title: A high-resolution comparative atlas across 74 fish genomes illuminates teleost evolution after whole-genome duplication

abstract: Teleost fishes are ancient tetraploids stemming from an ancestral whole-genome duplication that may have contributed to the impressive diversification of this clade. Whole-genome duplications can occur via self-doubling (autopolyploidy) or via hybridization between different species (allopolyploidy). The mode of tetraploidization conditions subsequent evolutionary processes by which descendant genomes return to a diploid state through gene losses and functional divergence. How teleosts became tetraploid remains however unresolved, leaving a fundamental gap to interpret their functional evolution. As legacy of the whole genome duplication, identifying orthologous and paralogous genomic regions across teleosts is challenging, hindering genome-wide investigations into their polyploid history. Here, we combine tailored gene phylogeny methodology together with the state-of-the-art ancestral karyotype reconstruction to establish the first high-resolution comparative atlas of paleopolyploid regions across 74 teleost genomes. We then leverage this atlas to investigate the genome-wide mechanisms of rediploidization after tetraploidization in teleosts. We uncover that meiotic recombination persisted between duplicated chromosomes for over 60 million years, with entire chromosomes only functionally diverging after the separation of major teleost families. This evidence suggests that the teleost ancestor was an autopolyploid. Further, ancient duplicated chromosomes have evolved asymmetrically in teleosts, disputing unbalanced evolution as a hallmark of polyploidization through hybridization.

category: genomics


title: Genome-wide mechanisms of rediploidization in paleopolyploid teleosts revealed by a high-resolution comparative atlas across 74 fishes


title: In vivo single-cell profiling of lncRNAs during Ebola virus infection

abstract: Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.


title: Dissecting the interactions of PINK1 with the TOM complex in depolarized mitochondria

abstract: Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinsons disease. PINK1, which is mutated in some cases of familiar Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria.

category: biochemistry


title: Deep Proteome Profiling Enabled Functional Annotation and Data-Independent Quantification of Proline Hydroxylation Targets

abstract: Proline hydroxylation (Hyp) regulates protein structure, stability and protein-protein interaction and is widely involved in diverse metabolic and physiological pathways in cells and diseases. To reveal functional features of the proline hydroxylation proteome, we integrated various data sources for deep proteome profiling of proline hydroxylation proteome in human and developed HypDB (https://www.HypDB.site), an annotated database and web server for proline hydroxylation proteome. HypDB provides site-specific evidence of modification based on extensive LC-MS analysis and literature mining with 15319 non-redundant Hyp sites and 8226 sites with high confidence on human proteins. Annotation analysis revealed significant enrichment of proline hydroxylation on key functional domains and tissue-specific distribution of Hyp abundance across 26 types of human organs and fluids and 6 cell lines. The network connectivity analysis further revealed a critical role of proline hydroxylation in mediating protein-protein interactions. Moreover, the spectral library generated by HypDB enabled data-independent analysis (DIA) of clinical tissues and the identification of novel Hyp biomarkers in lung cancer and kidney cancer. Taken together, our integrated analysis of human proteome with publicly accessible HypDB revealed functional diversity of Hyp substrates and provides a quantitative data source to characterize proline hydroxylation in pathways and diseases.


title: Dynamic Determinants of Quorum Quenching Mechanism Shared among N-terminal Serine Hydrolases

