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Neuron navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin brain-derived neurotropic factor (BDNF). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.

Science is a core curricular area of instruction for all students and the federal mandates of the Individuals with Disabilities Education Act (2004) and No Child Left Behind (2001) require that students with disabilities are educated in the least restrictive environment and have access to general education science content, based upon rigorous standards. While, most students with visual impairments are educated in the general science classroom, few studies have been done to determine whether appropriate accommodations and modifications are being made in those classrooms to meet the specialized needs of these students. A 35 question survey instrument was disseminated to teachers of the visually impaired through a Visual Impairments Listserve and Facebook group to help determine what pedagogical practices, accommodations, modifications, adaptive equipment and instructional practices are being used to educate students with visual impairments in the United States and Canada. This study helped inform how students with visual impairments are being educated in the science classroom.

This article presents the results of a study on the use of 3-D printed models in a science classroom for students with visual impairments and examines whether the use of these models impacts student conceptual understanding and misconceptions related to geosciences concepts, specifically plate tectonics. Data were collected one week prior to instruction, one week after instruction and throughout the 3-week instructional period. Results showed that students with visual impairments held many of the same misconceptions about plate tectonics as students who are typically sighted. All students in this study had fewer misconceptions after the instructional period than they held before instruction began; however, both the 3D group and the TG group continued to hold approximately equal numbers of misconceptions. The adaptations and hands-on experiences in this 3-week curriculum proved effective for students with visual impairments; helping them understand the unifying theory of plate tectonics. Some unique misconceptions held by the students with visual impairments in this research study include plates floating on the ocean, earthquakes moving with the plates, and volcanoes working together with the plates to cause earthquakes. There was a difference between students who had low vision and those with light perception only. The study helps to shed light on the use of 3-D printed models in the science classroom and their effectiveness at helping students with visual impairments learn important geoscience concepts.

Syndromic sensorineural hearing loss is multigenic and associated with malformations of the ear and other organ systems. Herein we describe a child admitted to the NIH Undiagnosed Diseases Program with global developmental delay, sensorineural hearing loss, gastrointestinal abnormalities, and absent salivation. Next-generation sequencing revealed a uniparental isodisomy in chromosome 5, and a 22 kb homozygous deletion in SLC12A2, which encodes for sodium, potassium, and chloride transporter in the basolateral membrane of secretory epithelia. Functional studies using patient-derived fibroblasts showed truncated SLC12A2 transcripts and markedly reduced protein abundance when compared with control. Loss of Slc12a2 in mice has been shown to lead to deafness, abnormal neuronal growth and migration, severe gastrointestinal abnormalities, and absent salivation. Together with the described phenotype of the Slc12a2-knockout mouse model, our results suggest that the absence of functional SLC12A2 causes a new genetic syndrome and is crucial for the development of auditory, neurologic, and gastrointestinal tissues.

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.

Domestic cats are the natural reservoir of Bartonella henselae, B. clarridgeiae and B. koehlerae. To determine the role of wild felids in the epidemiology of Bartonella infections, blood was collected from 14 free-ranging California mountain lions (Puma concolor) and 19 bobcats (Lynx rufus). Bartonella spp. were isolated from four (29%) mountain lions and seven (37%) bobcats. These isolates were characterized using growth characteristics, biochemical reactions, molecular techniques, including PCR-RFLP of selected genes or interspacer region, pulsed-field gel electrophoresis (PFGE), partial sequencing of several genes, and DNA-DNA hybridization. Two isolates were identical to B. henselae genotype II. All other isolates were distinguished from B. henselae and B. koehlerae by PCR-RFLP of the gltA gene using endonucleases HhaI, TaqI and AciI, with the latter two discriminating between the mountain lion and the bobcat isolates. These two novel isolates displayed specific PFGE profiles distinct from B. henselae, B. koehlerae and B. clarridgeiae. Sequences of amplified gene fragments from the three mountain lion and six bobcat isolates were closely related to, but distinct from, B. henselae and B. koehlerae. Finally, DNA-DNA hybridization studies demonstrated that the mountain lion and bobcat strains are most closely related to B. koehlerae. We propose naming the mountain lion isolates B. koehlerae subsp. boulouisii subsp. nov. (type strain: L-42-94), and the bobcat isolates B. koehlerae subsp. bothieri subsp. nov. (type strain: L-17-96), and to emend B. koehlerae as B. koehlerae subsp. koehlerae. The mode of transmission and the zoonotic potential of these new Bartonella subspecies remain to be determined.

