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We present cosmological constraints from a gravitational lensing mass map covering 9400 deg ^2 reconstructed from measurements of the cosmic microwave background (CMB) made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with measurements of baryon acoustic oscillations and big bang nucleosynthesis, we obtain the clustering amplitude σ _8 = 0.819 ± 0.015 at 1.8% precision, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.840\pm 0.028$ , and the Hubble constant H _0 = (68.3 ± 1.1) km s ^−1 Mpc ^−1 at 1.6% precision. A joint constraint with Planck CMB lensing yields σ _8 = 0.812 ± 0.013, ${S}_{8}\equiv {\sigma }_{8}{({{\rm{\Omega }}}_{{\rm{m}}}/0.3)}^{0.5}=0.831\pm 0.023$ , and H _0 = (68.1 ± 1.0) km s ^−1 Mpc ^−1 . These measurements agree with ΛCDM extrapolations from the CMB anisotropies measured by Planck. We revisit constraints from the KiDS, DES, and HSC galaxy surveys with a uniform set of assumptions and find that S _8 from all three are lower than that from ACT+Planck lensing by levels ranging from 1.7 σ to 2.1 σ . This motivates further measurements and comparison, not just between the CMB anisotropies and galaxy lensing but also between CMB lensing probing z ∼ 0.5–5 on mostly linear scales and galaxy lensing at z ∼ 0.5 on smaller scales. We combine with CMB anisotropies to constrain extensions of ΛCDM, limiting neutrino masses to ∑ m _ν < 0.13 eV (95% c.l.), for example. We describe the mass map and related data products that will enable a wide array of cross-correlation science. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the ΛCDM model, while paving a promising path for neutrino physics with lensing from upcoming ground-based CMB surveys.

We present new measurements of cosmic microwave background (CMB) lensing over 9400 deg ^2 of the sky. These lensing measurements are derived from the Atacama Cosmology Telescope (ACT) Data Release 6 (DR6) CMB data set, which consists of five seasons of ACT CMB temperature and polarization observations. We determine the amplitude of the CMB lensing power spectrum at 2.3% precision (43 σ significance) using a novel pipeline that minimizes sensitivity to foregrounds and to noise properties. To ensure that our results are robust, we analyze an extensive set of null tests, consistency tests, and systematic error estimates and employ a blinded analysis framework. Our CMB lensing power spectrum measurement provides constraints on the amplitude of cosmic structure that do not depend on Planck or galaxy survey data, thus giving independent information about large-scale structure growth and potential tensions in structure measurements. The baseline spectrum is well fit by a lensing amplitude of A _lens = 1.013 ± 0.023 relative to the Planck 2018 CMB power spectra best-fit ΛCDM model and A _lens = 1.005 ± 0.023 relative to the ACT DR4 + WMAP best-fit model. From our lensing power spectrum measurement, we derive constraints on the parameter combination ${S}_{8}^{\mathrm{CMBL}}\equiv {\sigma }_{8}{\left({{\rm{\Omega }}}_{m}/0.3\right)}^{0.25}$ of ${S}_{8}^{\mathrm{CMBL}}=0.818\pm 0.022$ from ACT DR6 CMB lensing alone and ${S}_{8}^{\mathrm{CMBL}}=0.813\pm 0.018$ when combining ACT DR6 and Planck NPIPE CMB lensing power spectra. These results are in excellent agreement with ΛCDM model constraints from Planck or ACT DR4 + WMAP CMB power spectrum measurements. Our lensing measurements from redshifts z ∼ 0.5–5 are thus fully consistent with ΛCDM structure growth predictions based on CMB anisotropies probing primarily z ∼ 1100. We find no evidence for a suppression of the amplitude of cosmic structure at low redshifts.

Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p

Intensity mapping has attracted significant interest as an approach to measuring the properties of the interstellar medium in typical galaxies at high redshift. Intensity mapping measures the statistics of surface brightness as a function of frequency, making it sensitive to not only all line emission of interest but also radiation from all other sources. Significant effort has gone into developing approaches that reject foreground contamination. Additionally, the target galaxies have multiple sources of emission that can complicate the interpretation of the line brightness. We describe the problem of jointly estimating correlated continuum emission and cleaning uncorrelated continuum emission, such as from the Milky Way. We apply these considerations to a cross-correlation of Planck data with BOSS quasars for a determination of [C ii] for . Intensity mapping surveys with few bands have unique challenges for treating foregrounds and avoiding bias from correlated continuum emission. We show how a future intensity mapping survey with many bands can separate line from continuum emission in cross-correlation. [ABSTRACT FROM AUTHOR]

A full account of galaxy evolution in the context of ΛCDM cosmology requires measurements of the average star-formation rate (SFR) and cold gas abundance across cosmic time. Emission from the CO ladder traces cold gas, and [C ii] fine structure emission at traces the SFR. Intensity mapping surveys the cumulative surface brightness of emitting lines as a function of redshift, rather than individual galaxies. CMB spectral distortion instruments are sensitive to both the mean and anisotropy of the intensity of redshifted CO and [C ii] emission. Large-scale anisotropy is proportional to the product of the mean surface brightness and the line luminosity-weighted bias. The bias provides a connection between galaxy evolution and its cosmological context, and is a unique asset of intensity mapping. Cross-correlation with galaxy redshift surveys allows unambiguous measurements of redshifted line brightness despite residual continuum contamination and interlopers. Measurement of line brightness through cross-correlation also evades cosmic variance and suggests new observation strategies. Galactic foreground emission is times larger than the expected signals, and this places stringent requirements on instrument calibration and stability. Under a range of assumptions, a linear combination of bands cleans continuum contamination sufficiently that residuals produce a modest penalty over the instrumental noise. For PIXIE, the sensitivity to CO and [C ii] emission scales from at low redshift to by reionization. [ABSTRACT FROM AUTHOR]

Variable-delay Polarization Modulators (VPMs) are currently being implemented in experiments designed to measure the polarization of the cosmic microwave background on large angular scales because of their capability for providing rapid, front-end polarization modulation and control over systematic errors. Despite the advantages provided by the VPM, it is important to identify and mitigate any time-varying effects that leak into the synchronously modulated component of the signal. In this paper, the effect of emission from a 300 K VPM on the system performance is considered and addressed. Though instrument design can greatly reduce the influence of modulated VPM emission, some residual modulated signal is expected. VPM emission is treated in the presence of rotational misalignments and temperature variation. Simulations of time-ordered data are used to evaluate the effect of these residual errors on the power spectrum. The analysis and modeling in this paper guides experimentalists on the critical aspects of observations using VPMs as front-end modulators. By implementing the characterizations and controls as described, front-end VPM modulation can be very powerful for mitigating 1/f noise in large angular scale polarimetric surveys. None of the systematic errors studied fundamentally limit the detection and characterization of B-modes on large scales for a tensor-to-scalar ratio of r = 0.01. Indeed, r < 0.01 is achievable with commensurately improved characterizations and controls. [ABSTRACT FROM AUTHOR]

Intensity mapping experiments survey the spectrum of diffuse line radiation rather than detect individual objects at high signal-to-noise ratio. Spectral maps of unresolved atomic and molecular line radiation contain three-dimensional information about the density and environments of emitting gas and efficiently probe cosmological volumes out to high redshift. Intensity mapping survey volumes also contain all other sources of radiation at the frequencies of interest. Continuum foregrounds are typically ~102–103 times brighter than the cosmological signal. The instrumental response to bright foregrounds will produce new spectral degrees of freedom that are not known in advance, nor necessarily spectrally smooth. The intrinsic spectra of foregrounds may also not be well known in advance. We describe a general class of quadratic estimators to analyze data from single-dish intensity mapping experiments and determine contaminated spectral modes from the data themselves. The key attribute of foregrounds is not that they are spectrally smooth, but instead that they have fewer bright spectral degrees of freedom than the cosmological signal. Spurious correlations between the signal and foregrounds produce additional bias. Compensation for signal attenuation must estimate and correct this bias. A successful intensity mapping experiment will control instrumental systematics that spread variance into new modes, and it must observe a large enough volume that contaminant modes can be determined independently from the signal on scales of interest. [ABSTRACT FROM AUTHOR]

