title: Optical activation of TrkB neurotrophin receptor in mouse ventral hippocampus promotes plasticity and facilitates fear extinction

abstract: Successful extinction of traumatic memories depends on neuronal plasticity in the fear extinction network. However, the mechanisms involved in the extinction process remain poorly understood. Here, we investigated the fear extinction network by using a new optogenetic technique that allows temporal and spatial control of neuronal plasticity in vivo. We optimized an optically inducible TrkB (CKII-optoTrkB), the receptor of the brain-derived neurotrophic factor, which can be activated upon blue light exposure to increase plasticity specifically in pyramidal neurons. The activation of CKII-optoTrkB facilitated the induction of LTP in Schaffer collateral-CA1 synapses after brief theta-burst stimulation and increased the expression of FosB in the pyramidal neurons of the ventral hippocampus, indicating enhanced plasticity in that brain area. We showed that optical stimulation of the CA1 region of the ventral hippocampus during fear extinction training led to an attenuated conditioned fear memory. This was a specific effect only observed when combining extinction training with CKII-optoTrkB activation, and not when using either intervention alone. Thus, TrkB activation in ventral CA1 pyramidal neurons promotes a state of neuronal plasticity that allows extinction training to guide neuronal network remodeling to overcome fear memories. Our methodology is a powerful tool to induce neuronal network remodeling in the adult brain, and can attenuate neuropsychiatric symptoms caused by malfunctioning networks.


title: Two distinct neuronal populations in the rat parafascicular nucleus oppositely encode the engagement in stimulus-driven reward-seeking

abstract:
The thalamus is a phylogenetically well-preserved structure. Known to densely contact cortical regions, its role in the transmission of sensory information to the striatal complex has been widely reconsidered in recent years. The parafascicular of the thalamus (Pf) has been implicated the orientation of attention towards salient sensory stimuli. In a stimulus-driven reward seeking task, we sought to characterize the electrophysiological activity of Pf neurons in rats. We observed a predominance of excitatory responses over inhibitory responses for all events of the task. Neurons responded more strongly to the stimulus compared to lever-pressing and collecting reward, confirming the strong involvement of the Pf in sensory information processing. The use of long sessions allowed us to compare neuronal responses to stimuli when the animal engaged in action or when it did not. We distinguished two populations of neurons responding in an opposite way: MOTIV+ neurons responded more intensively to stimuli followed by a behavioral response than those that did not. Conversely, MOTIV-neurons responded more strongly when the stimulus was ignored by the animal. In addition, MOTIV-neurons excitations appeared at a shorter latency after the stimulus than MOTIV+ neurons. Through this encoding, Pf could perform an early selection of environmental stimuli transmitted to the striatum according to motivational level.

HIGHLIGHTSO_LIPf neurons respond to reward-predicting stimuli and reward-related actions
C_LIO_LIMOTIV+ Pf neurons were more active to stimuli evoking reward-seeking
C_LIO_LIMOTIV- Pf neurons were more active to stimuli ignored by the animal
C_LIO_LIStimuli-evoked excitations latencies were shorter in MOTIV- than MOTIV+ neurons
C_LI

category: neuroscience


title: Predictive coding is a consequence of energy efficiency in recurrent neural networks

abstract: Predictive coding represents a promising framework for understanding brain function. It postulates that the brain continuously inhibits predictable sensory input, ensuring a preferential processing of surprising elements. A central aspect of this view is its hierarchical connectivity, involving recurrent message passing between excitatory bottom-up signals and inhibitory top-down feedback. Here we use computational modelling to demonstrate that such architectural hard-wiring is not necessary. Rather, predictive coding is shown to emerge as a consequence of energy efficiency. When training recurrent neural networks to minimise their energy consumption while operating in predictive environments, the networks self-organise into prediction and error units with appropriate inhibitory and excitatory interconnections, and learn to inhibit predictable sensory input. Moving beyond the view of purely top-down driven predictions, we furthermore demonstrate, via virtual lesioning experiments, that networks perform predictions on two timescales: fast lateral predictions among sensory units, and slower prediction cycles that integrate evidence over time.


title: Simulating the emergence of the Visual Word Form Area: Recycling a convolutional neural network for reading

abstract: The visual word form area (VWFA) is a region of human inferotemporal cortex that emerges at a fixed location in occipitotemporal cortex during reading acquisition, and systematically responds to written words in literate individuals. According to the neuronal recycling hypothesis, this region arises through the repurposing, for letter recognition, of a subpart of the ventral visual pathway initially involved in face and object recognition. Furthermore, according to the biased connectivity hypothesis, its universal localization is due to pre-existing connections from this subregion to areas involved in spoken language processing. Here, we evaluate those hypotheses in an explicit computational model. We trained a deep convolutional neural network of the ventral visual pathway, first to categorize pictures, and then to recognize written words invariantly for case, font and size. We show that the model can account for many properties of the VWFA, particularly when a subset of units possesses a biased connectivity to word output units. The network develops a sparse, invariant representation of written words, based on a restricted set of reading-selective units. Their activation mimics several properties of the VWFA, and their lesioning causes a reading-specific deficit. Our simulation fleshes out the neuronal recycling hypothesis, and make several testable predictions concerning the neural code for written words.


title: The Relationship between Birth Timing, Circuit Wiring, and Physiological ResponseProperties of Cerebellar Granule Cells

abstract:
Cerebellar granule cells (GrCs) are usually regarded as a uniform cell type that collectively expands the coding space of the cerebellum by integrating diverse combinations of mossy fiber inputs. Accordingly, stable molecularly or physiologically defined GrC subtypes within a single cerebellar region have not been reported. The only known cellular properties that distinguishes otherwise homogeneous GrCs is the correspondence between GrC birthtime and the depth of the molecular layer to which their axons (parallel fibers) project. To determine the role birth timing plays in GrC wiring and function, we developed genetic strategies to access early- and late-born GrCs. We initiated retrograde monosynaptic rabies virus tracing from control, early-born, and late-born GrCs, revealing the different patterns of mossy fiber input to GrCs in vermis lobule 6 and simplex, as well as to early- and late-born GrCs of vermis lobule 6: sensory and motor nuclei provide more input to early-born GrCs, while basal pontine and cerebellar nuclei provide more input to late-born GrCs. In vivo multi-depth 2-photon Ca2+ imaging of parallel fibers of early- and late-born GrCs revealed representations of diverse task variables and stimuli by both populations, with differences in the proportions of parallel fibers encoding movement, reward anticipation, and reward consumption. Our results suggest neither organized parallel processing nor completely random organization of mossy fiber[->]GrC circuitry, but instead a moderate influence of birth timing on GrC wiring and encoding. Our imaging data also suggest that GrCs can represent general aversiveness, in addition to recently described reward representations.

Significance StatementCerebellar granule cells (GrCs) comprise the majority of all neurons in the mammalian brain and are usually regarded as a uniform cell type. However, the birth timing of an individual GrC dictates where its axon projects. Using viral-genetic techniques, we find that early- and late-born GrCs receive different proportions of inputs from the same set of input regions. Using in vivo multi-depth 2-photon Ca2+ imaging of axons of early- and late-born GrCs, we found that both populations represent diverse task variables and stimuli, with differences in the proportions of axons in encoding of a subset of movement and reward parameters. These results indicate that birth timing contributes to the input selection and physiological response properties of GrCs.


title: Molecular View of Biomimetic Peptide in Action with Membrane

abstract:
Amphiphilic {beta}-peptides, which are synthetically designed short-chain helical foldamer of {beta}-amino acids, are established potent biomimetic alternatives of natural antimicrobial peptides. An intriguing question is: how does the distinct molecular architecture of these short-chain and rigid synthetic peptides translates to its potent membrane disruption ability? Here, we address this question via a combination of all atom and coarse-grained molecular dynamics simulations of the interaction of mixed phospholipid bilayer with an antimicrobial 10-residue globally amphiphilic helical {beta}-peptide at wide range of concentrations. The simulation demonstrates that multiple copies of this synthetic peptide, initially placed in aqueous solution, readily self-assemble and adsorb at membrane interface. Subsequently, beyond a threshold peptide-to-lipid ratio, the surface-adsorbed oligomeric aggregate moves inside the membrane and spontaneously forms stable water-filled transmembrane pore via a cooperative mechanism. The defects induced by these pores lead to the dislocation of interfacial lipid head groups, membrane thinning and substantial water leakage inside the hydrophobic core of the membrane. A molecular analysis reveals that, despite having a short architecture, these synthetic peptides, once inside the membrane, would stretch themselves towards the distal leaflet in favour of potential contact with polar head groups and interfacial water layer. The pore formed in coarse-grained simulation was found to be resilient upon structural refinement. Interestingly, the pore-inducing ability was found to be elusive in a non-globally amphiphilic sequence isomer of the same {beta}-peptide, indicating strong sequence dependence. Taken together, this work put forward key perspectives of membrane-activity of minimally designed synthetic biomimetic oligomers relative to the natural antimicrobial peptides.