abstract: Growing concerns about microbial antibiotic resistance have motivated extensive research into ways of overcoming antibiotic resistance. Quorum quenching (QQ) processes disrupt bacterial communication via quorum sensing, which enables bacteria to sense the surrounding bacterial cell density and markedly affects their virulence. Due to its indirect mode of action, QQ is believed to exert limited pressure on essential bacterial functions and may thus avoid inducing resistance. Although many enzymes display QQ activity against various bacterial signaling molecules, their mechanisms of action are poorly understood, limiting their potential optimization as QQ agents. Here we evaluate the capacity of three N-terminal serine hydrolases to degrade N-acyl homoserine lactones that serve as signaling compounds for Gram-negative bacteria. Using molecular dynamics simulations of the free enzymes and their complexes with two signaling molecules of different lengths, followed by quantum mechanics/molecular mechanics molecular dynamics simulations of their initial catalytic steps, we clarify the molecular processes underpinning their QQ activity. We conclude that all three enzymes degrade bacterial signaling molecules via similar reaction mechanisms. Moreover, we experimentally confirmed the activity of two penicillin G acylases from Escherichia coli (ecPGA) and Achromobacter spp. (aPGA), adding these biotechnologically well-optimized enzymes to the QQ toolbox. We also observed enzyme- and substrate-dependent differences in the catalytic actions of these enzymes, arising primarily from the distinct structures of their acyl-binding cavities and the dynamics of their molecular gates. As a consequence, the first reaction step catalyzed by ecPGA with a longer substrate had an elevated energy barrier because its shallow acyl binding site could not accommodate a productive substrate-binding configuration. Conversely, aPGA in complex with both substrates exhibited unfavorable energetics in both reaction steps due to the dynamics of the residues gating the acyl binding cavity entrance. Finally, the energy barriers of the second reaction step catalyzed by Pseudomonas aeruginosa acyl-homoserine lactone acylase with both substrates were higher than in the other two enzymes due to the unique positioning of Arg297{beta} in this enzyme. The discovery of these dynamic determinants will guide future efforts to design robust QQ agents capable of selectively controlling virulence in resistant bacterial species.


title: Common Dynamic Determinants Govern Quorum Quenching Activity in N-terminal Serine Hydrolases


title: Histone chaperones exhibit conserved functionality in nucleosome remodeling

abstract: Chromatin homeostasis mediates some of the most fundamental processes in the eukaryotic cell. In this regard, histone chaperones have emerged as major regulatory factors during DNA replication, repair, and transcription. However, the dynamic nature of these processes has severely impeded their characterization at the molecular level. Here we apply single-molecule probing by fluorescence optical tweezers to follow histone chaperone dynamics in real-time. The molecular action of SET/template-activating factor-I{beta} and nucleophosmin 1--representing the two most common histone chaperone folds--were examined using both nucleosomes and isolated core histones. We show that these chaperones present binding specificity for partially dismantled nucleosomes and are able to recognize and disrupt non-native histone-DNA interactions. Furthermore, we reveal that cytochrome c inhibition of histone chaperones is coupled to chaperone accumulation on DNA-bound histones. Our single-molecule approach shows that despite the drastically different structures of these chaperones, they present conserved modes of action mediating nucleosome remodeling.

category: biophysics


title: Continuous B- to A- Transition in Protein-DNA Binding - How Well Is It Described by Current AMBER Force Fields?

abstract: When DNA interacts with a protein, its structure often undergoes significant conformational adaptation. Perhaps the most common is the transition from canonical B-DNA towards the A-DNA form, which is not a two-state, but rather a continuous transition. The A- and B-forms differ mainly in sugar pucker P (north/south) and glycosidic torsion {chi} (high-anti/anti). The combination of A-like P and B-like {chi} (and vice versa) represents the nature of the intermediate states lying between the pure A- and B- forms. In this work, we study how the A/B equilibrium and in particular the A/B intermediate states, which are known to be over-represented at protein-DNA interfaces, are modeled by current AMBER force fields. Eight protein-DNA complexes and their naked (unbound) DNAs were simulated with OL15 and bsc1 force fields as well as an experimental combination OL15{chi}OL3. We found that while the geometries of the A-like intermediate states in the molecular dynamics (MD) simulations agree well with the native X-ray geometries found in the protein-DNA complexes, their populations (stabilities) are significantly underestimated. Different force fields predict different propensities for A-like states growing in the order OL15 < bsc1 < OL15{chi}OL3, but the overall populations of the A-like form are too low in all of them. Interestingly, the force fields seem to predict the correct sequence-dependent A-form propensity, as they predict larger populations of the A-like form in naked (unbound) DNA in those steps that acquire A-like conformations in protein-DNA complexes. The instability of A-like geometries in current force fields may significantly alter the geometry of the simulated protein-DNA complex, destabilize the binding motif, and reduce the binding energy, suggesting that refinement is needed to improve description of protein-DNA interactions in AMBER force fields.