DNA methylation, a form of epigenetic gene regulation, is important for normal cellular function. In cells, proteins called DNA methyltransferases (DNMTs) establish and maintain the DNA methylation pattern. Changes to the normal DNA methylation pattern are linked to cancer development and progression, making DNMTs potential cancer drug targets. Thus, identifying and characterizing novel small molecule inhibitors of these enzymes is of great importance. This paper presents a protocol that can be used to screen for DNA methyltransferase inhibitors. The continuous coupled kinetics assay allows for initial velocities of DNA methylation to be determined in the presence and absence of potential small molecule inhibitors. The assay uses the methyl-sensitive endonuclease Gla I to couple methylation of a hemimethylated DNA substrate to fluorescence generation. This continuous assay allows for enzyme activity to be monitored in real time. Conducting the assay in small volumes in microtiter plates reduces the cost of reagents. Using this assay, a small example screen was conducted for inhibitors of DNMT1, the most abundant DNMT isozyme in humans. The highly substituted anthraquinone natural product, laccaic acid A, is a potent, DNA-competitive inhibitor of DNMT1. Here, we examine three potential small molecule inhibitors - anthraquinones or anthraquinone-like molecules with one to three substituents - at two concentrations to describe the assay protocol. Initial velocities are used to calculate the percent activity observed in the presence of each molecule. One of three compounds examined exhibits concentration-dependent inhibition of DNMT1 activity, indicating that it is a potential inhibitor of DNMT1.

Heterozygous mutations in the GBA1 gene - encoding lysosomal glucocerebrosidase (GCase) - are the most common genetic risk factors for Parkinson's disease (PD). Experimental evidence suggests a correlation between decreased GCase activity and accumulation of alpha-synuclein (aSyn). To enable a better understanding of the relationship between aSyn and GCase activity, we developed and characterized two mouse models that investigate aSyn pathology in the context of reduced GCase activity. The first model used constitutive overexpression of wild-type human aSyn in the context of the homozygous GCase activity-reducing D409V mutant form of GBA1. Although increased aSyn pathology and grip strength reductions were observed in this model, the nigrostriatal system remained largely intact. The second model involved injection of aSyn preformed fibrils (PFFs) into the striatum of the homozygous GBA1 D409V knock-in mouse model. The GBA1 D409V mutation did not exacerbate the pathology induced by aSyn PFF injection. This study sheds light on the relationship between aSyn and GCase in mouse models, highlighting the impact of model design on the ability to model a relationship between these proteins in PD-related pathology., Competing Interests: Competing interests The following coauthors are affiliated with commercial companies: S.R. at Psychogenics, Inc.; M.H. at Charles River Laboratories; R.S. at NeuroScience Associates; J.N.M. and S.M.S. at Merck & Co, Kenilworth, NJ, USA; S.W.C. previously at Amicus Therapeutics and currently at SwanBio Therapeutics. There are no patents, products in development or marketed products associated with this research to declare. No authors have competing interests to declare, and commercial affiliations do not alter our adherence to journal policies on sharing data and materials., (© 2022. Published by The Company of Biologists Ltd.)

Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher's disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson's disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms and novel therapeutic approaches, as well as to elucidate the molecular mechanisms leading to enhanced PD risk in GBA1 mutation carriers. The aim of this study was to develop and characterize a novel GBA1 mouse model and to facilitate wide accessibility of the model with phenotypic data. Herein we describe the results of molecular, biochemical, histological, and behavioral phenotyping analyses in a GBA1 D409V knock-in (KI) mouse. This mouse model exhibited significantly decreased GCase activity in liver and brain, with substantial increases in glycosphingolipid substrates in the liver. While no changes in the number of dopamine neurons in the substantia nigra were noted, subtle changes in striatal neurotransmitters were observed in GBA1 D409V KI mice. Alpha-synuclein pathology and inflammation were not observed in the nigrostriatal system of this model. In summary, the GBA1 D409V KI mouse model provides an ideal model for studies aimed at pharmacodynamic assessments of potential therapies aiming to restore GCase., Competing Interests: The authors have read the journal’s policy and have the following competing interests: The following coauthors are affiliated with commercial companies: TNM, AG, and RG at Taconic Biosciences; MH at Charles River Laboratories; RS at NeuroScience Associates; MC, MK, RED at Merck & Co; PDB previously at Pfizer and currently at Yumanity Therapeutics; WS, YC, and WDH previously at Pfizer and currently at Biogen; LJP previously at Amicus Therapeutics and currently at Oncoveda; GDE and LBD at Amicus Therapeutics, and SWC previously at Amicus Therapeutics and currently at SwanBio Therapeutics. The coauthor MS is associated with The Jackson Laboratory, the source of the GBA1 D409V KI mouse. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Over the past 10 years, three new MD schools have been created in the state of Michigan, while the Michigan State University College of Human Medicine (MSU-CHM) has increased their class size to 850 students. The aim of this study was to determine if MSU-CHM alumni who graduate from an MSU-affiliated primary care residency from a single graduate medical education (GME) training program in Michigan are more likely to go on to practice in close proximity to the location of their training program immediately after graduation compared to non MSU-CHM alumni. Changes over time in the proportion of primary care graduates who received fellowship training immediately following residency were also compared between these groups., Methods: A review of historical data was performed for all 2000-2016 primary care (Family Medicine, FM; Internal Medicine, IM; Internal Medicine-Pediatrics, IMP; Pediatrics, Peds) program graduates sponsored by Grand Rapids Medical Education Partners (GRMEP). Study variables included primary care program, gender, age at graduation, fellowship training, practice location immediately after graduation and undergraduate medical education location. Summary statistics were calculated for the data. Comparisons were made using the chi-square test or Fisher's Exact test when appropriate. Significance was assessed at p < 0.05., Results: There were 478 primary care program graduates who went into practice immediately following graduation, 102 of whom also graduated from MSU-CHM. Just over half of the graduates were female and the average age at graduation was 32 years. There were 152 FM, 150 IM, 50 IMP and 126 Peds graduates. Those that graduated from both MSU-CHM and GRMEP were more likely to practice in Michigan immediately after residency training (79.4% vs 52.0%; p < 0.001), as well as within 100 miles of GRMEP (71.6% vs 46.4%; p < 0.001). There were 8% of MSU-CHM primary care graduates who went on to fellowship training from 2000 to 2009, increasing to 34% from 2010 to 2016 (p < 0.001)., Conclusion: Medical school graduates of MSU-CHM who receive GME training in primary care are more likely to practice medicine within close proximity to their training site than non MSU-CHM graduates. However, plans for fellowship after training may add one caveat to this finding.

Background and Purpose: The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood-brain barrier. I.c.v. delivery is a promising route to the brain; however, it is unclear how efficiently antibodies delivered i.c.v. penetrate the cerebrospinal spinal fluid (CSF)-brain barrier and distribute throughout the brain parenchyma., Experimental Approach: We evaluated the pharmacokinetics and pharmacodynamics of an inhibitory monoclonal antibody against β-secretase 1 (anti-BACE1) following continuous infusion into the left lateral ventricle of healthy adult cynomolgus monkeys., Key Results: Animals infused with anti-BACE1 i.c.v. showed a robust and sustained reduction (~70%) of CSF amyloid-β (Aβ) peptides. Antibody distribution was near uniform across the brain parenchyma, ranging from 20 to 40 nM, resulting in a ~50% reduction of Aβ in the cortical parenchyma. In contrast, animals administered anti-BACE1 i.v. showed no significant change in CSF or cortical Aβ levels and had a low (~0.6 nM) antibody concentration in the brain., Conclusion and Implications: I.c.v. administration of anti-BACE1 resulted in enhanced BACE1 target engagement and inhibition, with a corresponding dramatic reduction in CNS Aβ concentrations, due to enhanced brain exposure to antibody., (© 2017 The British Pharmacological Society.)