STATEMENT OF SIGNIFICANCEThe development of bacterial resistance to conventional antibiotics is a major concern towards public health. Antimicrobial peptides, which provide a natural defence against a large range of pathogens, including bacteria and fungi, are emerging as a sustainable substitute of antibiotics. However, serious issues with the naturally occurring antimicrobial peptides which have prevented their wide-spread appreciations are their susceptibility to degradation and lack of specificity for microbial targets. In this regard, synthetic biomimetic peptides are coming up as a viable alternative. In this work we provide clarity on how these synthetic antimicrobial peptides, which often involves distinctly short architecture, acts on the membrane. We show that despite its short architecture, a 10-residue biomimetic peptide, {beta}-peptide, can spontaneously form stable membrane-spanning pore and induce water-leakage inside the membrane.

category: biophysics


title: Spontaneous Transmembrane Pore Formation by Short-chain Synthetic Peptide


title: Potential of fungicides, botanicals and biocontrol agents to induce physio-biochemical tolerance on Curcuma longa impaired by Colletotrichum gloeosporioides

abstract:
Necrotic leaf spot of Curcuma longa (turmeric) limits the chief physio-biochemical activity for maintaining the plant health and productivity. In the present study, polyhouse and open field trials were conducted to estimate the pathogenicity of C. gloeosporioides on turmeric and to evaluate the foliar efficiency of propiconazole @ RD and copper oxychloride, extracts of A. indica, A. sativum and O. sanctum @ 40%, and culture filtrates of T. viride, T. harzianum and T. virens @ 4x106 cfu/ml in inducing physio-biochemical tolerance of pathogen inoculated and non-inoculated plants. In both the trials, these three agents yielded the highest efficiency to enhance the physio-biochemical traits. The induced physio-biochemical tolerance in treated turmeric plants showed variation in the elevation of plant health and immunity in response to pathogen aggressiveness or disease severity. However, phytophenol content was quite higher in infected plants than non-infected plants due to initiation of defense reaction in response of pathogenic elicitors. Thus, the present study demonstrated the novelty of physio-biochemical tolerance induction on turmeric plants by using fungicides, biocontrol agents and phytoextracts.

HighlightsO_LIFoliar treatments improve desirable plant physio-biochemical traits against pathogen.
C_LIO_LIPhysio-biochemical variation induces the innate plant defense system.
C_LIO_LIHigh phytophenol accumulation counteracts the pathogenic stress.
C_LIO_LITurmeric plants health and yield enhance by the reduction of disease intensity.
C_LI

category: pathology


title: A multi-phase multi-objective genome-scale model shows diverse redox balance strategies in yeasts

abstract: Yeasts constitute over 1500 species with great potential for biotechnology. Still, the yeast Saccharomyces cerevisiae dominates industrial applications and many alternative physiological capabilities of lesser-known yeasts are not being fully exploited. While comparative genomics receives substantial attention, little is known about yeasts metabolic specificity in batch cultures. Here we propose a multi-phase multi-objective dynamic genome-scale model of yeast batch cultures that describes the uptake of carbon and nitrogen sources and the production of primary and secondary metabolites. The model integrates a specific metabolic reconstruction, based on the consensus Yeast8, and a kinetic model describing the time-varying culture environment. Besides, we proposed a multi-phase multi-objective flux balance analysis to compute the dynamics of intracellular fluxes. We then compared the metabolism of S. cerevisiae and S. uvarum strains in wine fermentation. The model successfully explained the experimental data and brought novel insights into how cryotolerant strains achieve redox balance. The proposed modeling captures the dynamics of metabolism throughout the batch and offers a systematic approach to prospect or engineer novel yeast cell factories.

category: systems biology


title: Generalization of motor learning in psychological space

abstract: To generate adaptive movements, we must generalize what we have previously learned to novel situations. The generalization of learned movements has typically been framed as a consequence of neural tuning functions that overlap for similar movement kinematics. However, as is true in many domains of human behavior, situations that require generalization can also be framed as inference problems. Here, we attempt to broaden the scope of theories about motor generalization, hypothesizing that part of the typical motor generalization function can be characterized as a consequence of top-down decisions about different movement contexts. We tested this proposal by having participants make explicit similarity ratings over traditional contextual dimensions (movement directions) and abstract contextual dimensions (target shape), and perform a visuomotor adaptation generalization task where trials varied over those dimensions. We found support for our predictions across five experiments, which revealed a tight link between subjective similarity and motor generalization. Our findings suggest that the generalization of learned motor behaviors is influenced by both low-level kinematic features and high-level inferences.


title: Cortical compensation for hearing loss, but not age, in neural tracking of the fundamental frequency of the voice

abstract: Auditory processing is affected by advancing age and hearing loss, but the underlying mechanisms are still unclear. We investigated the effects of age and hearing loss on temporal processing of naturalistic stimuli in the auditory system. We analysed neural phase-locking to the fundamental frequency of the voice (f0) in 54 normal-hearing and 14 hearing-impaired adults between 17 and 82 years old. We found that both subcortical and cortical neural sources contributed to the responses. Results indicated that advancing age was related to smaller responses with less cortical response contributions, consistent with an age-related decrease in neural phase-locking ability. Conversely, hearing impaired subjects displayed larger responses compared to age-matched normal hearing controls. This was due to additional cortical response contributions which were stronger for participants with more severe hearing loss. This is consistent with the recruitment of additional cortical sources for auditory processing in persons with hearing impairment.


title: Relation of inflammatory marker trajectories with frailty and aging in a 20-year longitudinal study

abstract: Little is known about the development of low-grade inflammation with age and its relationship with the onset of frailty. In this exploratory study, we investigated 18 inflammatory markers measured in blood of 144 individuals aged 65-75 years at study endpoint, collected over 20 years at five-year intervals. IFN{gamma}-induced markers and platelet activation markers changed in synchrony over time. Chronically elevated levels of IL-6-related markers, such as CRP and sIL-6R, were associated with frailty and becoming frail over time, poorer lung function, or less physical strength. Overweight was a possible driver of these associations. More and stronger associations were detected in women, such as between increasing sCD14 levels and frailty, indicating possible monocyte overactivation. Multivariate prediction of frailty showed low accuracy but confirmed the main results. In summary, we documented 20-year temporal changes of inflammatory markers in an aging population, and related these to clinically relevant health outcomes.

category: immunology


title: Initial HCV infection of adult hepatocytes triggers a temporally structured transcriptional program containing diverse pro- and anti-viral elements

abstract:
Transcriptional profiling provides global snapshots of virus-mediated cellular reprogramming, which can simultaneously encompass pro- and antiviral components. To determine early transcriptional signatures associated with HCV infection of authentic target cells, we performed ex vivo infections of adult primary human hepatocytes (PHHs) from seven donors. Longitudinal sampling identified minimal gene dysregulation at six hours post infection (hpi). In contrast, at 72 hpi, massive increases in the breadth and magnitude of HCV-induced gene dysregulation were apparent, affecting gene classes associated with diverse biological processes. Comparison with HCV-induced transcriptional dysregulation in Huh-7.5 cells identified limited overlap between the two systems. Of note, in PHHs, HCV infection initiated broad upregulation of canonical interferon (IFN)-mediated defense programs, limiting viral RNA replication and abrogating virion release. We further find that constitutive expression of IRF1 in PHHs maintains a steady-state antiviral program in the absence of infection, which can additionally reduce HCV RNA translation and replication. We also detected infection-induced downregulation of [~]90 genes encoding components of the EIF2 translation initiation complex and ribosomal subunits in PHHs, consistent with a signature of translational shutoff. As HCV polyprotein translation occurs independently of the EIF2 complex, this process is likely pro-viral: only translation initiation of host transcripts is arrested. The combination of antiviral intrinsic and inducible immunity, balanced against pro-viral programs, including translational arrest, maintains HCV replication at a low-level in PHHs. This may ultimately keep HCV under the radar of extra-hepatocyte immune surveillance while initial infection is established, promoting tolerance, preventing clearance and facilitating progression to chronicity.

IMPORTANCEAcute HCV infections are often asymptomatic and therefore frequently undiagnosed. We endeavored to recreate this understudied phase of HCV infection using explanted PHHs and monitored host responses to initial infection. We detected temporally distinct virus-induced perturbations in the transcriptional landscape, which were initially narrow but massively amplified in breadth and magnitude over time. At 72 hpi, we detected dysregulation of diverse gene programs, concurrently promoting both virus clearance and virus persistence. On the one hand, baseline expression of IRF1 combined with infection-induced upregulation of IFN-mediated effector genes suppresses virus propagation. On the other, we detect transcriptional signatures of host translational inhibition, which likely reduces processing of IFN-regulated gene transcripts and facilitates virus survival. Together, our data provide important insights into constitutive and virus-induced transcriptional programs in PHHs, and identifies simultaneous antagonistic dysregulation of pro-and anti-viral programs which may facilitate host tolerance and promote viral persistence.


title: Transcriptional and translational responsiveness of the Neisseria gonorrhoeae type IV secretion system to conditions of host infections

abstract: The type IV secretion system of Neisseria gonorrhoeae translocates single-stranded DNA into the extracellular space, facilitating horizontal gene transfer and initiating biofilm formation. Expression of this system has been observed to be low under laboratory conditions, and multiple levels of regulation have been identified. We used a translational fusion of lacZ to traD, the gene for the type IV secretion system coupling protein, to screen for increased type IV secretion system expression. We identified several physiologically relevant conditions, including surface adherence, decreased manganese or iron, and increased zinc or copper, which increase gonococcal type IV secretion system protein levels through transcriptional and/or translational mechanisms. These metal treatments are reminiscent of the conditions in the macrophage phagosome. The ferric uptake regulator, Fur, was found to repress traD transcript levels, but to also have a second role, acting to allow TraD protein levels to increase only in the absence of iron. To better understand type IV secretion system regulation during infection, we examined transcriptomic data from active urethral infection samples from five men. These data demonstrated differential expression of 20 of 21 type IV secretion system genes during infection, indicating upregulation of genes necessary for DNA secretion during host infection.

category: microbiology


title: Dynamic association of IκBα to chromatin is regulated by acetylation and cleavage of histone H4

abstract:
I{kappa}Bs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for I{kappa}B homologues have been described including association to chromatin and transcriptional regulatioin. Phosphorylated and SUMOylated I{kappa}B (pS-I{kappa}B) binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unstudied.