title: Von Willebrand factor A1 domain affinity for GPIbα and stability are differentially regulated by its O-glycosylated N-linker and C-linker

abstract:
Hemostasis in the arterial circulation is mediated by binding of the A1 domain of the ultralong protein von Willebrand factor to GPIb on platelets to form a platelet plug. A1 is activated by tensile force on VWF concatemers imparted by hydrodynamic drag force. The A1 core is protected from force-induced unfolding by a long-range disulfide that links cysteines near its N and C-termini. The O-glycosylated linkers between A1 and its neighboring domains, which transmit tensile force to A1, are reported to regulate A1 activation for binding to GPIb, but the mechanism is controversial and incompletely defined. Here, we study how these linkers, and their polypeptide and O-glycan moieties, regulate A1 affinity by measuring affinity, kinetics, thermodynamics, hydrogen deuterium exchange (HDX), and unfolding by temperature and urea. The N-linker lowers A1 affinity 40-fold with a stronger contribution from its O-glycan than polypeptide moiety. The N-linker also decreases HDX in specific regions of A1 and increases thermal stability and the energy gap between its native state and an intermediate state, which is observed in urea-induced unfolding. The C-linker also decreases affinity of A1 for GPIb, but in contrast to the N-linker, has no significant effect on HDX or A1 stability. Among different models for A1 activation, our data are consistent with the model that the intermediate state has high affinity for GPIb, which is induced by tensile force physiologically and regulated allosterically by the N-linker.

Impact StatementBoth the polypeptide and attached O-glycans N-terminal to the A1 domain in von Willebrand factor lower its affinity for its ligand GPIb on platelets, its stability, and structural dynamics and decrease population of a high-affinity, intermediate state in unfolding.

Key pointsO_LILigand-binding affinity of A1 and the stability of its native state is regulated by an N-terminal interdomain, O-glycosylated linker
C_LI


title: Inhibition of the JAK/STAT pathway with baricitinib reduces the multiple organ dysfunction caused by hemorrhagic shock in rats

abstract:
ObjectiveThe aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-{kappa}B and NLRP3 caused by HS.

BackgroundPost-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown.

MethodsAn acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-{kappa}B and NLRP3 pathways were analyzed by western blotting in the kidney and liver.

ResultsWe demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-{kappa}B and NLRP3 pathways caused by HS in the rat.

ConclusionsOur results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

category: pharmacology and toxicology


title: Chemical control and herbicide resistance of hairy fleabane  in Jordan

abstract: Two field experiments were conducted to evaluate the effectiveness of 12 herbicides in controlling hairy fleabane [Conyza bonariensis (L.) Cronquist] in a date palm orchard located in the central Jordan valley during the spring of 2017. Results showed that C. bonariensis resists paraquat (2.5, 5 and 7.5kgha-1), oxadiazon (5kgha-1) and oxyflourfen (3.3kgha-1) herbicides applied at normal or higher than the recommended rates. None of the three herbicides was significantly effective against the weed and treated plants continued growing normally similar to those of untreated control. Higher rates (10-fold of the recommended rates) of the same herbicides failed to control the weed. The effect of other tested herbicides on the weed was varied with bromoxynil plus MCPA (buctril(R)M), 2,4-D-iso-octyl ester, glyphosate, glyphosate trimesium and triclopyr were most effective and completely controlled the weed at recommended rates of application. Testing paraquat, oxadiazon and oxyflourfen using the normal recommended and 10-fold higher rates on two populations of C. bonariensis grown from seeds of the date palm and al-Twal (another site in the Jordan Valley) weed populations and grown in pots under glasshouse conditions showed that Date palm population was resistant to the three herbicides at both application rates while al-Twal site population was highly susceptible and completely controlled at normal and high rates of the three herbicides. It is concluded that certain populations of C. bonariensis developed resistance to paraquat, oxadiazon and oxyflourfen but control of this weed was possible using other herbicides of different mechanism of action. Herbicide rotation or other nonchemical weed control methods have been suggested to prevent or reduce the buildup and spread of resistant populations of this weed species. These results represent the first report on herbicide resistance of C. bonariensis in Jordan.