Multiple sclerosis (MS) causes demyelinating lesions in the white matter and increased iron deposition in the subcortical gray matter. Myelin protons have an extremely short T2* (<1ms) and are not directly detected with conventional clinical magnetic resonance (MR) imaging sequences. Iron deposition also reduces T2*, leading to reduced signal on clinical sequences. In this study we tested the hypothesis that the inversion recovery ultrashort echo time (IR-UTE) pulse sequence can directly and simultaneously image myelin and iron deposition using a clinical 3T scanner. The technique was first validated on a synthetic myelin phantom (myelin powder in D 2 O) and a Feridex iron phantom. This was followed by studies of cadaveric MS specimens, healthy volunteers and MS patients. UTE imaging of the synthetic myelin phantom showed an excellent bi-component signal decay with two populations of protons, one with a T2* of 1.2ms (residual water protons) and the other with a T2* of 290μs (myelin protons). IR-UTE imaging shows sensitivity to a wide range of iron concentrations from 0.5 to ~30mM. The IR-UTE signal from white matter of the brain of healthy volunteers shows a rapid signal decay with a short T2* of ~300μs, consistent with the T2* values of myelin protons in the synthetic myelin phantom. IR-UTE imaging in MS brain specimens and patients showed multiple white matter lesions as well as areas of high signal in subcortical gray matter. This in specimens corresponded in position to Perl's diaminobenzide staining results, consistent with increased iron deposition. IR-UTE imaging simultaneously detects lesions with myelin loss in the white matter and iron deposition in the gray matter., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We used controlled cortical impact in mice to model human traumatic brain injury (TBI). Local injury was accompanied by distal diaschisis lesions that developed within brain regions anatomically connected to the injured cortex. At 7 days after injury, histochemistry documented broadly distributed lesions, particularly in the contralateral cortex and ipsilateral thalamus and striatum. Reactive astrocytosis and microgliosis were noted in multiple neural pathways that also showed silver-stained cell processes and bodies. Wisteria floribunda agglutinin (WFA) staining, a marker of perineuronal nets, was substantially diminished in the ipsilateral, but less so in the contralateral cortex. Contralateral cortical silver positive diaschisis lesions showed loss of both phosphorylated and unphosphorylated neurofilament staining, but overall preservation of microtubule-associated protein (MAP)-2 staining. Thalamic lesions showed substantial loss of MAP-2 and unphosphorylated neurofilaments in addition to moderate loss of phosphorylated neurofilament. One animal demonstrated contralateral cerebellar degeneration at 7 days post-injury. After 21 days, the gliosis had quelled, however persistent silver staining was noted. Using a novel serial section technique, we were able to perform electron microscopy on regions fully characterized at the light microscopy level. Cell bodies and processes that were silver positive at the light microscopy level showed hydropic disintegration consisting of: loss of nuclear heterochromatin; dilated somal and neuritic processes with a paucity of filaments, tubules, and mitochondria; and increased numbers of electron-dense membranous structures. Importantly the cell membrane itself was still intact 3 weeks after injury. Although the full biochemical nature of these lesions remains to be deciphered, the morphological preservation of damaged neurons and processes raises the question of whether this is a reversible process., Competing Interests: Author Disclosure Statement No competing financial interests exist.

The Advanced Topographic Laser Altimeter System (ATLAS) Instrument has been in integration and testing over the past 18 months in preparation for the Ice, Cloud and Land Elevation Satellite - 2 (ICESat-2) Mission, scheduled to launch in 2017. ICESat-2 is the follow on to ICESat which launched in 2003 and operated until 2009. ATLAS will measure the elevation of ice sheets, glaciers and sea ice or the "cryosphere" (as well as terrain) to provide data for assessing the earth's global climate changes. Where ICESat's instrument, the Geo-Science Laser Altimeter (GLAS) used a single beam measured with a 70 m spot on the ground and a distance between spots of 170 m, ATLAS will measure a spot size of 10 m with a spacing of 70 cm using six beams to measure terrain height changes as small as 4 mm.[1] The ATLAS pulsed transmission system consists of two lasers operating at 532 nm with transmitter optics for beam steering, a diffractive optical element that splits the signal into 6 separate beams, receivers for start pulse detection and a wavelength tracking system. The optical receiver telescope system consists of optics that focus all six beams into optical fibers that feed a filter system that transmits the signal via fiber assemblies to the detectors. Also included on the instrument is a system that calibrates the alignment of the transmitted pulses to the receiver optics for precise signal capture. The larger electro optical subsystems for transmission, calibration, and signal receive, stay aligned and transmitting sufficiently due to the optical fiber system that links them together. The robust design of the fiber optic system, consisting of a variety of multi fiber arrays and simplex assemblies with multiple fiber core sizes and types, will enable the system to maintain consistent critical alignments for the entire life of the mission. Some of the development approaches used to meet the challenging optical system requirements for ATLAS are discussed here.