We here show that serine 32-36 phosphorylation of I{kappa}B favors its binding with nucleosomes and demonstrated that p-I{kappa}B association to H4 is favored by acetylation at specific H4 lysine residues. N-terminal tail of H4 is lost during intestinal cell differentiation by proteolytic cleavage at residues 17-19 imposed ny trypsin or chymotrypsin, which interferes p-I{kappa}B binding. Paradoxically, inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-I{kappa}B chromatin binding and impaired goblet cell differentiation, comparable to I{kappa}B deletion. Together our results indicate that dynamic binding of I{kappa}B to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-I{kappa}B at specific stem cell compartments.

category: molecular biology


title: The cohesin regulator Stag1 promotes cell plasticity through heterochromatin regulation.

abstract: Fundamental biological processes such as embryo development and stem cell control rely on cellular plasticity. We present a role for the cohesin regulator, Stag1 in cellular plasticity control via heterochromatin regulation. Stag1 localises to heterochromatin domains and repetitive sequences in embryonic stem (ES) cells and contains intrinsically disordered regions in its divergent terminal ends which promote heterochromatin compaction. ES cells express Stag1 protein isoforms lacking the disordered ends and fluctuations in isoform abundance skews the cell state continuum towards increased differentiation or reprogramming. The role for Stag1 in heterochromatin condensates and nucleolar function is dependent on its unique N-terminus. Stag1N{Delta} ESCs have decompacted chromatin and reprogram towards totipotency, exhibiting MERVL derepression, reduced nucleolar transcription and decreased translation. Our results move beyond protein-coding gene regulation via chromatin loops into a new role for Stag1 in heterochromatin and nucleolar function and offer fresh perspectives on its contribution to cell identity and disease.

category: cell biology


title: Differentially accessible Cdc4 phospho-degrons regulate Ctf19CCAN kinetochore subunit stability in mitosis

abstract: Kinetochores are multi-subunit protein assemblies that link chromosomes to microtubules of the mitotic and meiotic spindle. How effective, yet strictly centromere-dependent kinetochore assembly is coupled to cell cycle progression is incompletely understood. Here, by combining comprehensive phosphorylation analysis of native Ctf19CCAN subunits with biochemical and functional assays in the model system budding yeast, we demonstrate that Cdk1 phosphorylation activates phospho-degrons on the essential subunit Ame1CENP-U which are recognized by the E3 ubiquitin ligase complex SCF-Cdc4. Gradual phosphorylation of degron motifs culminates in M-Phase and targets the protein for degradation. Binding of the Mtw1 complex shields the proximal phospho-degron, protecting kinetochore-bound Ame1 from the degradation machinery. Artificially increasing degron strength partially suppresses the temperature-sensitivity of a cdc4 mutant, while overexpression of Ame1-Okp1 is toxic to cells, demonstrating the physiological importance of this mechanism. We propose that phospho-regulated clearance of excess CCAN subunits protects against ectopic kinetochore assembly and contributes to mitotic checkpoint silencing. Our results suggest a novel strategy for how phospho-degrons can be used to regulate the assembly of multi-subunit complexes.


title: Akkermansia muciniphila secretome promotes α-synuclein aggregation in enteroendocrine cells.

abstract:
The notion that the gut microbiota play a role in neurodevelopment, behavior and outcome of neurodegenerative disorders is recently taking place. A number of studies have consistently reported a greater abundance of Akkermansia muciniphila in Parkinsons disease (PD) fecal samples. Nevertheless, a functional link between A.muciniphila and sporadic PD remained unexplored. Here, we investigated whether A.muciniphila secretome could initiate the misfolding process of -synuclein (Syn) in enteroendocrine cells (EECs), which are part of the gut epithelium and possess many neuron-like properties. We found that A.muciniphila secretome is directly modulated by mucin, induces intracellular calcium (Ca2+) release, and causes increased mitochondrial Ca2+ uptake in EECs, which in turn leads to production of reactive oxygen species (ROS) and Syn aggregation. However, these events were efficiently inhibited once we buffered mitochondrial Ca2+. Thereby, these molecular insights provided here offer evidence that bacterial secretome is capable of inducing Syn aggregation in enteroendocrine cells.

SYNOPSIS FIGURE DESCRIPTIONThe secretome isolated from the commensal gut bacterium Akkermansia muciniphila triggers intracellular Ca2+ signaling in enteroendocrine cells, leading to increased mitochondrial Ca2+ uptake. Mitochondrial Ca2+ overload leads to ROS generation culminating with Syn phosphorylation and aggregation (left panel). All these events were inhibited once mitochondrial Ca2+ is buffered (right panel).

O_LIGram-negative gut bacterium Akkermansia muciniphila is consistently found more abundant in Parkinsons disease patients.
C_LIO_LIAkkermansia muciniphila protein secretome composition is directly modulated by mucin and induces an IP3-independent endoplasmic reticulum (ER)-calcium release in enteroendocrine cells.
C_LIO_LIThis Ca2+ release is triggered by direct activation of Ryanodine Receptors leading to increased mitochondrial Ca2+ uptake.
C_LIO_LIMitochondrial Ca2+ overload leads to ROS generation culminating with Syn aggregation.
C_LIO_LIBuffering mitochondrial Ca2+ efficiently inhibits A.muciniphila-induced Syn aggregation in enteroendocrine cells.
C_LI


title: Sensitive and reproducible cell-free methylome quantification with synthetic spike-in controls

abstract:
BackgroundCell-free methylated DNA immunoprecipitation-sequencing (cfMeDIP-seq) identifies genomic regions with DNA methylation, using a protocol adapted to work with low-input DNA samples and with cell-free DNA (cfDNA). This method allows for DNA methylation profiling of circulating tumour DNA in cancer patients blood samples. Such epigenetic profiling of circulating tumour DNA provides information about in which tissues tumour DNA originates, a key requirement of any test for early cancer detection. In addition, DNA methylation signatures provide prognostic information and can detect relapse. For robust quantitative comparisons between samples, immunoprecipitation enrichment methods like cfMeDIP-seq require normalization against common reference controls.

MethodsTo provide a simple and inexpensive reference for quantitative normalization, we developed a set of synthetic spike-in DNA controls for cfMeDIP-seq. These controls account for technical variation in enrichment efficiency due to biophysical properties of DNA fragments. Specifically, we designed 54 DNA fragments with combinations of methylation status (methylated and unmethylated), fragment length (80 bp, 160 bp, 320 bp), G+C content (35%, 50%, 65%), and fraction of CpG dinucleotides within the fragment (1/80 bp, 1/40 bp, 1/20 bp). We ensured that the spike-in synthetic DNA sequences do not align to the human genome. We integrated unique molecular indices (UMIs) into cfMeDIP-seq to control for differential amplification after enrichment. To assess enrichment bias according to distinct biophysical properties, we conducted cfMeDIP-seq solely on spike-in DNA fragments. To optimize the amount of spike-in DNA required, we added varying quantities of spike-in control DNA to sheared HCT116 colon cancer genomic DNA prior to cfMeDIP-seq. To assess batch effects, three separate labs conducted cfMeDIP-seq on peripheral blood plasma samples from acute myeloid leukemia (AML) patients.

ResultsWe show that cfMeDIP-seq enriches for highly methylated regions, capturing [≥] 97% of methylated spike-in control fragments with [≤] 3% non-specific binding and preference for both high G+C content fragments and fragments with more CpGs. The use of 0.01 ng of spike-in control DNA in each sample provided sufficient sequencing reads to adjust for variance due to fragment length, G+C content, and CpG fraction. Using the known amount of each spiked-in fragment, we created a generalized linear model that absolutely quantifies molar amount from read counts across the genome, while adjusting for fragment length, G+C content, and CpG fraction. Employing our spike-in controls greatly mitigates batch effects, reducing batch-associated variance to [≤] 1% of the total variance within the data.

DiscussionIncorporation of spike-in controls enables absolute quantification of methylated cfDNA generated from methylated DNA immunoprecipitation-sequencing (MeDIP-seq) experiments. It mitigates batch effects and corrects for biases in enrichment due to known biophysical properties of DNA fragments and other technical biases. We created an R package, spiky, to convert read counts to picomoles of DNA fragments, while adjusting for fragment properties that affect enrichment. The spiky package is available on Bioconductor (https://bioconductor.org/packages/spiky) and GitHub (https://github.com/trichelab/spiky).