category: plant biology


title: Role of Yap1 in adult neural stem cell activation

abstract: Most adult hippocampal neural stem cells (NSCs) remain quiescent with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger eventually the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional activator Yap1 to be enriched in active NSCs. Genetic deletion of Yap1 led to a significant reduction in the relative proportion of active NSCs supporting a physiological role of Yap1 in regulating the transition from quiescence to activation. Overexpression of wild type Yap1 in adult NSCs did not induce NSC activation suggesting tight upstream control mechanisms, but overexpression of a gain-of-function mutant (Yap1-5SA) elicited cell cycle entry in NSCs and hilar astrocytes. Consistent with a role of Yap1 in NSC activation, single cell RNA sequencing revealed the partial induction of an activated NSC gene expression program. Yet, Yap1-5SA expression also induced Taz and other key components of the Yap/Taz regulon previously identified in glioblastoma stem cell-like cells. Consequently, dysregulated Yap1 activity led to repression of hippocampal neurogenesis, promoting aberrant differentiation instead.

category: neuroscience


title: Comparable human spatial memory distortions in physical, desktop virtual and immersive virtual environments

abstract: Boundaries define regions of space and are integral to episodic memories. The impact of boundaries on spatial memory and neural representations of space has been extensively studied in freely-moving rodents. But less is known in humans and many prior studies have employed desktop virtual reality (VR) which lacks the body-based self-motion cues of the physical world, diminishing the potentially strong input from path integration to spatial memory. We replicated a desktop-VR study testing the impact of boundaries on spatial memory (Hartley et al., 2004) in a physical room (2.4m x 2.4m, 2m tall) by having participants (N = 27) learn the location of a circular stool and then after a short delay replace it where they thought they had found it. During the delay, the wall boundaries were either expanded or contracted. We compared performance to groups of participants undergoing the same procedure in a laser-scanned replica in both desktop VR (N = 44) and freely-walking head mounted display (HMD) VR (N = 39) environments. Performance was measured as goodness of fit between the spatial distributions of group responses and seven modelled distributions that prioritised different metrics based on boundary geometry or walking paths to estimate the stool location. The best fitting model was a weighted linear combination of all the geometric spatial models, but an individual model derived from place cell firing in Hartley et al. 2004 also fit well. High levels of disorientation in all three environments prevented detailed analysis on the contribution of path integration. We found identical model fits across the three environments, though desktop VR and HMD-VR appeared more consistent in spatial distributions of group responses than the physical environment and displayed known variations in virtual depth perception. Thus, while human spatial representation appears differentially influenced by environmental boundaries, the influence is similar across virtual and physical environments. Despite differences in body-based cue availability, desktop and HMD-VR allow a good and interchangeable approximation for examining human spatial memory in small-scale physical environments.