Domestic cats are the natural reservoir of Bartonella henselae, B. clarridgeiae and B. koehlerae. To determine the role of wild felids in the epidemiology of Bartonella infections, blood was collected from 14 free-ranging California mountain lions (Puma concolor) and 19 bobcats (Lynx rufus). Bartonella spp. were isolated from four (29%) mountain lions and seven (37%) bobcats. These isolates were characterized using growth characteristics, biochemical reactions, molecular techniques, including PCR-RFLP of selected genes or interspacer region, pulsed-field gel electrophoresis (PFGE), partial sequencing of several genes, and DNA-DNA hybridization. Two isolates were identical to B. henselae genotype II. All other isolates were distinguished from B. henselae and B. koehlerae by PCR-RFLP of the gltA gene using endonucleases HhaI, TaqI and AciI, with the latter two discriminating between the mountain lion and the bobcat isolates. These two novel isolates displayed specific PFGE profiles distinct from B. henselae, B. koehlerae and B. clarridgeiae. Sequences of amplified gene fragments from the three mountain lion and six bobcat isolates were closely related to, but distinct from, B. henselae and B. koehlerae. Finally, DNA-DNA hybridization studies demonstrated that the mountain lion and bobcat strains are most closely related to B. koehlerae. We propose naming the mountain lion isolates B. koehlerae subsp. boulouisii subsp. nov. (type strain: L-42-94), and the bobcat isolates B. koehlerae subsp. bothieri subsp. nov. (type strain: L-17-96), and to emend B. koehlerae as B. koehlerae subsp. koehlerae. The mode of transmission and the zoonotic potential of these new Bartonella subspecies remain to be determined.

A man with newly diagnosed AIDS presented with months of back pain and fever. Computed tomography (CT) results demonstrated aortitis with periaortic tissue thickening. DNA amplification of biopsy tissue revealed Bartonella quintana, and Bartonella serologies were subsequently noted to be positive. The patient improved with prolonged doxycycline and rifabutin treatment. This case illustrates how molecular techniques are increasingly important in diagnosing Bartonella infections.

An excess of strength on the low-energy tail of the giant dipole resonance recently has been observed in the γ-decay from the quasicontinuum of 195,196Pt. The nature of this phenomenon is not yet fully investigated. If this feature is present also in the γ-ray strength of the neutron-rich isotopes, it can affect the neutron-capture reactions involved in the formation of heavy-elements in stellar nucleosynthesis. The experimental level density and γ-ray strength function of 195,196Pt are presented together with preliminary calculations of the corresponding neutron-capture cross sections.

The synthesis of the neutron deficient 138La nucleus has been a puzzle for a long time. It has not been clear whether it is produced through photodisintegration processes or neutrino induced reactions due to unavailability of experimental data for nuclear level densities and γ strength functions of 138,139La nuclei. In the present work these nuclear properties have been measured and are used to investigate the synthesis of 138La. The results support the neutrino interactions as a dominant production process for 138La.

We report gamma-ray spectroscopy measurements of trinitite samples and analogous samples obtained from detonation sites in Nevada and Semipalatinsk, as well as in situ measurements of topsoil at the Trinity site. We also report the first isotopic composition measurements of trinitite using the novel forensics technique of decay energy spectroscopy (DES) as a complement to traditional forensics techniques. Our gamma spectroscopy and DES measurements are compared to other published results. [ABSTRACT FROM AUTHOR]

The article highlights the evidentiary weaknesses of trash-pull evidence in establishing probable cause for search warrants of homes and its potential for abuse by law enforcement and others.