Background: Dental caries is a highly prevalent, yet preventable disease that is commonly overlooked in the adult population. It is strongly related to health-related behaviors and knowledge, and therefore, is potentially receptive to a behavioral health intervention. However, prevention strategies that target health behaviors in adults are fundamentally different from those in children, whom most current intervention strategies for dental caries target. This study attempts to pilot design, implement, and assess health behavior intervention tools for adults, in order to improve their oral health., Objective: To increase knowledge about dental caries by 80% and increase positive self-reported oral hygiene behaviors by 80% in low-income adult participants at Interfaith Dental Clinic by piloting novel interventional and educational tools based on the Transtheoretical Model of Health Behavior., Methods: A convenience sample of newly registered participants to the Interfaith Dental Clinic between August 2011 and May 2013, were interviewed on each participant's first appointment, exposed to the interventional tools, and subsequently interviewed at their next appointment. A control group, comprised of participants who had completed their caries care as deemed by the clinic and had not been exposed to the interventional tools, were also interviewed on their last appointment before graduating the clinic's program., Results: A total of 112 participants were exposed to the intervention, and forty-two participants comprised the control group. Follow-up for the intervention group was 20.5% (n = 23). Knowledge about the cause of caries increased by 29.9%, and positive self-reported oral hygiene behaviors increased by 25.4%. A Wilcoxon rank sum test showed no significance between the interview scores of the post-intervention group and that of the control group (p = 0.18 for knowledge, p = 0.284 for behaviors). Qualitative results show the vast majority of participants blamed diet for cause of caries, that this participant population prioritized practical advice over factual education, and that flossing was perceived to be the largest barrier to proper oral care, citing pain, lack of time, and technique as common reasons., Conclusion: Educational tools based on current models of health behavior theory have the potential to improve participant knowledge and health behaviors, while also remaining low-cost and convenient for clinical use.

Species loss can lead to cascading effects on communities, including the disruption of ecological processes such as seed dispersal. The endangered 'Alalā (Corvus hawaiiensis), the largest remaining species of native Hawaiian forest bird, was once common in mesic and dry forests on the Big Island of Hawai'i, but today it exists solely in captivity. Prior to its extinction in the wild, the 'Alalā may have helped to establish and maintain native Hawaiian forest communities by dispersing seeds of a wide variety of native plants. In the absence of 'Alalā, the structure and composition of Hawai'i's forests may be changing, and some large-fruited plants may be dispersal limited, persisting primarily as ecological anachronisms. We fed captive 'Alalā a variety of native fruits, documented behaviors relating to seed dispersal, and measured the germination success of seeds that passed through the gut of 'Alalā relative to the germination success of seeds in control groups. 'Alalā ate and carried 14 native fruits and provided germination benefits to several species by ingesting their seeds. Our results suggest that some plants rely heavily on 'Alalā for these services. In captivity, juvenile birds displayed seed dispersal behaviors more often than adult birds for most fruiting plants in our study. We introduced captive 'Alalā to two large-fruited, dry-forest plants, not previously recorded as 'Alalā food resources, but which may once have been part of their natural diet. The seed dispersal behavior that 'Alalā displayed toward these species supports the inclusion of dry and mesic forests in 'Alalā habitat restoration plans and adds weight to the idea that plant dispersal limitation may contribute to the rarity of these plants. Our study provides evidence that 'Alalā have the capacity to play a vital role in maintaining the diversity of fruiting plants in native Hawaiian forests through seed dispersal and enhanced seed germination, thus adding greater urgency to efforts to restore 'Alalā to their former range.