title: Detailed measurements and simulations of electric field distribution of two TMS coils cleared for obsessive compulsive disorder in the brain and in specific regions associated with OCD

abstract: The FDA cleared deep transcranial magnetic stimulation (Deep TMS) with the H7 coil for obsessive-compulsive disorder (OCD) treatment, following a double-blinded placebo-controlled multicenter trial. Two years later the FDA cleared TMS with the D-B80 coil on the basis of substantial equivalence. In order to investigate the induced electric field characteristics of the two coils, these were placed at the treatment position for OCD over the prefrontal cortex of a head phantom, and the field distribution was measured. Additionally, numerical simulations were performed in eight Population Head Model repository models with two sets of conductivity values and three Virtual Population anatomical head models and their homogeneous versions. The H7 was found to induce significantly higher maximal electric fields (p<0.0001, t=11.08) and to stimulate two to five times larger volumes in the brain (p<0.0001, t=6.71). The rate of decay of electric field with distance is significantly slower for the H7 coil (p < 0.0001, Wilcoxon matched-pairs test). The field at the scalp is 306% of the field at a 3 cm depth with the D-B80, and 155% with the H7 coil. The H7 induces significantly higher intensities in broader volumes within the brain and in specific brain regions known to be implicated in OCD (dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC) and pre-supplementary motor area (pre-SMA)) compared to the D-B80. Significant field [≥] 80 V/m is induced by the H7 (D-B80) in 15% (1%) of the dACC, 78% (29%) of the pre-SMA, 50% (20%) of the dlPFC, 30% (12%) of the OFC and 15% (1%) of the IFG. Considering the substantial differences between the two coils, the clinical efficacy in OCD should be tested and verified separately for each coil.


title: Systematic analysis of human antibody response to ebolavirus glycoprotein reveals high prevalence of neutralizing public clonotypes

abstract: Understanding the human antibody response to emerging viral pathogens is key to epidemic preparedness. As the size of the B cell response to a pathogenic virus protective antigen is undefined, we performed deep paired heavy and light chain sequencing in EBOV-GP specific memory B cells, allowing analysis of the ebolavirus-specific antibody repertoire both genetically and functionally. This approach facilitated investigation of the molecular and genetic basis for evolution of cross-reactive antibodies by elucidating germline-encoded properties of antibodies to EBOV and identification of the overlap between antibodies in the memory B-cell and serum repertoire. We identified 73 public clonotypes to EBOV, 20% of which encoded antibodies with neutralization activity and capacity to protect in vivo. This comprehensive analysis of the public and private antibody repertoire provides insight into the molecular basis of the humoral immune response to EBOV-GP, which informs vaccine design of new vaccines and improved therapeutics.

category: immunology


title: Local-scale virome depiction supports significant differences between Aedes aegypti and Aedes albopictus

abstract: Aedes spp. comprise the primary group of mosquitoes that transmit arboviruses such as dengue, Zika, and chikungunya viruses to humans, and thus these insects pose a significant burden on public health worldwide. Advancements in next-generation sequencing and metagenomics have expanded our knowledge on the richness of RNA viruses harbored by arthropods such as Ae. aegypti and Ae. albopictus; increasing evidence suggests that vectorial competence can be modified by the microbiome (comprising both bacteriome and virome) of mosquitoes present in endemic zones. Using an RNA-seq-based metataxonomic approach, this study determined the virome structure of field-caught Ae. aegypti and Ae. albopictus mosquitoes in Medellin, Colombia, a municipality with a high incidence of mosquito-transmitted arboviruses. The two species are sympatric, but their core viromes differed considerably in richness, diversity, and abundance; the viromes were dominated by a few viruses. BLAST searches of assembled contigs suggested that at least 17 virus species (16 of which are insect-specific viruses [ISVs]) infect the Ae. aegypti population. Dengue virus 3 was detected in one sample. In Ae. albopictus, up to 11 ISVs and one plant virus were detected. Therefore, the virome composition was species-specific. The bacterial endosymbiont Wolbachia was identified in all Ae. albopictus samples and in some Ae. aegypti samples collected after 2017. The presence of Wolbachia sp. in Ae. aegypti was not related to significant changes in the richness, diversity, or abundance of this mosquitos virome, although it was related to an increase in the abundance of Aedes aegypti To virus 2 (unclassified). The mitochondrial diversity of these mosquitoes suggested that the Ae. aegypti population underwent a change that started in the second half of 2017, which coincides with the release of Wolbachia-infected mosquitoes in Medellin, indicating that the population of wMel-infected mosquitoes has expanded. However, additional studies are required on the dispersal speed and intergenerational stability of wMel in Medellin and nearby areas as well as on the introgression of genetic variants in the native mosquito population.