Contactmichael.hoffman@utoronto.ca

category: genomics


title: Environmental enrichment mitigates stroke-induced change in sharp-wave associated ripple characteristics

abstract: Cognitive and memory impairments are common sequelae after stroke, yet how middle cerebral artery (MCA) stroke chronically affects the neural activity of the hippocampus, a brain region critical for memory but remote from the stroke epicenter, is poorly understood. Environmental enrichment (EE) improves cognition following stroke; however, the electrophysiology that underlies this behavioral intervention is still elusive. We recorded local field potentials simultaneously from sensorimotor cortex and hippocampus in rats following MCA occlusion and subsequent EE treatment. We found that MCA stroke significantly impacted the electrophysiology in the hippocampus, in particular it disrupted characteristics of sharp-wave associated ripples (SPW-Rs) which are known correlates of memory and cognition. Importantly, we show that EE mitigates stroke-induced changes to SPW-R characteristics. These results begin to uncover the complex interaction between cognitive deficit following stroke and EE treatment, providing a testbed to assess different strategies for therapeutics following stroke.


title: Individual variability of neural computations in the primate retina

abstract: Variation in the neural code contributes to making each individual unique. We probed neural code variation using [~]100 neural population recordings from major ganglion cell types in the macaque retina, combined with an interpretable computational representation of individual variability using machine learning. This representation captured individual variation and covariation in properties such as nonlinearity, temporal dynamics, and spatial receptive field size, while preserving invariances, such as asymmetries between ON and OFF cells. The covariation of response properties in different cell types was associated with the proximity of lamination of their synaptic inputs. Surprisingly, male retinas exhibited higher firing rates and faster temporal integration than female retinas. Exploiting data from previously recorded macaque retinas enabled efficient characterization of a new macaque retina, and of a human retina. Simulations indicated that combining a vast dataset of healthy macaque recordings with behavioral feedback could be used to identify the neural code and thus improve retinal implants for vision restoration.


title: Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of secretory proteins

abstract: Neuronal abundance and thickness of each cortical layer is specific to each area, but how this fundamental feature arises during development remains poorly understood. While some of area-specific features are controlled by intrinsic cues such as morphogens and transcription factors, the exact influence and mechanisms of action by extrinsic cues, in particular the thalamic axons, have not been fully established. Here we identify a thalamus-derived factor, VGF, which is indispensable for thalamocortical axons to maintain the proper amount of layer 4 neurons in the mouse sensory cortices. This process is prerequisite for further maturation of the primary somatosensory area, such as barrel field formation instructed by a neuronal activity-dependent mechanism. Our results also provide an insight into regionalization of brain in that highly site-specific axon projection anterogradely confers further regional complexity upon the target field through locally secreting signaling molecules from axon terminals.


title: Unravelling processes between phenotypic plasticity and population dynamics in migratory birds

abstract:
O_LIPopulations can rapidly respond to environmental change via adaptive phenotypic plasticity, which can also modify interactions between individuals and their environment, affecting population dynamics. Bird migration is a highly plastic resource-tracking strategy in seasonal environments. However, the link between the population dynamics of migratory birds and migration strategy plasticity is not well understood.
C_LIO_LIThe quality of staging habitats affects individuals migration timing and energy budgets in the course of migration, and can consequently affect individuals breeding and overwintering performance, and impact population dynamics. Given staging habitats being lost in many parts of the world, our goal is to investigate responses of individual migration strategies and population dynamics in the face of loss of staging habitat, and to identify the key processes connecting them.
C_LIO_LIWe started by constructed and analysed a general full-annual-cycle individual-based model with a stylized migratory population to generate hypotheses on how changes in the size of staging habitat might drive changes in individual stopover duration and population dynamics, and to identify the key processes connecting them. Next, through the interrogation of census data, we tested these hypotheses by analysing population trends and stopover duration of migratory waterbirds experiencing loss of staging habitat.
C_LIO_LIWe found empirical support for our modelling-identified hypotheses: the loss of staging habitat generates plasticity in migration strategies, with individuals remaining on the staging habitat for longer to obtain food due to a reduction in per capita food availability. The subsequent increasing population density on the staging habitat has knock on effects on population dynamics in the breeding and overwintering stage.
C_LIO_LIOur results demonstrate how environmental change that impacts one energetically costly life history stage in migratory birds can have population dynamics impacts across the entire annual cycle via phenotypic plasticity.
C_LI

category: ecology


title: What are housekeeping genes?

abstract: The concept of "housekeeping genes" has been used for four decades but remains loosely defined. Housekeeping genes are commonly described as "essential for cellular existence regardless of their specific function in the tissue or organism", and "stably expressed irrespective of tissue type, developmental stage, cell cycle state, or external signal". However, experimental support for the tenet that gene essentiality is linked to stable expression across cell types, conditions, and organisms has been limited. Here we use genome-scale functional genomic screens, bulk and single-cell sequencing technologies to test this link and optimize a quantitative and experimentally validated definition of housekeeping gene. Using the optimized definition, we identify, characterize, and provide as resources, housekeeping gene lists extracted from several human datasets, and 12 other animal species that include primates, chicken, and C. elegans. We find that stably expressed genes are not necessarily essential, and that the individual genes that are essential and stably expressed can considerably differ across organisms; yet the pathways enriched among these genes are conserved. Further, the level of conservation of housekeeping genes across the analyzed organisms captures their taxonomic groups, showing evolutionary relevance for our definition. Therefore, we here present a quantitative and experimentally validated definition of housekeeping genes that can contribute to better understanding of their unique biological and evolutionary characteristics.

category: evolutionary biology


title: Effects of kinship correction on inflation of genetic interaction statistics in commonly used mouse populations

abstract: It is well understood that variation in relatedness among individuals, or kinship, can lead to false genetic associations. Multiple methods have been developed to adjust for kinship while maintaining power to detect true associations. However, relatively unstudied, are the effects of kinship on genetic interaction test statistics. Here we performed a survey of kinship effects on studies of six commonly used mouse populations. We measured inflation of main effect test statistics, genetic interaction test statistics, and interaction test statistics reparametrized by the Combined Analysis of Pleiotropy and Epistasis (CAPE). We also performed linear mixed model (LMM) kinship corrections using two types of kinship matrix: an overall kinship matrix calculated from the full set of genotyped markers, and a reduced kinship matrix, which left out markers on the chromosome(s) being tested. We found that test statistic inflation varied across populations and was driven largely by linkage disequilibrium. In contrast, there was no observable inflation in the genetic interaction test statistics. CAPE statistics were inflated at a level in between that of the main effects and the interaction effects. The overall kinship matrix overcorrected the inflation of main effect statistics relative to the reduced kinship matrix. The two types of kinship matrices had similar effects on the interaction statistics and CAPE statistics, although the overall kinship matrix trended toward a more severe correction. In conclusion, we recommend using a LMM kinship correction for both main effects and genetic interactions and further recommend that the kinship matrix be calculated from a reduced set of markers in which the chromosomes being tested are omitted from the calculation. This is particularly important in populations with substantial population structure, such as recombinant inbred lines in which genomic replicates are used.

category: genetics


title: Fast Numerical Optimization for Genome Sequencing Data in Population Biobanks

abstract: We develop two efficient solvers for optimization problems arising from large-scale regularized regressions on millions of genetic variants sequenced from hundreds of thousands of individuals. These genetic variants are encoded by the values in the set {0, 1, 2, NA}. We take advantage of this fact and use two bits to represent each entry in a genetic matrix, which reduces memory requirement by a factor of 32 compared to a double precision floating point representation. Using this representation, we implemented an iteratively reweighted least square algorithm to solve Lasso regressions on genetic matrices, which we name snpnet-2.0. When the dataset contains many rare variants, the predictors can be encoded in a sparse matrix. We utilize the sparsity in the predictor matrix to further reduce memory requirement and computational speed. Our sparse genetic matrix implementation uses both the compact 2-bit representation and a simplified version of compressed sparse block format so that matrix-vector multiplications can be effectively parallelized on multiple CPU cores. To demonstrate the effectiveness of this representation, we implement an accelerated proximal gradient method to solve group Lasso on these sparse genetic matrices. This solver is named sparse-snpnet, and will also be included as part of snpnet R package. Our implementation is able to solve group Lasso problems on sparse genetic matrices with more than 1, 000, 000 columns and almost 100, 000 rows within 10 minutes and using less than 32GB of memory.

category: bioinformatics


title: Paths to Oblivion: Common Neural Mechanisms of Anaesthesia and Disorders of Consciousness

abstract: The human brain generates a rich repertoire of spatiotemporal dynamics during normal wakefulness, supporting a wide variety of conscious experiences and cognitive functions. However, neural dynamics are reconfigured, in comparable ways, when consciousness is lost either due to anaesthesia or disorders of consciousness (DOC). Here, leveraging a neurobiologically realistic whole-brain computational model informed by functional MRI, diffusion MRI, and PET, we sought to identify the neurobiological mechanisms that explain the common reconfiguration of neural dynamics observed both for transient pharmacological intervention and chronic neuroanatomical injury. Our results show that, by incorporating local inhibitory action through a PET-based GABA receptor density map, our model can reproduce the brain dynamics of subjects undergoing propofol anaesthesia, and that this effect depends specifically on the spatial distribution of GABA receptors across cortical regions. Additionally, using a structural connectome obtained from DOC patients, we demonstrate how the dynamics that characterise loss of consciousness can emerge from changes in neuroanatomical connectivity. Crucially, we find that each of these two interventions generalises across datasets: a model with increased GABA-mediated inhibition can reproduce the dynamics of DOC patients brains, and a model with a DOC connectome is also compatible with brain dynamics observed during propofol anaesthesia. These results demonstrate how increased inhibition and connectome randomisation represent different neurobiological paths towards the characteristic dynamics of the unconscious brain. Overall, the present findings begin to disentangle the neurobiological mechanisms by which highly dissimilar perturbations of the brains neurodynamics can lead to unconsciousness.


title: Stress diminishes outcome but enhances response representations during instrumental learning

abstract: Stress may shift behavioural control from a goal-directed system that encodes action-outcome relationships to a habit system that learns stimulus-response associations. Although this shift to habits is highly relevant for stress-related psychopathologies, limitations of existing behavioural paradigms hindered previous research to answer the fundamental question of whether the stress-induced bias to habits is due to impaired goal-directed or enhanced habitual processing (or both). Here, we leveraged EEG-based multivariate pattern analysis to decode neural outcome representations, crucial for goal-directed control, and response representations, essential for habitual responding, during instrumental learning. We show that stress reduces outcome representations but enhances response representations, both of which were directly associated with a behavioural index of habitual responding. Further, changes in outcome and response representations were uncorrelated, suggesting that these may reflect distinct processes. Our findings indicate that habit behaviour under stress is the result of both enhanced habitual and diminished goal-directed processing.


title: Typical somatomotor physiology of the hand is preserved in a patient with an amputated arm

abstract:
Electrophysiological signals in the human motor system may change in different ways after deafferentation, with some studies emphasizing reorganization while others propose retained physiology. Understanding whether motor electrophysiology is retained over longer periods of time can be invaluable for patients with paralysis (e.g. ALS or brainstem stroke) when signals from sensorimotor areas may be used for communication or control over neural prosthetic devices. In addition, a maintained electrophysiology can potentially benefit the treatment of phantom limb pains through prolonged use of these signals in a brain-machine interface (BCI).