In-situ captive rearing of endangered passerines for reintroduction has rarely been used as a conservation tool. Nests of Mauritius fodies threatened with predation by introduced mammalian predators were harvested from the wild, and chicks were reared to independence for release onto an offshore, predator-free island. The daily probability of the survival was higher in captivity than in the wild, and 69 chicks were reared to fledging of which 47 would have been expected to fledge in the wild. Harvesting of nests probably had little impact on the wild population. Captive breeding trials on Mauritius fodies showed that large numbers of individuals could be produced for a release program from a small number of pairs if enough space was provided. Artificial incubation of passerine eggs and rearing of chicks can be used to increase the productivity of endangered taxa. Zoos can play an important role in in-situ conservation programs through provision of avicultural expertise and training of local staff. Zoo Biol 27:255-268, 2008. (c) 2008 Wiley-Liss, Inc.

Cell minicolumns were shown to be narrower in frontal regions in brains of autistic patients compared with controls. This was not found in primary visual cortex. Within the frontal cortex, dorsal and orbital regions displayed the greatest differences while the mesial region showed the least change. We also found that minicolumns in the brain of a 3-year-old autistic child were indistinguishable from those of the autistic adult in two of three frontal regions, in contrast to the control brains. This may have been due to the small size of the columns in the adult autistic brain rather than to an accelerated development. The presence of narrower minicolumns supports the theory that there is an abnormal increase in the number of ontogenetic column units produced in some regions of the autistic brain during corticoneurogenesis.

The spontaneous incidence and distribution of beta-amyloid (Abeta) peptide and argyrophilic deposits were extensively investigated in the common marmoset (Callithrix jacchus). In 12 young marmosets, up to 67 coronal step sections were evaluated in the brain. One brain hemisphere was stained by a silver method and also immunohistochemically with a primary antibody directed against Abeta. Argyrophilic deposits were observed in 4 (33%) of 12 animals with silver stain, and Abeta was seen in 4 (33%) of 12 animals with anti-4G8 antibody. The overall incidence was 6 (50%) of 12 affected animals. These results show that the young marmoset brain displays Abeta deposits at a low incidence and that immunohistochemistry is more suitable than silver staining to reveal rare amyloid plaques. These findings also provide evidence for the early onset of amyloid deposits in marmoset brain.

In mammals, iron regulatory proteins 1 and 2 (IRP1 and IRP2) posttranscriptionally regulate expression of several iron metabolism proteins including ferritin and transferrin receptor. Genetically engineered mice that lack IRP2, but have the normal complement of IRP1, develop adult-onset neurodegenerative disease associated with inappropriately high expression of ferritin in degenerating neurons. Here, we report that mice that are homozygous for a targeted deletion of IRP2 and heterozygous for a targeted deletion of IRP1 (IRP1+/- IRP2-/-) develop a much more severe form of neurodegeneration, characterized by widespread axonopathy and eventually by subtle vacuolization in several areas, particularly in the substantia nigra. Axonopathy develops in white matter tracts in which marked increases in ferric iron and ferritin expression are detected. Axonal degeneration is significant and widespread before evidence for abnormalities or loss of neuronal cell bodies can be detected. Ultimately, neuronal cell bodies degenerate in the substantia nigra and some other vulnerable areas, microglia are activated, and vacuoles appear. Mice manifest gait and motor impairment at stages when axonopathy is pronounced, but neuronal cell body loss is minimal. These observations suggest that therapeutic strategies that aim to revitalize neurons by treatment with neurotrophic factors may be of value in IRP2-/- and IRP1+/- IRP2-/- mouse models of neurodegeneration.

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.

Seizures evoked by electroshock induce rapid changes in the expression of several genes in the adult brain, including those encoding for neurotrophic factors. Some of the neurotrophic factors induced by brief seizures such as basic fibroblast growth factor and nerve growth factor have been shown to have neuroprotective action. We reasoned therefore that these seizures may protect against neural injury. To test this hypothesis, we examined the effect of electroshock-induced seizures on the vulnerability to cell death in the hippocampus. Cell death was induced by adrenalectomy, which results in a highly selective apoptotic neuronal death in the dentate granule cell layer of the hippocampus. Daily electroshock seizures were administered for seven days to sham-operated and adrenalectomized rats. Neuronal degeneration was evaluated by the highly sensitive and reliable cupric-silver impregnation method. Animals experiencing electroshock seizures were completely protected against adrenalectomy-induced cell death, whereas adrenalectomized animals not exposed to electroshock seizures exhibited substantial neuronal cell degeneration in the dentate granule cell layer. Daily restraint stress did not prevent the adrenalectomy-induced neuronal death, indicating that the neuroprotective effect of the seizure treatment is not accounted for by stress. We conclude that brief controlled seizure-evoked neural activation may allow the sparing of otherwise vulnerable neuronal populations in the injured adult brain. This prompts a need to explore the possibility that controlled administration of electroshock seizures may have therapeutic potential in treating neurodegenerative disorders.