category: microbiology


title: Ocimum sanctum, OscWRKY1, regulates phenylpropanoid pathway genes and promotes resistance to pathogen infection in Arabidopsis

abstract: WRKY transcription factor (TF) family regulates various developmental and physiological functions in plants. PAL genes encode enzymes which are involved in plant defense responses, but the direct regulation of PAL genes and phenylpropanoid pathway through WRKY TFs is not well characterized. In the present study, we have characterized an OscWRKY1 gene from O. sanctum which shows induced expression after methyl jasmonate (MeJA), salicylic acid (SA), and wounding. Recombinant OscWRKY1 protein binds to the W-box cis-element TTGAC[C/T] and activates the reporter gene in yeast. Overexpression of OscWRKY1 enhances Arabidopsis resistance towards Pseudomonas syringae pv. tomato Pst DC3000. Upstream activator sequences of PAL and C4H have identified the conserved W-box cis-element (TTGACC) in both O. sanctum and Arabidopsis. OscWRKY1 was found to interact with W-box cis-element present in the PAL and C4H promoters. Silencing of OscWRKY1 using VIGS resulted in reduced expression of PAL, C4H, COMT, F5H and 4CL transcripts. OscWRKY1 silenced plants exhibit reduced PAL activity, whereas, the overexpression lines of OscWRKY1 in Arabidopsis exhibit increased PAL activity. These results revealed that OscWRKY1 positively regulates the phenylpropanoid pathway genes and enhances the resistance against bacterial pathogen in Arabidopsis.


title: Identification of candidate virulence loci in Striga hermonthica, a devastating parasite of African cereal crops

abstract:
O_LIParasites have evolved proteins, Virulence Factors (VFs), that facilitate plant colonization, yet VFs mediating parasitic plant-host interactions are poorly understood. Striga hermonthica is an obligate, root-parasitic plant of cereal hosts in sub-Saharan Africa, causing devastating yield losses. Understanding the molecular nature and allelic variation of VFs in S. hermonthica is essential for breeding resistance and delaying the evolution of parasite virulence.
C_LIO_LIWe assembled the S. hermonthica genome and identified secreted proteins by in silico prediction. Pooled sequencing of parasites growing on a susceptible and a strongly resistant rice host allowed us to scan for loci where selection imposed by the resistant host had elevated the frequency of alleles contributing to successful colonisation.
C_LIO_LIThirty-eight putatively secreted VFs had extremely different allele frequencies with functions including host cell wall modification, protease inhibitors, oxidoreductase and kinase activities. These candidate loci had significantly higher Tajimas D than the genomic background, consistent with balancing selection.
C_LIO_LIOur results reveal diverse strategies used by S. hermonthica to overcome different layers of host resistance. Understanding the maintenance of variation at virulence loci by balancing selection will be critical to managing the evolution of virulence as a part of a sustainable control strategy.
C_LI


title: Histopathological analysis of selected organs of Oreochromis niloticus due to sub-lethal industrial effluents exposure.