Neutron diagnosed subcritical experiments (NDSEs) aim to measure the fission chain decay of subcritical test objects initiated by neutrons from an external source. The ultimate goal of future NDSEs is to make such measurements on dynamic subcritical objects as they are imploded. As a step toward that goal, we made measurements on three static subcritical assemblies containing highly enriched uranium. Specifically, we measured the die-off of both fission gamma rays and neutrons, with nanosecond resolution over several hundred microseconds, relative to the emission time of neutrons from a source in close proximity to the subcritical objects. As simulations are expected to play a key role in interpreting future NDSEs, we compared our data to detailed MCNP® calculations. There was good agreement between the data and MCNP over die-off times expected to be most important to future NDSEs, but there were significant differences at both earlier and later times. We attempted to reconcile these differences by several changes to the simulations. In particular, we found that reducing the 235U(n,n') cross section to 80% of the current ENDF7.1 evaluation resulted in much better agreement. [ABSTRACT FROM AUTHOR]

The tendencies of salmon and trout to spawn in proximity to their natal sites and follow the parental timing of breeding are fundamental to their population structure and also affect the performance of enhancement facilities. Specifically, an understanding of how parental spawning date and offspring release location affect the timing and place of breeding by returning adults is important for the evaluation of hatchery supplementation programs and their integration with sympatric naturally spawning populations. We collected Sockeye Salmon Oncorhynchus nerka carcasses in the Cedar River, Washington, over three spawning seasons to evaluate spawn timing and distribution. Thermal marks on the otoliths of hatchery‐origin carcasses allowed assignment of fish to parents that spawned in the early, middle, and late parts of the season and to fry release locations in the lower, middle, and upper parts of the river. The early portion of the spawning run was composed of a higher proportion of hatchery‐origin fish than was the case later in the season. Hatchery‐origin adults that were released early in the spring as fry (from early spawning parents) were recovered early in the season, and those released later in the spring as fry were recovered later in the season. The natural‐origin spawn timing most closely matched the spawn timing of middle and late hatchery fry release groups in all years. Our data also demonstrated a correspondence between hatchery fry release location and adult recovery location; fry released at river kilometer (rkm) 1.0 were recovered 7.0 km lower (median value) in the river than fry released at rkm 21.7 and were recovered 10.0 km lower than fry released at rkm 35.1. These data contribute to the substantial body of evidence that population characteristics of anadromous salmonids are sensitive to influence from fish culture practices—even under benign regimes—because of the strong connections between parental and progeny timing and the fine‐scale homing of salmon to release sites within a river. [ABSTRACT FROM AUTHOR]

Background: The optimal diagnostic strategy for patients with chest pain and detectable to mildly elevated serum troponin is not known. The objective was to compare clinical outcomes among an early decision for a noninvasive versus an invasive-based care pathway. Methods: The CMR-IMPACT trial (Cardiac Magnetic Resonance Imaging Strategy for the Management of Patients with Acute Chest Pain and Detectable to Elevated Troponin) was conducted at 4 United States tertiary care hospitals from September 2013 to July 2018. A convenience sample of 312 participants with acute chest pain symptoms and a contemporary troponin between detectable and 1.0 ng/mL were randomized early in their care to 1 of 2 care pathways: invasive-based (n=156) or cardiac magnetic resonance (CMR)–based (n=156) with modification allowed as the patient condition evolved. The primary outcome was a composite including death, myocardial infarction, and cardiac-related hospital readmission or emergency visits. Results: Participants (N=312, mean age, 60.6 years, SD 11.3; 125 women [59.9%]), were followed over a median of 2.6 years (95% CI, 2.4–2.9). Early assigned testing was initiated in 102 out of 156 (65.3%) CMR-based and 110 out of 156 (70.5%) invasive-based participants. The primary outcome (CMR-based versus invasive-based) occurred in 59% versus 52% (hazard ratio, 1.17 [95% CI, 0.86–1.57]), acute coronary syndrome after discharge 23% versus 22% (hazard ratio, 1.07 [95% CI, 0.67–1.71]), and invasive angiography at any time 52% versus 74% (hazard ratio, 0.66 [95% CI, 0.49–0.87]). Among patients completing CMR imaging, 55 out of 95 (58%) were safely identified for discharge based on a negative CMR and did not have angiography or revascularization within 90 days. Therapeutic yield of angiography was higher in the CMR-based arm (52 interventions in 81 angiographies [64.2%] versus 46 interventions in 115 angiographies [40.0%] in the invasive-based arm [ P =0.001]). Conclusions: Initial management with CMR or invasive-based care pathways resulted in no detectable difference in clinical and safety event rates. The CMR-based pathway facilitated safe discharge, enriched the therapeutic yield of angiography, and reduced invasive angiography utilization over long-term follow-up. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01931852. [ABSTRACT FROM AUTHOR]