Methods have been developed for the preparation of radioiodinated N-substituted 2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropanes. The syntheses, physical properties, radiolabeling, and characterization of the pharmacological properties of N-(3(Z)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (12) and N-(3(E)-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane (13) are described. 2 beta-Carbomethoxy-3 beta-(p-substituted-phenyl)tropanes are potent ligands for the dopamine transporter. The radioiodinated derivatives are of interest because of the high uptake and prolonged striatal retention that may result from specific binding to low-capacity, high-affinity, dopamine reuptake sites. Radioiodine was introduced into the 3Z and 3E-position of N-(3-iodopropen-1-yl)-2 beta-carbomethoxy-3 beta-(4-chlorophenyl)tropane by iododemetalation of the corresponding 3-(tri-n-butylstannyl) derivatives. Competition binding data of various dopamine reuptake ligands with rat striatal tissue preparation for either [125I]-12 or [125I]-13 exhibited the following order of potency: E-13 > Z-12 > GBR 12909 >> mazindol >>> (-)-cocaine. Tissue distribution studies in rats showed that the E-13 was the best analogue. E-13 showed high striatal uptake (60 min, 1.23% dose/g; 120 min, 0.61% dose/g) and high striatal to cerebellum ratios (60 min, 15.9/1; 120 min, 16.5/1). These studies indicate that iodine-123-labeled E-13 is a potentially useful agent for imaging the dopamine reuptake sites by single-photon-emission computerized tomography.

True extrarenal Wilms' tumor is a rare malignant neoplasm most frequently presenting in the retroperitoneal or inguinal regions. We report an unusual subcutaneous lumbosacral (LS) region extrarenal Wilms' tumor without associated teratomatous tumor elements or associated neural tube defect in a 2 1/2-year-old girl. Pathologic review revealed features of true extrarenal Wilms' tumor, and the patient remains in complete remission following surgery and combination chemotherapy. This report illustrates the importance of early surgical intervention and pathologic examination of similar soft tissue masses in children.

Simultaneous demonstration of acetylcholinesterase (AChE) and horseradish peroxidase (HRP) has been achieved by staining frozen sections with a modified Koelle-Friedenwald thiocholine method for AChE followed directly by the Graham-Karnovsky procedure for HRP. By using sodium sulfite instead of sodium sulfide in the AChE procedure, the final reaction product appears as black AChE granules that contrast sharply with the yellowish-brown HRP granules.

Ten adult male Sprague-Dawley rats were infused with hemicholinium (HC-3) using mini-osmotic pumps over a 14 day period through bilateral, chronically implanted cannulae in the nucleus basalis magnocellularis (nbm). Ten matched controls were infused in the same fashion with saline. HC-3 rats receiving implants demonstrated a significant deficit in maze-learning ability compared with individual and group performances before receiving the implants. In saline rats there was no significant difference in maze-learning ability before and after receiving implants. The HC-3 group receiving implants demonstrated a significant deficit in maze-learning ability compared with the saline control group. Serial sections through nbm from control and HC-3 rats indicated that all cannulae were located within infusion range of nbm. In HC-3 subjects, cholinergic cell bodies were destroyed with concurrent degeneration of terminal fields in cortex. Except for cannula insertion damage, the cholinergic neurotransmitter system appeared unharmed in controls. Stains for neuritic plaques and neurofibrillary damage were negative in both groups. The memory deficit in experimental subjects supported by the demonstrated destruction of nbm cholinergic neurons suggests that HC-3 may be useful in the development of an animal model for Alzheimer's Disease.