Here, we were presented with the unique opportunity to investigate the physiology of the sensorimotor cortex in a patient with an amputated arm using electrocorticographic (ECoG) measurements. While implanted with an ECoG grid for clinical evaluation of electrical stimulation for phantom limb pain, the patient performed attempted finger movements with the contralateral (lost) hand and executed finger movements with the ipsilateral (healthy) hand.

The electrophysiology of the sensorimotor cortex contralateral to the amputated hand remained very similar to that of hand movement in healthy people, with a spatially focused increase of high-frequency band (65-175Hz; HFB) power over the hand region and a distributed decrease in low-frequency band (15-28Hz; LFB) power. The representation of the three different fingers (thumb, index and little) remained intact and HFB patterns could be decoded using support vector learning at single-trial classification accuracies of >90%, based on the first 1-3s of the HFB response. These results demonstrate that hand representations are largely retained in the motor cortex. The intact physiological response of the amputated hand, the high distinguishability of the fingers and fast temporal peak are encouraging for neural prosthetic devices that target the sensorimotor cortex.


title: The genetic code is not optimized for resource conservation

abstract: Shenhav and Zeevi conclude in a recent article (Science 370:683-687) that the universal genetic code (UGC) is optimized for resource conservation because mutations are less likely to increase proteomic nitrogen and carbon uses under the UGC than under random genetic codes (RGCs). Their finding results from miscalculating mutational effects and benchmarking against biased RGCs. Our reanalysis refutes their conclusion.


title: Changes of mind after movement onset: a motor-state dependent decision-making process

abstract:
Decision-making is traditionally described as a cognitive process of deliberation followed by commitment to an action choice, preceding the planning and execution of the chosen action. However, this is challenged by recent data suggesting that multiple options are specified simultaneously and compete in pre-motor cortical areas for selection and execution. Previous studies focused on the competition during planning, and leave unaddressed the dynamics of decisions during movement. Does deliberation extend into the execution phase? Are non-selected options still considered? Here we studied a decision-making task in which human participants were instructed to select a reaching path trajectory from an origin to a rectangular target, where reward was distributed non-uniformly at the target. Critically, we applied mechanical perturbations to the arm during movement to study under which conditions such perturbations produce changes of mind. Our results show that participants initially selected the direction of movement towards the highest reward region, and changed their mind most frequently when the two choices offered the same reward, showing that deliberation continues and follows cost-benefit considerations during movement. Furthermore, changes of mind were dependent upon the intensity of the perturbation and the current state of the motor system, including velocity and distance to targets. Although reward remains most relevant, our results indicate that the state of the motor system when the perturbation occurs is a crucial determinant of changes of mind. This indicates that the neural circuits that assess reward and those that control movements operate synergistically rather than sequentially during decision-making.

Significance StatementOur study provides supporting evidence for the notion that deliberation during decision-making continues after movement onset because unselected potential actions are not completely suppressed or discarded. From a neurophysiological perspective, our findings suggest that the competition between actions is not over before action initiation, possibly because the initially unselected neuronal population retains some sub-threshold activation, which enables them to take control afterwards. Furthermore, our findings also suggest that decision-makers have a variable degree of commitment to their initial choice, which depends on the relative reward of the offers and on the state of the motor system. The commitment is stronger if the initially selected plan leads to higher rewards, and changes of mind occur more frequently if the velocity and relative position of the end-point are within specific ranges.


title: Primary motor cortex activity traces distinct trajectories of population dynamics during spontaneous facial motor sequences in mice

abstract:
We explore the link between on-going neuronal activity at primary motor cortex (M1) and face movement in awake mice. By combining custom-made behavioral sequencing analysis and fast volumetric Ca2+-imaging, we simultaneously tracked M1 population activity during many different facial motor sequences. We show that a facial area of M1 displays distinct trajectories of neuronal population dynamics across different spontaneous facial motor sequences, suggesting an underlying population dynamics code.

Significance statementHow our brain controls a seemingly limitless diversity of body movements remains largely unknown. Recent research brings new light into this subject by showing that neuronal populations at the primary motor cortex display different dynamics during forelimb reaching movements versus grasping, which suggests that different motor sequences could be associated with distinct motor cortex population dynamics. To explore this possibility, we designed an experimental paradigm for simultaneously tracking the activity of neuronal populations in motor cortex across many different motor sequences. Our results support the concept that distinct population dynamics encode different motor sequences, bringing new insight into the role of motor cortex in sculpting behavior while opening new avenues for future research.


title: Effect of aging-related network changes on unimanual sensorimotor learning - a simultaneous EEG-fMRI study

abstract:
Sensorimotor coordination requires orchestrated network activity mediated by inter- and intra-hemispheric, excitatory and inhibitory neuronal interactions. Aging-related structural changes may alter these interactions. Disbalancing strength and timing of excitation and inhibition may limit motor performance. This is particularly true during motor coordination tasks that have to be learned through practice. To investigate this, we simultaneously acquired electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) in two groups of healthy adults (young N=13: 20-25y and elderly N=14: 59-70y), while they were practicing a unimanual motor task. Both groups learned the task during brain scanning, which was confirmed by a 24h follow-up retention test. On average, quality of performance of older participants stayed significantly below that of the younger ones. Accompanying decreases in motor-event-related EEG-source beta band power ({beta}, 15-30 Hz) were lateralized in both groups towards the contralateral side, albeit more so in younger participants. In the latter, the mean {beta}-power during motor learning in bilateral pre-motor cortex (PM1) was significantly higher than in the older group. Combined EEG/fMRI analysis revealed positive correlations between fMRI signals and source-reconstructed {beta}-amplitude time courses in contralateral and ipsilateral M1, and negative correlations in bilateral PM1 for both groups. The {beta}-positive fMRI response in bilateral M1 might be explained by an increased cross-talk between hemispheres during periods of pronounced {beta}-activity. During learning, the Rolandic {beta}-power relative to rest was higher in bilateral PM1 in younger participants, suggesting less task-related beta band desynchronization in this (better performing) group. We also found positive correlations between Rolandic {beta}-amplitude and fMRI-BOLD in bilateral M1 and negative correlations bilateral in PM1. This indicates that increased {beta}-amplitudes are associated with increased M1 "activity" (positive BOLD response) and decreased PM1 "activity" (negative BOLD response). Our results point at decreased pre-motor inhibitory inputs to M1 as possible source for increased interhemispheric crosstalk and an aging-related decline in motor performance.

HighlightsO_LISensorimotor coordination performance decreases with increasing age.
C_LIO_LIDuring motor learning the {beta}-power in pre-motor areas is reduced with age.
C_LIO_LIEEG/fMRI points at less effective inhibitory inputs from PM1 to ipsilateral M1 in older adults.
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title: The relationship between dynamic functional network connectivity and spatial orientation in healthy young adults

abstract: Spatial orientation is essential to interacting with a physical environment, and better understanding it could contribute to a better understanding of a variety of diseases and disorders that are characterized by deficits in spatial orientation. Many previous studies have focused on the relationship between spatial orientation and individual brain regions, though in recent years studies have begun to examine spatial orientation from a network perspective. This study analyzes dynamic functional network connectivity (dFNC) values extracted from over 800 resting-state fMRI recordings of healthy young adults (age 22-37 years) and applies unsupervised machine learning methods to identify neural brain states that occur across all subjects. We estimated the occupancy rate (OCR) for each subject, which was proportional to the amount of time that they spent in each state, and investigated the link between the OCR and spatial orientation and the state-specific FNC values and spatial orientation controlling for age and sex. Our findings showed that the amount of time subjects spent in a state characterized by increased connectivity within and between visual, auditory, and sensorimotor networks and within the default mode network while at rest corresponded to their performance on tests of spatial orientation. We also found that increased sensorimotor network connectivity in two of the identified states negatively correlated with decreased spatial orientation, further highlighting the relationship between the sensorimotor network and spatial orientation. This study provides insight into how the temporal properties of the functional brain connectivity within and between key brain networks may influence spatial orientation.


title: Separate functional subnetworks of excitatory neurons show preference to periodic and random sound structures

abstract:
Auditory cortex (ACX) neurons are sensitive to spectro-temporal sound patterns and violations in patterns induced by rare stimuli embedded within streams of sounds. We investigate the auditory cortical representation of repeated presentations of sequences of sounds with standard stimuli (common) with an embedded deviant (rare) stimulus in two conditions - Periodic (Fixed deviant position) or Random (Random deviant position), using extracellular single-unit and 2-photon Ca+2 imaging recordings in Layer 2/3 neurons of the mouse ACX. In the population average, responses increased over repetitions in the Random-condition and were suppressed or did not change in the Periodic-condition, showing irregularity preference. A subset of neurons also showed the opposite behavior, indicating regularity preference. Pairwise noise correlations were higher in Random-condition over Periodic-condition, suggesting the role of recurrent connections. 2-photon Ca+2 imaging of excitatory (EX) and parvalbumin-positive (PV) and somatostatin-positive (SOM) inhibitory neurons, showed different categories of adaptation or change in response over repetitions (categorized by the sign of the slope of change) as observed with single units. However, the examination of functional connectivity between pairs of neurons of different categories showed that EX-PV connections behaved opposite to the EX-EX and EX-SOM pairs that show more functional connections outside category in Random-condition than Periodic-condition. Finally considering Regularity preference, Irregularity preference and no preference categories, showed that EX-EX and EX-SOM connections to be in largely separate functional subnetworks with the different preferences, while EX-PV connections were more spread. Thus separate subnetworks could underly the coding of periodic and random sound sequences.

