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Background: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. Objective: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤750 g or Methods: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤750 g or Bayesian analyses will be performed as a secondary analysis. Discussion: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. Trial Registration: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol Version: Version 3.2 (10/5/2022)

There is growing interest in the therapeutic potential of 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) for psychiatric disorders. While 5-MeO-DMT can be chemically synthesized, the parotoid gland secretions of Incilius alvarius (also known as the Colorado River or Sonoran Desert toad) contain 5-MeO-DMT and other molecules including bufotenine, bufagenins, bufotoxins, and indole alkylamines that may have individual clinical utility or act as entourage molecules to enhance the activity of 5-MeO-DMT. Incilius alvarius is currently under severe ecological pressure due to demand for natural 5-MeO-DMT and habitat loss. We established a cell line from tissue obtained by wedge biopsy of the Incilius alvarius parotoid gland and confirmed the cell-based biosynthesis of 5-MeO-DMT by LC-MS/MS. Cell-based biosynthesis of Incilius alvarius parotoid gland secretions is a potentially cruelty-free and sustainable source of naturally derived 5-MeO-DMT for research and drug development.Graphical Abstract

Several troubling trends in cannabis use have converged in recent years. The average concentration of psychoactive tetrahydrocannabinol in cannabis has steadily increased while the concentration of psychoprotective cannabidiol has fallen. 1 This trend coincides with a wave of legalization as well as novel methods for consuming marijuana, quite often in the form of “vaping” concentrated oils with concentrations of THC up to 80%. 6 Recent literature also reveals significant psychiatric morbidity with the vaping of high potency cannabis products, similar to those seen with the use of synthetic cannabinoids. 26 , 20 , 21 , 22 , 23 , 18 We present a case of catatonia associated with vaping cannabis oil. A 20-year-old man presented after vaping cannabis oil daily for 2 weeks and was diagnosed with catatonia with a Bush-Francis catatonia rating score of 19 and refusal to eat or drink. He responded favorably to a lorazepam challenge and was titrated to a daily dose of 5mg which was then tapered off slowly as an outpatient with no further episodes of catatonia, mania, or psychosis after cessation of cannabis use. This case adds to a limited but growing body of literature associating high potency cannabis use with severe psychiatric symptoms such as psychosis and catatonia. Caution regarding the proliferation of laws legalizing marijuana is encouraged until these dangers can be better understood. Additionally it is important, especially for adolescents and young adults, to receive more education regarding the psychiatric risks of cannabis use especially given the recent development and increased availability of high potency products.

In vertebrates, several forms of memory-relevant synaptic plasticity involve postsynaptic rearrangements of glutamate receptors. In contrast, previous work indicates that Drosophila and other invertebrates store memories using presynaptic plasticity of cholinergic synapses. Here, we provide evidence for postsynaptic plasticity at cholinergic output synapses from the Drosophila mushroom bodies (MBs). We find that the nicotinic acetylcholine receptor (nAChR) subunit α5 is required within specific MB output neurons (MBONs) for appetitive memory induction, but is dispensable for aversive memories. In addition, nAChR α2 subunits mediate memory expression and likely functions downstream of α5 and the postsynaptic scaffold protein Dlg. We show that postsynaptic plasticity traces can be induced independently of the presynapse, and that in vivo dynamics of α2 nAChR subunits are changed both in the context of associative and non-associative memory formation, underlying different plasticity rules. Therefore, regardless of neurotransmitter identity, key principles of postsynaptic plasticity support memory storage across phyla.

Luc Besson's "Valerian and the City of a Thousand Planets" is set in 'a universe without boundaries' and this aptly describes the diversity of creatures and worlds that Weta Digital was tasked with bringing to life. From the range of different environments to the array of creatures that inhabit them, Weta Digital developed some of Valerian's most iconic characters such as the Pearls, the Doghan Daguis and Rihanna as the shapeshifting Bubble.