We describe a novel nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum among 30 children (ages 1.0 to 28 years) from diverse Amish demes. Children with nephrocerebellar syndrome had progressive microcephaly, visual impairment, stagnant psychomotor development, abnormal extrapyramidal movements and nephrosis. Fourteen died between ages 2.7 and 28 years, typically from renal failure. Post-mortem studies revealed (i) micrencephaly without polymicrogyria or heterotopia; (ii) atrophic cerebellar hemispheres with stunted folia, profound granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation; (iii) selective striatal cholinergic interneuron loss; and (iv) optic atrophy with delamination of the lateral geniculate nuclei. Renal tissue showed focal and segmental glomerulosclerosis and extensive effacement and microvillus transformation of podocyte foot processes. Nephrocerebellar syndrome mapped to 700 kb on chromosome 15, which contained a single novel homozygous frameshift variant (WDR73 c.888delT; p.Phe296Leufs*26). WDR73 protein is expressed in human cerebral cortex, hippocampus, and cultured embryonic kidney cells. It is concentrated at mitotic microtubules and interacts with α-, β-, and γ-tubulin, heat shock proteins 70 and 90 (HSP-70; HSP-90), and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase multi-enzyme complex. Recombinant WDR73 p.Phe296Leufs*26 and p.Arg256Profs*18 proteins are truncated, unstable, and show increased interaction with α- and β-tubulin and HSP-70/HSP-90. Fibroblasts from patients homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early. Our data suggest that in humans, WDR73 interacts with mitotic microtubules to regulate cell cycle progression, proliferation and survival in brain and kidney. We extend the Galloway-Mowat syndrome spectrum with the first description of diencephalic and striatal neuropathology.

The average electromagnetic dipole response of levels in the quasicontinuum of 197,198Au has been measured using (³He,³He') and (d,p) reactions. The extracted y-ray strength functions have been normalized according to three model assumptions for the nuclear spin distribution. An enhancement in the energy region Eγ = 3.0-6.5 MeV is observed for both isotopes. The EI component of such excess of strength is studied in detail for 198Au and is interpreted as the pygmy dipole resonance with an energy centroid of 5.9(1) MeV and exhausts about 1% of the total integrated strength. The pygmy dipole resonance is shown to have a significant impact on the calculated 197Au(n,γ)198Au cross section. [ABSTRACT FROM AUTHOR]

The nuclear level densities and γ-ray strength functions of 138,139,140La were measured using the 139La(³He, α), 139La(³He,' ³He), and 139La(d, p) reactions. The particle-γ coincidences were recorded with the silicon particle telescope (SiRi) and NaI(Tl) (CACTUS) arrays. In the context of these experimental results, the low-energy enhancement in the A ~ 140 region is discussed. The 137,138,139La(n, γ) cross sections were calculated at s- and p-process temperatures using the experimentally measured nuclear level densities and γ-ray strength functions. Good agreement is found between 139La (n, γ) calculated cross sections and previous measurements. [ABSTRACT FROM AUTHOR]