EphB2 Deficiency Induces Depression-Like Behaviors and Memory Impairment: Involvement of NMDA 2B Receptor Dependent Signaling

Receptor tyrosine kinase EphB2 mediates development of the neurogenic niche of excitatory neurons, suggesting the possibility that its inactivation plays a role in neuropsychiatric disorders including depression and memory impairment. While N-methyl-D-aspartate (NMDA) receptor is involved in regulating memory formation and neurogenesis in adult animal, it remains unclear how NMDA receptor subtypes mediate depression and cognitive deficits caused by EphB2 loss. The present study shows that EphB2 inactivation results in depression-like behaviors, memory impairment and defects of adult hippocampal neurogenesis. Compared to wild-type littermates, EphB2 KO mice exhibited depression-like behavior and deficits in spatial memory and cognition in forced swimming, tail suspension, Morris water maze, object recognition test and object location test. These behavioral abnormalities were accompanied by substantial decreases in the number of BrdU+ progenitor neurons, phosphorylation of cAMP-response element binding protein (pCREB) and brain derived neurotrophic factor (BDNF), and increased NMDA receptor 2B (NR2B) expression. These molecular, cellular and behavioral alterations induced by EphB2 inactivation were reversed by NR2B antagonist Ro25-6981, suggesting that EphB2 functions to prevent the progression of depression-like behavior and memory impairment by downregulating NR2B. Our findings highlight that NR2B is responsible for EphB2-dependent behavioral and morphological changes. EphB2 may thus be as an important candidate target for treating psychiatric and cognitive disorders

Metabolic constraints on the evolution of antibiotic resistance

Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in terms of speed and mode of resistance acquisition. To interpret and explore the space of metabolome changes, we developed a novel constraint‐based modeling approach using the concept of shadow prices. This analysis, together with genome resequencing of resistant populations, identified condition‐dependent compensatory mechanisms of antibiotic resistance, such as the shift from respiratory to fermentative metabolism of glucose upon overexpression of efflux pumps. Moreover, metabolome‐based predictions revealed emerging weaknesses in resistant strains, such as the hypersensitivity to fosfomycin of ampicillin‐resistant strains. Overall, resolving metabolic adaptation throughout antibiotic‐driven evolutionary trajectories opens new perspectives in the fight against emerging antibiotic resistance.ISSN:1744-429

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Medial LMC axons in the mutant are redirected from the ventral limb into the ventral flank

<p><b>Copyright information:</b></p><p>Taken from "Lateral motor column axons execute a ternary trajectory choice between limb and body tissues"</p><p>http://www.neuraldevelopment.com/content/2/1/13</p><p>Neural Development 2007;2():13-13.</p><p>Published online 2 Jul 2007</p><p>PMCID:PMC1949814.</p><p></p> Scip immunostaining and retrograde labeling (HRP or RDA) of nerves at E13.5 was used to define the contribution of Scip+ neurons to each nerve branch. Retrograde labeling from normal dorsal or ventral limb mesenchyme. Dorsal nerves originate from Scip- lateral LMC neurons (a, i-vi). HRP-labeled cells do not express Scip and are Isl1- Lim1+ lateral LMC cells (white arrows). Scip+ medial LMC cells contribute to ventral nerves (a, vii-xii). Many HRP-labeled cells express Scip and all Scip+ cells are Isl1+ Lim1- medial LMC neurons (white arrows). Retrograde labeling from normal or mutant ventral flank mesenchyme. In normal and mutant embryos retrogradely labeled Scip- cells are readily detected in sections of rostral spinal cord (b, i-vi). Labeled cells are detected in caudal lumbar spinal cord only in mutants (b, vii-xii, white arrows). Many of these labeled neurons are also Scip+. Similar staining patterns were observed in three embryos for each labeling experiment. Representative sections are shown of labeled motor columns co-immunostained for HRP and Scip. Experiments in (a,b) are diagrammed schematically to the right, and boxed areas show the regions of the images. Quantification of flank retrograde labeling data. The fraction of HRP+ or RDA+ flank-labeled cells that are also Scip+ differs significantly (P < 0.02) between normal and mutant (normal: white bar, 6.4% ± 2.6%, n = 6 embryos, N = 1,018 labeled neurons; mutant: black bar, 23.6% ± 4.7%; n = 5 embryos, N = 784 labeled neurons). The anteroposterior span of the Scip+ pool within the E13.5 lumbar LMC does not differ significantly between normal and mutant embryos (normal: 701 ± 26 μm, n = 6 embryos; mutant: 592 ± 94 μm, n = 5; P = 0.219)

Medial LMC axons enter only the ventral flank nerve branch in the hindlimb

<p><b>Copyright information:</b></p><p>Taken from "Lateral motor column axons execute a ternary trajectory choice between limb and body tissues"</p><p>http://www.neuraldevelopment.com/content/2/1/13</p><p>Neural Development 2007;2():13-13.</p><p>Published online 2 Jul 2007</p><p>PMCID:PMC1949814.</p><p></p> Anterograde labeling was used to determine the trajectories of axons originating within the medial LMC. Schematic showing the dorsal approach used for the anterograde HRP labeling of spinal cord neurons at E12.5. Regions of interest in (b,c) are boxed. Triple co-immunostaining showing spinal cords in which the vast majority of HRP+ cells are Isl1+ Lim1- medial LMC neurons. In normal hindlimbs, both ventral flank and ventral limb branches are labeled with HRP (n = 5 embryos, label detected in ventral flank branch = 5/5, ventral limb branch = 5/5, dorsal limb branch = 0/5), while neurofilament labeling identifies all three nerve branches. In mutant hindlimbs, only the ventral flank branch is HRP+ (n = 5 embryos, ventral flank branch = 5/5, ventral limb branch = 0/5, dorsal limb branch = 0/5). Adjacent sections from anterior plexus are shown for both normal and mutant. Arrowheads: representative HRP+ Isl1+ neurons. Arrows: HRP+ nerve branches. Dotted lines: outlines of lateral and medial LMC. D, dorsal limb nerve branch; F, ventral flank nerve branch; V, ventral limb nerve branch