Summary Neural information processing depends on precisely timed, Ca 2+ -activated synaptic vesicle exocytosis from release sites within active zones (AZs), but molecular details are unknown. Here, we identify that the (M)Unc13-family member Unc13A generates release sites and show the physiological relevance of their restrictive AZ targeting. Super-resolution and intravital imaging of Drosophila neuromuscular junctions revealed that (unlike the other release factors Unc18 and Syntaxin-1A) Unc13A was stably and precisely positioned at AZs. Local Unc13A levels predicted single AZ activity. Different Unc13A portions selectively affected release site number, position, and functionality. An N-terminal fragment stably localized to AZs, displaced endogenous Unc13A, and reduced the number of release sites, while a C-terminal fragment generated excessive sites at atypical locations, resulting in reduced and delayed evoked transmission that displayed excessive facilitation. Thus, release site generation by the Unc13A C terminus and their specific AZ localization via the N terminus ensure efficient transmission and prevent ectopic, temporally imprecise release.

Brain function relies on fast and precisely timed synaptic vesicle (SV) release at active zones (AZs). Efficacy of SV release depends on distance from SV to Ca(2+) channel, but molecular mechanisms controlling this are unknown. Here we found that distances can be defined by targeting two unc-13 (Unc13) isoforms to presynaptic AZ subdomains. Super-resolution and intravital imaging of developing Drosophila melanogaster glutamatergic synapses revealed that the Unc13B isoform was recruited to nascent AZs by the scaffolding proteins Syd-1 and Liprin-α, and Unc13A was positioned by Bruchpilot and Rim-binding protein complexes at maturing AZs. Unc13B localized 120 nm away from Ca(2+) channels, whereas Unc13A localized only 70 nm away and was responsible for docking SVs at this distance. Unc13A(null) mutants suffered from inefficient, delayed and EGTA-supersensitive release. Mathematical modeling suggested that synapses normally operate via two independent release pathways differentially positioned by either isoform. We identified isoform-specific Unc13-AZ scaffold interactions regulating SV-Ca(2+)-channel topology whose developmental tightening optimizes synaptic transmission.

Transgenesis of large DNA constructs is essential for gene function analysis. Recently, Tol2 transposase-mediated transgenesis has emerged as a powerful tool to insert bacterial artificial chromosome (BAC) DNA constructs into the genome of zebrafish. For efficient transgenesis, the genomic DNA piece in the BAC construct needs to be flanked by Tol2 transposon sites, and the constructs should contain a transgenesis marker for easy identification of transgenic animals. We report a set of plasmids that contain targeting cassettes that allow the insertion of Tol2 sites and different transgenesis markers into BACs. Using BACs containing these targeting cassettes, we show that transgenesis is as efficient as iTol2, that preselecting for expression of the transgenesis marker increases the transgenesis rate, and that BAC transgenics faithfully recapitulate the endogenous gene expression patterns and allow for the estimation of the endogenous gene expression levels.

Intraosseous lipoma is a rare bone tumor that may be encountered in clinical practice. It is benign and is described as a well-defined, radiolucent lesion that must be differentiated from other lytic lesions. Most of these lesions may be treated without surgery; however, when surgery is needed, the classic approach involves curettage and packing using autologous bone grafts, allografts, or synthetic bone substitutes. This article reports two cases using a synthetic bone substitute, TheriLok, to fill the void made from surgical curettage of the intraosseous lipoma. Both patients tolerated the TheriLok bone substitute without developing adverse reactions and precluded the need for a secondary donor site. (J Am Podiatr Med Assoc 100(6): 487–492, 2010)

Summary Nervous system function relies on the polarized architecture of neurons, established by directional transport of pre- and postsynaptic cargoes. While delivery of postsynaptic components depends on the secretory pathway, the identity of the membrane compartment(s) supplying presynaptic active zone (AZ) and synaptic vesicle (SV) proteins is unclear. Live imaging in Drosophila larvae and mouse hippocampal neurons provides evidence that presynaptic biogenesis depends on axonal co-transport of SV and AZ proteins in presynaptic lysosome-related vesicles (PLVs). Loss of the lysosomal kinesin adaptor Arl8 results in the accumulation of SV- and AZ-protein-containing vesicles in neuronal cell bodies and a corresponding depletion of SV and AZ components from presynaptic sites, leading to impaired neurotransmission. Conversely, presynaptic function is facilitated upon overexpression of Arl8. Our data reveal an unexpected function for a lysosome-related organelle as an important building block for presynaptic biogenesis.

