The netrin receptor DCC is required in the pubertal organization of mesocortical dopamine circuitry

Netrins are guidance cues involvedinneural connectivity.Wehave shownthat the netrin-1 receptor DCC (deletedin colorectal cancer) is involvedinthefunctionalorganizationofthemesocorticolimbic dopamine(DA)system.Adult micewithaheterozygousloss-of-function mutation in dcc exhibit changes in indexes of DA function, including DA-related behaviors. These phenotypes are only observed after puberty,acritical periodinthe maturationofthe mesocortical DAprojection. Here, weexamined whether dcc heterozygous mice exhibit structural changes in medial prefrontal cortex (mPFC) DA synaptic connectivity, before and after puberty. Stereological counts of tyrosine-hydroxylase (TH)-positive varicosities were increased in the cingulate 1 and prelimbic regions of the pregenual mPFC. dcc heterozygous mice also exhibited alterations in the size, complexity, and dendritic spine density of mPFC layer V pyramidal neuron basilar dendritic arbors. Remarkably, these presynaptic and postsynaptic partner phenotypes were not observed in juvenile mice, suggesting that DCC selectively influences the extensive branching and synaptic differentiation that occurs in the maturing mPFC DA circuitatpuberty.Immunolabelingexperimentsinwild-typemice demonstratedthat DCCissegregatedtoTH-positivefibersinnervating the nucleus accumbens, with only scarce DCC labeling in mPFC TH-positive fibers. Netrin had an inverted target expression pattern. Thus, DCC-mediated netrin-1 signaling may influence the formation/maintenance of mesocorticolimbic DA topography. In support of this, we report that dcc heterozygous mice exhibit a twofold increase in the density of mPFC DCC/TH-positive varicosities. Our results implicate DCC-mediated netrin-1 signaling in the establishment of mPFC DA circuitry during puberty

Npas4: Linking Neuronal Activity to Memory

Immediate-early genes (IEGs) are rapidly activated after sensory and behavioral experience and are believed to be crucial for converting experience into long-term memory. Neuronal PAS domain protein 4 (Npas4), a recently discovered IEG, has several characteristics that make it likely to be a particularly important molecular link between neuronal activity and memory: it is among the most rapidly induced IEGs, is expressed only in neurons, and is selectively induced by neuronal activity. By orchestrating distinct activity-dependent gene programs in different neuronal populations, Npas4 affects synaptic connections in excitatory and inhibitory neurons, neural circuit plasticity, and memory formation. It may also be involved in circuit homeostasis through negative feedback and psychiatric disorders. We summarize these findings and discuss their implications.National Institutes of Health (U.S.) (Grant MH091220-01

A novel tightly regulated gene expression system for the human intestinal symbiont Bacteroides thetaiotaomicron

There is considerable interest in studying the function of Bacteroides species resident in the human gastrointestinal (GI)-tract and the contribution they make to host health. Reverse genetics and protein expression techniques, such as those developed for well-characterized Escherichia coli cannot be applied to Bacteroides species as they and other members of the Bacteriodetes phylum have unique promoter structures. The availability of useful Bacteroides-specific genetic tools is therefore limited. Here we describe the development of an effective mannan-controlled gene expression system for Bacteroides thetaiotaomicron containing the mannan-inducible promoter–region of an α-1,2-mannosidase gene (BT_3784), a ribosomal binding site designed to modulate expression, a multiple cloning site to facilitate the cloning of genes of interest, and a transcriptional terminator. Using the Lactobacillus pepI as a reporter gene, mannan induction resulted in an increase of reporter activity in a time- and concentration-dependent manner with a wide range of activity. The endogenous BtcepA cephalosporinase gene was used to demonstrate the suitability of this novel expression system, enabling the isolation of a His-tagged version of BtCepA. We have also shown with experiments performed in mice that the system can be induced in vivo in the presence of an exogenous source of mannan. By enabling the controlled expression of endogenous and exogenous genes in B. thetaiotaomicron this novel inducer-dependent expression system will aid in defining the physiological role of individual genes and the functional analyses of their products

Netflix and Forget: Efficient and Exact Machine Unlearning from Bi-linear Recommendations

People break up, miscarry, and lose loved ones. Their online streaming and shopping recommendations, however, do not necessarily update, and may serve as unhappy reminders of their loss. When users want to renege on their past actions, they expect the recommender platforms to erase selective data at the model level. Ideally, given any specified user history, the recommender can unwind or "forget", as if the record was not part of training. To that end, this paper focuses on simple but widely deployed bi-linear models for recommendations based on matrix completion. Without incurring the cost of re-training, and without degrading the model unnecessarily, we develop Unlearn-ALS by making a few key modifications to the fine-tuning procedure under Alternating Least Squares optimisation, thus applicable to any bi-linear models regardless of the training procedure. We show that Unlearn-ALS is consistent with retraining without \emph{any} model degradation and exhibits rapid convergence, making it suitable for a large class of existing recommenders.Comment: 8 pages, 8 figure

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.National Institutes of Health (U.S.) (New Innovator Award 1DP2OD008435)National Centers for Systems Biology (U.S.) (Grant 1P50GM098792)United States. Defense Threat Reduction Agency (HDTRA1-14-1-0007)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (W911NF13D0001)National Institute of General Medical Sciences (U.S.) (Interdepartmental Biotechnology Training Program 5T32 GM008334)Fonds de la recherche en sante du Quebec (Master's Training Award

A transatlantic perspective on 20 emerging issues in biological engineering

Advances in biological engineering are likely to have substantial impacts on global society. To explore these potential impacts we ran a horizon scanning exercise to capture a range of perspectives on the opportunities and risks presented by biological engineering. We first identified 70 potential issues, and then used an iterative process to prioritise 20 issues that we considered to be emerging, to have potential global impact, and to be relatively unknown outside the field of biological engineering. The issues identified may be of interest to researchers, businesses and policy makers in sectors such as health, energy, agriculture and the environment

The draft genome of Ditylenchus dipsaci.

Ditylenchus dipsaci is a devastating pest to many crops worldwide. We present the first genome sequence for this species, produced with PacBio sequencing and assembled with CANU. Ditylenchus dipsaci is a devastating pest to many crops worldwide. We present the first genome sequence for this species, produced with PacBio sequencing and assembled with CANU

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Genome annotation. (XLSX 9 kb