinary approach with input from neurosurgeons, neurologists, radiologists, pathologists and basic scientists. This article reviews the current literature regarding the incidence, treatment, and aetiology of TAE.

MHCI requires MEF2 transcription factors to negatively regulate synapse density during development and in disease.

Major histocompatibility complex class I (MHCI) molecules negatively regulate cortical connections and are implicated in neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. However, the mechanisms that mediate these effects are unknown. Here, we report a novel MHCI signaling pathway that requires the myocyte enhancer factor 2 (MEF2) transcription factors. In young rat cortical neurons, MHCI regulates MEF2 in an activity-dependent manner and requires calcineurin-mediated activation of MEF2 to limit synapse density. Manipulating MEF2 alone alters synaptic strength and GluA1 content, but not synapse density, implicating activity-dependent MEF2 activation as critical for MHCI signaling. The MHCI-MEF2 pathway identified here also mediates the effects of a mouse model of maternal immune activation (MIA) on connectivity in offspring. MHCI and MEF2 levels are higher, and synapse density is lower, on neurons from MIA offspring. Most important, dysregulation of MHCI and MEF2 is required for the MIA-induced reduction in neural connectivity. These results identify a previously unknown MHCI-calcineurin-MEF2 signaling pathway that regulates the establishment of cortical connections and mediates synaptic defects caused by MIA, a risk factor for autism spectrum disorders and schizophrenia.

Major histocompatibility complex class I proteins in brain development and plasticity.

Proper development of the central nervous system (CNS) requires the establishment of appropriate connections between neurons. Recent work suggests that this process is controlled by a balance between synaptogenic molecules and proteins that negatively regulate synapse formation and plasticity. Surprisingly, many of these newly identified synapse-limiting molecules are classic 'immune' proteins. In particular, major histocompatibility complex class I (MHCI) molecules regulate neurite outgrowth, the establishment and function of cortical connections, activity-dependent refinement in the visual system, and long-term and homeostatic plasticity. This review summarizes our current understanding of MHCI expression and function in the CNS, as well as the potential mechanisms used by MHCI to regulate brain development and plasticity.

RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions.

Viral drug toxicity, resistance, and an increasing immunosuppressed population warrant continued research into new avenues for limiting diseases associated with human cytomegalovirus (HCMV). In this study, a small interfering RNA (siRNA), siX3, was designed to target coding sequences within shared exon 3 of UL123 and UL122 transcripts encoding IE1 and IE2 immediate-early proteins of HCMV. Pretreatment of cells with siX3 reduced the levels of viral protein expression, DNA replication, and progeny virus production compared to control siRNA. Two siRNAs against UL54 and overlapping transcripts (UL55-57) were compared to siX3 in HCMV infection and were also found to be effective at inhibiting HCMV replication. Further investigation into the effects of the siRNAs on viral replication showed that pretreatment with each of the siRNAs resulted in an inhibition in the formation of mature replication compartments. The ability of these siRNAs to prevent or reduce certain cytopathic effects associated with HCMV infection was also examined. Infected cells pretreated with siX3, but not siUL54, retained promyelocytic leukemia (PML) protein in cellular PML bodies, an essential component of this host intrinsic antiviral defense. DNA damage response proteins, which are localized in nuclear viral replication compartments, were reduced in the siX3- and siUL54-treated cells. siX3, but not siUL54, prevented DNA damage response signaling early after infection. Therapeutic efficacy was demonstrated by treating cells with siRNAs after HCMV replication had commenced. Together, these findings suggest that siRNAs targeting exon 3 of the major IE genes or the UL54-57 transcripts be further studied for their potential development into anti-HCMV therapeutics.

MHCI negatively regulates synapse density during the establishment of cortical connections.

Major histocompatibility complex class I (MHCI) molecules modulate activity-dependent refinement and plasticity. We found that MHCI also negatively regulates the density and function of cortical synapses during their initial establishment both in vitro and in vivo. MHCI molecules are expressed on cortical neurons before and during synaptogenesis. In vitro, decreasing surface MHCI (sMHCI) on neurons increased glutamatergic and GABAergic synapse density, whereas overexpression decreased it. In vivo, synapse density was higher throughout development in ß2m(-/-) mice. MHCI also negatively regulated the strength of excitatory, but not inhibitory, synapses and controlled the balance of excitation and inhibition onto cortical neurons. sMHCI levels were modulated by activity and were necessary for activity to negatively regulate glutamatergic synapse density. Finally, acute changes in sMHCI and activity altered synapse density exclusively during early postnatal development. These results identify a previously unknown function for immune proteins in the negative regulation of the initial establishment and function of cortical connections.

Use of the angularis oris cutaneous flap for repair of a rostral mandibular skin defect in a cat.

The angularis oris axial pattern flap is based on the blood supply of the angularis oris artery and vein. While the use of this flap for repair of canine facial wounds is well documented, this technique has not been reported in the cat. This case report presents the reconstruction of a large ventral chin and rostral lip wound with the use of this flap. Complete survival of this flap was observed in this patient.