Sequence-specific nuclear magnetic resonance (NMR) assignments have been determined for the peptide alphaS2-CN(2-20) containing the multiphosphorylated motif-8Ser(P)-Ser(P)-Ser(P)-Glu-Glu12- in the presence of molar excess Ca2+. The secondary structure of the peptide was characterized by sequential (i,i + 1), medium-range (i,i + 2/3/4) nOes and H alpha chemical shifts. Molecular modelling of the peptide based on these constraints suggests a nascent helix for residues Ser(P)9 to Glu12. The spectral data for alphaS2-CN(2-20) were compared with those of other casein phosphopeptides beta-CN(1-25) and alphaS1-CN(59-79) that also contain the multiphosphorylated motif. This comparison revealed a similar pattern of secondary amide chemical shifts in the multiphosphorylated motif. However, the patterns of medium-range nOe connectivities in the three peptides suggests they have distinctly different conformations in the presence of Ca2+ despite having a high degree of sequential similarity.

Left ventricular diastolic dysfunction has been well described; diastolic abnormalities of the LA are less frequently recognized and poorly understood.The purpose of this study was to investigate the clinical, hemodynamic and echocardiographic features of left atrial (LA) diastolic dysfunction.Patients with atrial fibrillation (AF), severe LA enlargement, and pulmonary venous hypertension (PVH, Group 1) were compared to patients with pulmonary arterial hypertension (PAH), normal LA size and sinus rhythm (Group 2). All underwent right heart catheterization and transthoracic echo to evaluate hemodynamics and LA function. Mitral regurgitation was evaluated by transesophageal echocardiography. LA diastolic function was measured by comparing filling fraction, pulmonary venous flow and compliance.Right atrial, pulmonary artery systolic and mean pressures were similar. Mean wedge pressure were increased in Group 1, 20.8±2.6 versus 9.7±2.8 mm of Hg (p0.0001). The most striking hemodynamic difference was large V wave in Group 1 without significant mitral regurgitation. LA filling fraction was abnormal in Group 1, 11.4%±8.5 compared to Group 2, 111.5%±44 (p0.0001). LA compliance was 0.39±0.27 ml/m2/mmHg in Group 1 versus 6.8±4.54 ml/m2/mmHg in Group 2 (p=0.001). There was a strong negative correlation between the V wave and LA filling fraction (r= 0.756, p0.001). The ratio of the height of the transmitral E wave divided by the S/D ratio (the LA diastolic dysfunction index) correlated very strongly with the V wave (r=0.907, p0.001).LA diastolic dysfunction is present in some patients with long standing AF and PVH. LA diastolic dysfunction, in addition to left ventricular diastolic dysfunction, may contribute to the syndrome of heart failure with preserved left ventricular systolic function.

Summary Glutamate-releasing synapses dominate excitatory release in the brain. Mechanisms governing their assembly are of major importance for circuit development and long-term plasticity underlying learning and memory. AMPA/Kainate-type glutamate receptors (GluRs) are tetrameric ligand-gated ion channels that open their ion-conducting pores in response to binding of the neurotransmitter. Changes in subunit composition of postsynaptic GluRs are highly relevant for plasticity and development of glutamatergic synapses [1–4]. To date, posttranslational modifications, mostly operating via the intracellular C-terminal domains (CTDs) of GluRs, are presumed to be the major regulator of trafficking [5]. In recent years, structural and electrophysiological analyses have improved our understanding of GluR gating mechanism [6–11]. However, whether conformational changes subsequent to glutamate binding may per se be able to influence GluR trafficking has remained an unaddressed question. Using a Drosophila system allowing for extended visualization of GluR trafficking in vivo, we here provide evidence that mutations changing the gating behavior alter GluR distribution and trafficking. GluR mutants associated with reduced charge transfer segregated from coexpressed wild-type GluRs on the level of individual postsynaptic densities. Segregation was lost upon blocking of evoked glutamate release. Photobleaching experiments suggested increased mobility of mutants with reduced charge transfer, which accumulated prematurely during early steps of synapse assembly, but failed to further increase their level in accordance with assembly of the presynaptic scaffold. In summary, gating characteristics seem to be a new variable for the understanding of GluR trafficking relevant to both development and plasticity.