Significance StatementStudying how the ACX neurons respond to streams of sound sequences help us understand the importance of changes in dynamic acoustic noisy scenes around us. Humans and animals are sensitive to regularity and its violations in sound sequences. Psychophysical tasks in humans show that auditory brain differentially responds to periodic and random structures, independent of the listeners attentional states. Here we show that mouse ACX L2/3 neurons detect a change and respond differentially to changing patterns over long-time scales. The differential functional connectivity profile obtained in response to two different sound contexts, suggest the stronger role of recurrent connections in the auditory cortical network. Furthermore, the excitatory-inhibitory neuronal interactions can contribute to detecting the changing sound patterns.


title: Synthetic dysmobility screen unveils an integrated STK40-YAP-MAPK system driving cell migration

abstract:
Integrating signals is essential for cell survival, leading to the concept of synthetic lethality. However, how signaling is integrated to control cell migration remains unclear. By conducting a "two-hit" screen, we revealed the synergistic reduction of cell migration when serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK) were simultaneously suppressed. Single-cell analyses showed that STK40 knockdown reduced cell motility and coordination by strengthening focal adhesion (FA) complexes. Furthermore, STK40 knockdown reduced translocation of yes-associated protein (YAP) into the nucleus, while MAPK inhibition further weakened YAP activities in the nucleus to disturb FA remodeling. Altogether, we unveiled an integrated STK40-YAP-MAPK system regulating cell migration, and introduced "synthetic dysmobility" as a novel strategy to collaboratively control cell migration.

One Sentence SummaryBlocking collaborative pathways within the integrated signaling network synergistically disrupts the migration of cells.


title: How to reach a higher selection plateau with optimal contribution selection and compensatory mating?

abstract: In breeding, Optimal Contribution Selection (OCS) is one of the most effective strategies to balance short- and long-term genetic responses, by maximizing genetic gain and minimizing global coancestry. Considering genetic diversity in the selection dynamic - through coancestry - is undoubtedly the reason for the success of OCS, as it avoids initial loss of favorable alleles. Originally formulated with the pedigree relationship matrix, global coancestry can nowadays be assessed with one of the possible formulations of the realized genomic relationship matrix. Most formulations were optimized for genomic evaluation, but few for the management of coancestry. We introduce here an alternative formulation specifically developed for Genomic OCS (GOCS), intended to better control heterozygous loci, and thus better account for Mendelian sampling. We simulated a multi-generation breeding program with mate allocation and under GOCS for twenty generations, solved with quadratic programming. With the case study of Populus nigra, we have shown that, although the dynamic was mainly determined by the trade-off between genetic gain and genetic diversity, better formulations of the genomic relationship matrix, especially those fostering individuals carrying multiple heterozygous loci, can lead to better short-term genetic gain and a higher selection plateau.


title: How to achieve a higher selection plateau in forest tree breeding? Fostering Heterozygote x Homozygote relationships in Optimal Contribution Selection in the case study of Populus nigra


title: Copper signaling promotes proteostasis and animal development via allosteric activation of ubiquitin E2D conjugases

abstract:
Nutrient copper supply is critical for cell growth and differentiation, and its disturbance is associated with major pathologies including cancer and neurodegeneration. Although increasing copper bioavailability in late Precambrian facilitated emergence of novel cuproproteins, their intricate regulation by this essential trace element remains largely cryptic. We found that subtle rises in cellular copper strikingly increase polyubiquitination and accelerate protein degradation within 30 minutes in numerous mammalian cell lines. We track this surprising observation to allostery induced in the UBE2D ubiquitin conjugase clade through a conserved CXXXC sub-femtomolar-affinity Cu+ binding motif. Thus, physiologic fluctuation in cytoplasmic Cu+ is coupled to the prompt degradation of UBE2D protein targets, including p53. In Drosophila harboring a larval-lethal knockdown of the nearly identical fly orthologue UbcD1, complementation with human UBE2D2 restored near-normal development, but mutation of its CXXXC Cu+ binding motif profoundly disrupted organogenesis. Nutrient Cu+ emerges as a trophic allosteric modulator of UBE2D activity through a structural motif whose evolution coincides with animal multicellularity.

One Sentence SummaryModulation of nutrient copper impacts protein turnover and animal morphogenesis through conserved allostery of ubiquitin E2D conjugases.

HilightsO_LINutrient copper supply is critical for cell growth and differentiation
C_LIO_LIThe E2D clade of ubiquitin conjugases contains a sub-femtomolar-affinity Cu+ binding motif
C_LIO_LIAllosteric activation by Cu+ markedly accelerates protein polyubiquitination
C_LIO_LIThis sensor couples physiologic fluctuations in cytoplasmic Cu+ with the degradation rate of E2D targets, including p53
C_LIO_LIThis metazoan signaling mechanism is critical for drosophila morphogenesis
C_LI

In BriefConserved allostery of ubiquitin E2D conjugases links nutrient copper signaling to protein degradation and animal morphogenesis.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/431211v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@17009fforg.highwire.dtl.DTLVardef@a07f8eorg.highwire.dtl.DTLVardef@11664c7org.highwire.dtl.DTLVardef@1327ab7_HPS_FORMAT_FIGEXP  M_FIG Graphical Abstract

C_FIG

category: biochemistry


title: Nutrient copper signaling promotes protein turnover by allosteric activation of ubiquitin E2D conjugases


title: Enzyme engineering and in vivo testing of a formate-reduction pathway

abstract: Formate is an attractive feedstock for sustainable microbial production of fuels and chemicals, but its potential is limited by the lack of efficient assimilation pathways. The reduction of formate to formaldehyde would allow efficient downstream assimilation, but no efficient enzymes are known for this transformation. To develop a 2-step formate-reduction pathway, we screened natural variants of acyl-CoA synthetase (ACS) and acylating aldehyde dehydrogenase (ACDH) for activity on one-carbon substrates and identified active and highly expressed homologs of both enzymes. We then performed directed evolution, increasing ACDH specific activity by 2.5-fold and ACS lysate activity by 5-fold. To test for in vivo activity of our pathway, we expressed it in a methylotroph which can natively assimilate formaldehyde. Although the enzymes were active in cell extracts, we could not detect formate assimilation into biomass, indicating that further improvement will be required for formatotrophy. Our work provides a foundation for further development of a versatile pathway for formate assimilation.

category: bioengineering


title: PandoraGAN: Generating antiviral peptides using Generative Adversarial Network

abstract:
MotivationThe continuous increase in pathogenic viruses and the intensive laboratory research for development of novel antiviral therapies often poses challenge in terms of cost and time efficient drug design. This accelerates research for alternate drug candidates and contributes to recent rise in research of antiviral peptides against many of the viruses. With limited information regarding these peptides and their activity, modifying the existing peptide backbone or developing a novel peptide is very time consuming and a tedious process. Advanced deep learning approaches such as generative adversarial networks (GAN) can be helpful for wet lab scientist to screen potential antiviral candidates of interest and expedite the initial stage of peptide drug development. To our knowledge this is the first ever use of GAN models for antiviral peptides across the viral spectrum.

ResultsIn this study, we develop PandoraGAN that utilizes GAN to design bio active antiviral peptides. Available antiviral peptide data was manually curated for preparing highly active peptides data set to include peptides with lower IC50 values. We further validated the generated sequences comparing the physico-chemical properties of generated antiviral peptides with manually curated highly active training data.

AvailabilityAntiviral sequences generated by PandoraGAN are available on PandoraGAN server. https://pandora-gan.herokuapp.com/. The code is available at https://gitlab.com/shraddha.surana/antiviral-peptide-predictions-using-gan

Contactparora@thoughtworks.com


title: Cuban history of CRF19 recombinant subtype of HIV-1

abstract:
CRF19 is a recombinant form of HIV-1 subtypes D, A1 and G, which was first sampled in Cuba in 1999, but was already present there in 1980s. CRF19 was reported almost uniquely in Cuba, where it accounts for ~25% of new HIV-positive patients and causes rapid progression to AIDS (~ 3 years).

We analyzed a large data set comprising ~ 350 pol and env sequences sampled in Cuba over the last 15 years and ~ 350 from Los Alamos database. This data set contained both CRF19 (~ 315), and A1, D and G sequences. We performed and combined analyses for the three A1, G and D regions, using fast maximum likelihood approaches, including: (1) phylogeny reconstruction, (2) spatio-temporal analysis of the virus spread, and ancestral character reconstruction for (3) transmission mode and (4) drug resistance mutations (DRMs). This allowed us to acquire new insights on the CRF19 origin and transmission patterns. We showed that CRF19 recombined between 1966 and 1977, most likely in Cuban community stationed in Congo region. We further investigated CRF19 spread on the Cuban province level, and discovered that the epidemic started in 1970s, most probably in Villa Clara, that it was at first carried by heterosexual transmissions, and then quickly spread in the 1980s within the "men having sex with men" (MSM) community, with multiple transmissions back to heterosexuals. The analysis of the transmission patterns of common DRMs showed mostly acquired drug resistance rather than transmitted one.