Summary This paper reports an effort to create a community of practice for teachers' professional development via the World Wide Web. Beginning with a discussion of our theoretical foundations and current online models of professional development, we address the problem of how developing Web and video technologies may provide innovative and effective professional development for teachers. We describe the initial conceptions of the Internet Learning Forum (ILF), a Web site developed to support mathematics and science teachers sharing and evolving their pedagogical practices. This site includes exemplary instructional units, teachers' reflections, and peer discussion. Starting with video, ILF participants examine assumptions, reflect on practices, and share within the ILF community. The goal of this unique community of practice is to create quality professional development. While this paper provides an overview of our initial design work, the site has evolved into a nationally funded project. However, the w...

Schools are trying to keep pace with changes in instructional technology. Even skills that are assumed to be enhanced by this technology, such as creativity, may be hindered by careless application. Encouraging teachers and students to share their ideas helps to engender creativity and critical thinking and keep abreast of these changing times.

During the ICNARA 2 conference, a workshop was held on remineralization models. The group considered the role of remineralization models, whether there was one ideal in situ model design, what essential features should be incorporated into an in situ model, other alternative models, and what new methods for measuring remineralization were on the horizon. This paper summarizes the discussion. In situ and other caries models can be used as a surrogate for caries clinical trials but only when data exist to validate the model. In situ model design should be flexible to allow for investigation of different aspects of the caries process; however, several essential features were identified that should be incorporated into the study design. A range of other caries models was discussed, including the study of non-cavitated lesions, lesions post-orthodontic therapy, plaque retention models to form more standardized lesions, and the study of root caries lesions. Numerous new methods for quantifying remineralization were discussed, but it was considered that these require validation before they can be used in clinical trials.

Synapse formation and maturation requires bidirectional communication across the synaptic cleft. The trans-synaptic Neurexin-Neuroligin complex can bridge this cleft, and severe synapse assembly deficits are found in Drosophila melanogaster neuroligin (Nlg1, dnlg1) and neurexin (Nrx-1, dnrx) mutants. We show that the presynaptic active zone protein Syd-1 interacts with Nrx-1 to control synapse formation at the Drosophila neuromuscular junction. Mutants in Syd-1 (RhoGAP100F, dsyd-1), Nrx-1 and Nlg1 shared active zone cytomatrix defects, which were nonadditive. Syd-1 and Nrx-1 formed a complex in vivo, and Syd-1 was important for synaptic clustering and immobilization of Nrx-1. Consequently, postsynaptic clustering of Nlg1 was affected in Syd-1 mutants, and in vivo glutamate receptor incorporation was changed in Syd-1, Nrx-1 and Nlg1 mutants. Stabilization of nascent Syd-1-Liprin-α (DLiprin-α) clusters, important to initialize active zone formation, was Nlg1 dependent. Thus, cooperation between Syd-1 and Nrx-1-Nlg1 seems to orchestrate early assembly processes between pre- and postsynaptic membranes, promoting avidity of newly forming synaptic scaffolds. ispartof: Nature Neuroscience vol:15 issue:9 pages:1219-1226 ispartof: location:United States status: published