Our results show a very early introduction of CRF19 in Cuba, which could explain its local epidemiological success. Ignited by a major founder event, the epidemic then followed a similar pattern as other subtypes and CRFs in Cuba. The reason for the short time to AIDS remains to be understood and requires specific surveillance, in Cuba and elsewhere.

Author summaryCRF19 is a recombinant form of HIV-1, which causes rapid progression to AIDS (~ 3 years versus 5 - 10 years for other subtypes and CRFs). CRF19 is reported almost uniquely in Cuba, where it is highly prevalent (~ 25%) among newly detected HIV-1 patients. In this study, we found that CRF19 most likely recombined around the 1970s in the Cuban community that was stationed in Democratic Republic of the Congo and Angola at that time. It was introduced very early into the Cuban province of Villa Clara, from where it had several introductions to La Habana in the 1980s and then further spread to other Cuban provinces. The CRF19 epidemic most probably started with heterosexual transmissions, followed in the 1980s by multiple introductions into "men having sex with men" (MSM) community, followed by multiple transmissions back to heterosexuals (often females). The early introduction of CRF19 into Cuba most likely explains its success, not observed in other parts of the world. However, importantly, its rapid progression to AIDS makes it crucial to survey CRF19 sub-epidemics not only in Cuba, but also in other parts of the world having regular exchanges with Cuba.


title: Comparative Analysis of common alignment tools for single cell RNA sequencing

abstract:
With the rise of single cell RNA sequencing new bioinformatic tools became available to handle specific demands, such as quantifying unique molecular identifiers and correcting cell barcodes. Here, we analysed several datasets with the most common alignment tools for scRNA-seq data. We evaluated differences in the whitelisting, gene quantification, overall performance and potential variations in clustering or detection of differentially expressed genes.

We compared the tools Cell Ranger 5, STARsolo, Kallisto and Alevin on three published datasets for human and mouse, sequenced with different versions of the 10X sequencing protocol.

Striking differences have been observed in the overall runtime of the mappers. Besides that Kallisto and Alevin showed variances in the number of valid cells and detected genes per cell. Kallisto reported the highest number of cells, however, we observed an overrepresentation of cells with low gene content and unknown celtype. Conversely, Alevin rarely reported such low content cells.

Further variations were detected in the set of expressed genes. While STARsolo, Cell Ranger 5 and Alevin released similar gene sets, Kallisto detected additional genes from the Vmn and Olfr gene family, which are likely mapping artifacts. We also observed differences in the mitochondrial content of the resulting cells when comparing a prefiltered annotation set to the full annotation set that includes pseudogenes and other biotypes.

Overall, this study provides a detailed comparison of common scRNA-seq mappers and shows their specific properties on 10X Genomics data.

Key messagesO_LIMapping and gene quantifications are the most resource and time intensive steps during the analysis of scRNA-Seq data.
C_LIO_LIThe usage of alternative alignment tools reduces the time for analysing scRNA-Seq data.
C_LIO_LIDifferent mapping strategies influence key properties of scRNA-SEQ e.g. total cell counts or genes per cell
C_LIO_LIA better understanding of advantages and disadvantages for each mapping algorithm might improve analysis results.
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title: massiveGenesetsTest: a web tool to run enrichment analysis.

abstract:
MotivationInferring biological phenotypes from genomic data and sample clusters is a routinely task usually performed with Gene-Set Enrichment Analysis (GSEA), a tool that queries gene-profiles. In previous work, we scrutinized the approach based on Mann-Witney for Gene-Sets test. We highlighted the Mann-Witney test-statistics sensitivity to uncover weak signals and the drastic decreasing of time complexity.

ResultsWe propose web implementation of the Gene-sets testing based on the Mann-Witney procedure. The test-procedure has reshaped to decrease the computational expense, now about tens of seconds, even if a large collection of gene-sets queries the same gene-profile. The probabilistic interpretation of the normalized test-statistic has been investigated to a better understanding of the enrichment results. A novel prioritization method across enrichment-scores, gene-set dimensions, and p-values, draws attention to relevant gene-sets. The web tool provides both tabular and graphical enrichment results. A complimentary R function allows integrating the enrichment procedure in a complex context.

Contactpagnotta@unisannio.it

Supplementary informationExample data and guidelines are included in the supporting material of the web-site.


title: Dual MAPK and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death

abstract: The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically this effect was mediated through induction of the BH3-only pro-apoptotic proteins BIM and BMF. Importantly, we demonstrate that this treatment paradigm can be tailored to specific MAPK genotypes in CRCs, by combining HDACi with EGFR, KRASG12C or BRAFV600 inhibitors in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a novel ERK/MAPK genotype-targeted treatment paradigm for colorectal cancer.

category: cancer biology


title: The shifting of dominating roles between structural cells and immune cells are key regulators of human adipose tissues aging

abstract: Adipose tissue is a highly dynamic organ with complex cellular composition. Aging induces adipose tissue function decline and relocation of peripheral adipose tissue to abdominal compartment, which often associated with inflammation and metabolic disorders. Here we performed single-cell RNA sequencing to comprehensively and unbiasedly deconvolve how subcutaneous adipose tissue (SAT) responses to aging. We collected >25,000 stromal vascular cells from abdominal and gluteofemoral SAT of young and old donors. Analyses of transcription signatures and cell networks uncovered impaired adipogenesis and extracellular matrix synthesis capacity of APC, altered metabolic phenotype of immune cells and shifted tissue-dominating cells that can be used to predict adipose tissue aging. We also reported aging-associated distinct transcriptional program between gluteofemoral SAT and abdominal SAT. Our work thus reveals unanticipated cellular, immunological, metabolic and site-specific aspects of human adipose tissues aging process, providing valuable resource for better understanding of aging-associated adipose tissue dysfunction.


title: Can proteomics of snake venoms help drug discovery? A study on the venom of spectacled cobra (Naja naja) from the Western Ghats

abstract:
Venom proteome profiling of Naja naja from the Western Ghats region in Kerala was achieved through SDS-PAGE and RP-HPLC followed by Q-TOF LC-MS/MS analysis, incorporating PEAKS and Novor assisted de novo sequencing methodologies. A total of 115 proteins distributed across 17 different enzymatic and non-enzymatic venom protein families were identified through conventional and 39 peptides through homology-driven proteomics approaches. Fourteen peptides derived through de novo complements the Mascot data indicating the importance of homology-driven approaches in improving protein sequence information. Among the protein families identified, glutathione peroxidase and endonuclease were reported for the first time in the Indian cobra venom. Immunological cross-reactivity assessed using Indian polyvalent antivenoms suggested that VINS showed better EC50 (2.48 g/mL) value than that of PSAV (6.04 g/mL) and Virchow (6.03 g/mL) antivenoms. Western blotting experiments indicated that all the antivenoms elicited poor binding specificities, especially towards low molecular mass proteins. Second-generation antivenomics studies revealed that VINS antivenom was less efficient to detect many low molecular mass proteins such as three-finger toxins and Kunitz-type serine protease Inhibitors. Taken together, the present study enabled a large-scale characterization of the venom proteome of Naja naja from the Western Ghats and emphasized the need for developing more efficient antivenoms.

HighlightsO_LIProteomics of cobra venom resulted in the identification of 115 proteins representing 17 snake venom protein families.
C_LIO_LIDe novo approaches exclusively yielded 39 peptides harbouring multiple amino acid mutations.
C_LIO_LIGlutathione peroxidase and endonuclease were identified for the first time in Indian cobra venom.
C_LIO_LIIndian polyvalent antivenoms showed varying cross-reactivity towards cobra venom.
C_LIO_LIVINS antivenom was less efficient to detect many low molecular mass proteins (< 20 kDa).
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category: pharmacology and toxicology


title: Venomics and antivenomics of Indian spectacled cobra (Naja naja) from the Western Ghats


title: OBSTRUCTIVE APNEAS IN A MOUSE MODEL OF CONGENITAL CENTRAL HYPOVENTILATION SYNDROME

abstract:
RationaleCongenital Central Hypoventilation Syndrome (CCHS) is characterized by life-threatening sleep hypoventilation, and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome.

ObjectivesTo determine whether Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms.

MethodsApneas were classified as central, obstructive or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparation.

Measurements and Main ResultsThe median (interquartile range) of obstructive apnea frequency was 2.3/min (1.5-3.3) in Phox2b27Ala/+ pups versus 0.6/min (0.4-1.0) in wildtypes (P < 0.0001). Obstructive apnea duration was 2.7s (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7s (1.1-1.9) in wildtypes (P < 0.0001). Central and mixed apneas presented similar, significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared to wildtypes. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal with respect to phrenic activity onset (P < 0.001).

ConclusionsThe Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely due to hypoglossal dysgenesis. These results thus demand attention towards obstructive events in infants with CCHS.

category: physiology


title: High-pressure sprayed siRNA triggers influence the efficiency but not the profile of transitive silencing

abstract:
In plants, small interfering RNAs (siRNAs) are a quintessential class of RNA interference (RNAi)-inducing molecules produced by the endonucleolytic cleavage of double stranded RNAs (dsRNAs). In order to ensure robust RNAi, siRNAs are amplified through a positive feedback mechanism called transitivity. Transitivity relies on RNA-DIRECTED-RNA POLYMERASE 6 (RDR6)-mediated dsRNA synthesis using siRNA-targeted RNA. The newly synthesized dsRNA is subsequently cleaved into secondary siRNAs by DICER-LIKE (DCL) endonucleases. Just like primary siRNAs, secondary siRNAs are also loaded into ARGONAUTE proteins (AGOs) to form an RNA-induced silencing complex (RISC) reinforcing the cleavage of the target RNA. Although the molecular players underlying transitivity are well established, the mode of action of transitivity remains elusive. In this study, we investigated the influence of primary target sites on transgene silencing and transitivity using the GFP-expressing Nicotiana benthamiana 16C line, high pressure spraying protocol (HPSP), and synthetic 22-nucleotide (nt) long siRNAs. We found that the 22-nt siRNA targeting the 3 of the GFP transgene was less efficient in inducing silencing when compared to the siRNAs targeting the 5 and middle region of the GFP. Moreover, sRNA sequencing of locally silenced leaves showed that the amount but not the profile of secondary RNAs is shaped by the occupancy of the primary siRNA triggers on the target RNA. Our findings suggest that RDR6-mediated dsRNA synthesis is not primed by primary siRNAs and that dsRNA synthesis appears to be generally initiated at the 3 end of the target RNA.