Mycobacterium ulcerans is the causative agent of the debilitating skin disease Buruli ulcer, which is most prevalent in Western and Central Africa. M. ulcerans shares98% DNA sequence identity with Mycobacterium marinum, however, M. marinum produces granulomatous, but not ulcerative, lesions in humans and animals. Here we report the differential expression of a small heat shock protein (Hsp18) between strains of M. ulcerans (Hsp18(+) ) and M. marinum (Hsp18(-) ) and describe the molecular basis for this difference. We show by gene deletion and GFP reporter assays in M. marinum that a divergently transcribed gene called hspR_2, immediately upstream of hsp18, encodes a MerR-like regulatory protein that represses hsp18 transcription while promoting its own expression. Naturally occurring mutations within a 70 bp segment of the 144 bp hspR_2-hsp18 intergenic region among M. ulcerans strains inhibit hspR_2 transcription and explain the Hsp18(+) phenotype. We also propose a biological role for Hsp18, as we show that this protein significantly enhances bacterial attachment or aggregation during biofilm formation. This study has uncovered a new member of the MerR family of transcriptional regulators and suggests that upregulation of hsp18 expression was an important pathoadaptive response in the evolution of M. ulcerans from a M. marinum-like ancestor.

The casein phosphopeptides (CPP) are derived from the milk protein casein by tryptic digestion. The CPP, containing the sequence -Pse-Pse-Pse-Glu-Glu- where Pse is a phosphoseryl residue, stabilize calcium and phosphate ions in aqueous solution and make these essential nutrients bioavailable. Under alkaline conditions the calcium phosphate is present as an alkaline amorphous phase complexed by the CPP, referred to as casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). The CPP-ACP complexes readily incorporate fluoride ions forming casein phosphopeptide-amorphous calcium fluoride phosphate (CPP-ACFP). A mechanism is discussed which provides a rationale for the ability of the CPP-ACP to remineralize carious lesions in dental enamel. Clinical applications of the CPP-ACP as agents in the treatment of dental caries and other hypomineralized conditions are reviewed. It is concluded that the CPP are a safe and novel carrier for calcium, phosphate and hydroxide (fluoride) ions to promote enamel remineralization with application in oral care products, dental professional products and foodstuffs.

Accounts of the introductions of the large centropomid piscivore, Nile perch, Lates niloticus, into the waters of Lake Victoria have been provided by a number of writers (see Reynolds and Greboval, 1988, for a fuller review). There is a surprising vagueness in many of these accounts when it comes to the actual sequence of events and the main actors (or villains, depending on one’s point of view) involved. There is no doubt that the fish was placed into Lake Victoria at some point during the series of Nile perch transplantations to the Upper Nile-Lake Kyoga-Owen’s Falls Dam stretch of Nilotic waters, conducted by officials of the Uganda Game and Fisheries Department between 1954 and 1957 (Kinloch, 1972). Stock was captured from Lake Albert and the Nile below Murchison Falls. Unlike the earlier introductions of non-indigenous tilapiines beginning in 1953 (Welcomme, 1966;1967), the first placement of perch into Lake Victoria seems to have been carried out surreptitiously. It came as a surprise when the fish was discovered in waters close to Jinja (map, Chapter 2, Fig. 2.2) in May 1960, even as debate about whether the introduction ought to be carried out was continuing (EAFFRO, 1960; Fryer, 1960; Hamblyn, 1960; Anderson, 1961; Beadle, 1981). Two official‘deliberate’ introductions of Nile perch to Ugandan waters were later conducted in 1962 and 1963 (Gee, 1965).

Dear Ladies and Gentlemen of the American Science Community: As I write this from my troubled home state of Kansas, the State Board of Education is debating once again whether to de-emphasize the theory of evolution. Those in the majority on the Board have stated that they are considering changing the very definition of science to allow for science classes to discuss the merits of intelligent design. Kansas Attorney General Phill Kline has said that he would defend the Board's actions. Kansas may be a far-off, conservative state for most of you, largely unimportant in the affairs of your professional lives, but this is a strong indicator that the very foundation of science in the United States is at risk. Other states have had this problem recently, including Georgia, Alabama, and Ohio, and this could happen to your state. What a shame it would be if unqualified politicians succeed in undoing centuries of scientific progress in both the public's perception of science and its continuing advancement. This is a wake-up call, ladies and gentlemen. Please don't let this happen in your state. You may write to the Board by visiting their Web site at [www.ksbe.state.ks.us/Welcome.html][1]. [1]: http://www.ksbe.state.ks.us/Welcome.html