SIGNIFICANCE STATEMENTThis work answers a long-standing question about the role of siRNA triggers in initiating transitive silencing. By using high-pressure spraying-mediated delivery of synthetic siRNAs, we provided experimental evidence that target position of 22-nt-long primary siRNAs influences the efficiency of RDR6-driven double stranded RNA (dsRNA) synthesis, but it does not change the profile of accumulating secondary siRNAs originating from processing of RDR6-produced dsRNA.

category: plant biology


title: High-pressure sprayed siRNAs trigger influence the efficiency but not the profile of transitive silencing


title: Accuracy of the pneumatic method for estimating xylem vulnerability to embolism in temperate diffuse-porous tree species

abstract:
O_LIThe increasing frequency of global change-type droughts has created a need for fast, accurate and widely applicable techniques for estimating xylem embolism resistance to improve forecasts of future forest changes.
C_LIO_LIWe used data from 12 diffuse-porous temperate tree species covering a wide range of xylem safety to compare the pneumatic and flow-centrifuge method for constructing xylem vulnerability curves. We evaluated the agreement between parameters estimated with both methods and the sensitivity of pneumatic measurements to the measurement duration.
C_LIO_LIThe agreement between xylem water potentials at 50% air discharged (PAD) estimated with the Pneumatron and 50% loss of hydraulic conductivity (PLC) estimated with the flow-centrifuge method was high (mean signed deviation: 0.12 MPa, Pearson correlation: 0.96 after 15 sec of gas extraction). However, the relation between the estimated slopes was more variable, resulting in lower agreement in xylem water potential at 12% and 88% PAD/PLC. All parameters were sensitive to the duration of the pneumatic measurement, with highest overall agreement between methods after 16 sec.
C_LIO_LIWe conclude that, if applied correctly, the pneumatic method enables fast and inexpensive estimations of embolism resistance for a wide range of temperate, diffuse-porous species, which makes it attractive for predicting plant performance under climate change.
C_LI


title: A practical modification to a resting state fMRI protocol for improved characterization of cerebrovascular function

abstract: Cerebrovascular reactivity (CVR), defined here as the Blood Oxygenation Level Dependent (BOLD) response to a CO2 pressure change, is a useful metric of cerebrovascular function. Both the amplitude and the timing (hemodynamic lag) of the CVR response can bring insight into the nature of a cerebrovascular pathology and aid in understanding noise confounds when using functional Magnetic Resonance Imaging (fMRI) to study neural activity. This research assessed a practical modification to a typical resting-state fMRI protocol, to improve the characterization of cerebrovascular function. In 9 healthy subjects, we modelled CVR and lag in three resting-state data segments, and in data segments which added a 2-3 minute breathing task to the start of a resting-state segment. Two different breathing tasks were used to induce fluctuations in arterial CO2 pressure: a breath-hold task to induce hypercapnia (CO2 increase) and a cued deep breathing task to induce hypocapnia (CO2 decrease). Our analysis produced voxel-wise estimates of the amplitude (CVR) and timing (lag) of the BOLD-fMRI response to CO2 by systematically shifting the CO2 regressor in time to optimize the model fit. This optimization inherently increases grey matter CVR values and fit statistics. The inclusion of a simple breathing task, compared to a resting-state scan only, increases the number of voxels in the brain that have a significant relationship between CO2 and BOLD-fMRI signals, and improves our confidence in the plausibility of voxel-wise CVR and hemodynamic lag estimates. We demonstrate the clinical utility and feasibility of this protocol in an incidental finding of Moyamoya disease, and explore the possibilities and challenges of using this protocol in younger populations. This hybrid protocol has direct applications for CVR mapping in both research and clinical settings and wider applications for fMRI denoising and interpretation.

category: neuroscience


title: Exploring MEG brain fingerprints: evaluation, pitfalls and interpretations

abstract: Individual characterization of subjects based on their functional connectome (FC), termed "FC fingerprinting", has become a highly sought-after goal in contemporary neuroscience research. Recent functional magnetic resonance imaging (fMRI) studies have demonstrated unique characterization and accurate identification of individuals as an accomplished task. However, FC fingerprinting in magnetoencephalography (MEG) data is still widely unexplored. Here, we study resting-state MEG data from the Human Connectome Project to assess the MEG FC fingerprinting and its relationship with several factors including amplitude- and phase-coupling functional connectivity measures, spatial leakage correction, frequency bands, and behavioral significance. To this end, we first employ two identification scoring methods, differential identifiability and success rate, to provide quantitative fingerprint scores for each FC measurement. Secondly, we explore the edgewise and nodal MEG fingerprinting patterns across the different frequency bands (delta, theta, alpha, beta, and gamma). Finally, we investigate the cross-modality fingerprinting patterns obtained from MEG and fMRI recordings from the same subjects. We assess the behavioral significance of FC across connectivity measures and imaging modalities using partial least square correlation analyses. Our results suggest that fingerprinting performance is heavily dependent on the functional connectivity measure, frequency band, identification scoring method, and spatial leakage correction. We report higher MEG fingerprints in phase-coupling methods, central frequency bands (alpha and beta), and in the visual, frontoparietal, dorsal-attention, and default-mode networks. Furthermore, cross-modality comparisons reveal a certain degree of spatial concordance in fingerprinting patterns between the MEG and fMRI data, especially in the visual system. Finally, the multivariate correlation analyses show that MEG connectomes have strong behavioral significance, which however depends on the considered connectivity measure and temporal scale. This comprehensive, albeit preliminary investigation of MEG connectome test-retest identification offers a first characterization of MEG fingerprinting in relation to different methodological and electrophysiological factors and contributes to the understanding of fingerprinting cross-modal relationships. We hope that this first investigation will contribute to setting the grounds for MEG connectome identification.


title: Cerebral cortical communication overshadows computational energy-use, but these combine to predict synapse number

abstract:
Darwinian evolution tends to produce energy-efficient outcomes. On the other hand, energy limits computation, be it neural and probabilistic or digital and logical. Taking a particular energy-efficient viewpoint, we define neural computation and make use of an energy-constrained, computational function. This function can be optimized over a variable that is proportional to the number of synapses per neuron. This function also implies a specific distinction between ATP-consuming processes, especially computation per se vs the communication processes including action potentials and transmitter release. Thus to apply this mathematical function requires an energy audit with a partitioning of energy consumption that differs from earlier work. The audit points out that, rather than the oft-quoted 20 watts of glucose available to the brain (1, 2), the fraction partitioned to cortical computation is only 0.1 watts of ATP. On the other hand at 3.5 watts, long-distance communication costs are 35-fold greater. Other novel quantifications include (i) a finding that the biological vs ideal values of neural computational efficiency differ by a factor of 108 and (ii) two predictions of N, the number of synaptic transmissions needed to fire a neuron (2500 vs 2000).

Significance StatementEngineers hold up the human brain as a low energy form of computation. However from the simplest physical viewpoint, a neurons computation cost is remarkably larger than the best possible bits/J - off by a factor of 108. Here we explicate, in the context of energy consumption, a definition of neural computation that is optimal given explicit constraints. The plausibility of this definition as Natures perspective is supported by an energy-audit of the human brain. The audit itself requires certain novel perspectives and calculations revealing that communication costs are 35-fold computational costs.


title: Poly (I:C)-induced maternal immune activation affects mouse visual discrimination performance and reversal learning in a sex-dependent manner.

abstract: While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual discrimination (VD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the VD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a  two-hit stress model (MIA + loss of the social component of environmental enrichment (EE)), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right  dose, early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.


title: Hidden Talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner.


title: A hands-on tutorial on network and topological neuroscience

abstract: The brain is an extraordinarily complex system that facilitates the efficient integration of information from different regions to execute its functions. With the recent advances in technology, researchers can now collect enormous amounts of data from the brain using neuroimaging at different scales and from numerous modalities. With that comes the need for sophisticated tools for analysis. The field of network neuroscience has been trying to tackle these challenges, and graph theory has been one of its essential branches through the investigation of brain networks. Recently, topological data analysis has gained more attention as an alternative framework by providing a set of metrics that go beyond pair-wise connections and offer improved robustness against noise. In this hands-on tutorial, our goal is to provide the computational tools to explore neuroimaging data using these frameworks and to facilitate their accessibility, data visualisation, and comprehension for newcomers to the field. We will start by giving a concise (and by no means complete) overview of the field to introduce the two frameworks, and then explain how to compute both well-established and newer metrics on resting-state functional magnetic resonance imaging. We use an open-source language (Python) and provide an accompanying publicly available Jupyter Notebook that uses data from the 1000 Functional Connectomes Project. Moreover, we would like to highlight one part of our notebook that is solely dedicated to realistic visualisation of high order interactions in brain networks. This pipeline provides three-dimensional (3-D) plots of pair-wise and higher-order interactions projected in a brain atlas, a new feature tailor-made for network neuroscience.