abstract: On a daily basis, our environment is exposed to tons of a composite of industrial effluents, which has a negative impact on commercial fish production and, as a result, on humans. Present study was designed to evaluate the acute, sub-chronic, and chronic toxicity of a composite of raw industrial effluent from Sunder Industrial Estate in the freshwater fish Oreochromis niloticus biosystem by investigating at the histopathological changes in different organs such as heart, kidney, and muscle after exposure. Fish was exposed to 1/3rd, 1/5th and 1/10th of predetermined LC50. Significant histopathological alterations in heart (myocarditis, pericardium bending and lifting) kidney (renal tube degeneration, glomerulus structural alteration and necrotic proximal tubule) and muscle (inflammation, atrophy and tumor) were observed in treated groups. After the sub-lethal exposure histological alteration index (HAI) was highest in chronic group as compared to the acute and sub-chronic group as HAI group D> HAI group C> HAI group B. Moreover physicchemical parameters of water were found to be out of the range of the APHA standard approach.

category: zoology


title: Invariance in pitch perception

abstract: Information in speech and music is often conveyed through changes in fundamental frequency (f0), the perceptual correlate of which is known as "pitch". One challenge of extracting this information is that such sounds can also vary in their spectral content due to the filtering imposed by a vocal tract or instrument body. Pitch is envisioned as invariant to spectral shape, potentially providing a solution to this challenge, but the extent and nature of this invariance remain poorly understood. We examined the extent to which human pitch judgments are invariant to spectral differences between natural sounds. Listeners performed up/down and interval discrimination tasks with spoken vowels, instrument notes, or synthetic tones, synthesized to be either harmonic or inharmonic (lacking a well-defined f0). Listeners were worse at discriminating pitch across different vowel and instrument sounds compared to when vowels/instruments were the same, being biased by differences in the spectral centroids of the sounds being compared. However, there was no interaction between this effect and that of inharmonicity. In addition, this bias decreased when sounds were separated by short delays. This finding suggests that the representation of a sounds pitch is itself unbiased, but that pitch comparisons between sounds are influenced by changes in timbre, the effect of which weakens over time. Pitch representations thus appears to be relatively invariant to spectral shape. But relative pitch judgments are not, even when spectral shape variation is naturalistic, and when such judgments are based on representations of the f0.


title: Population demography maintains biogeographic boundaries

abstract: Global biodiversity is organized into biogeographic regions that comprise distinct biotas. The contemporary factors maintaining differences in species composition between biogeographic regions are poorly understood. Given the evidence that populations with sufficient genetic variation can adapt to fill new habitats, it is surprising that we do not see more homogenization of species assemblages among regions. Theory suggests that the expansion of populations across biogeographic transition zones could be limited by environmental gradients that affect population demography in ways that could limit adaptive capacity, but this has not been empirically explored. Using three independently curated data sets describing continental patterns of mammalian demography and population genetics, we show that populations closer to biogeographic transition zones have lower effective population sizes and genetic diversity, and are more genetically differentiated. These patterns are consistent with reduced adaptive capacity near biogeographic transition zones. The consistency of these patterns across mammalian species suggests they are stable, predictable, and generalizable in their contribution to long-term limits on expansion and homogenization of biodiversity across biogeographic transition zones. Understanding the contemporary processes acting on populations that maintain differences in the composition of regional biotas is crucial for our basic understanding of the current and future organization of global biodiversity. The importance of contemporary, population-level processes on the maintenance of global biogeographic regions suggests that biogeographic boundaries are susceptible to environmental perturbation associated with human-caused global change.

category: ecology


title: Involvement of prelimbic cortex neurons and related circuits in the acquisition of cooperative learning by pairs of rats

abstract:
Social behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cell type/s in the PrL contributing to cooperative behaviors. To this end, we collected rats brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL (glutamatergic cells containing D1 and D2 receptors and interneurons). Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. In addition, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). Spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as its connectivity with subcortical brain regions (BLA, NAc) during cooperation.

Significance StatementBrain mechanisms underlying cooperative behaviors remain unknown. The present study identified specific neuronal types from the PrL cortex engaged in the acquisition of a cooperative task, as well as their connectivity with subcortical projection sites, such as the NAc and the BLA during cooperation. Rats leading the cooperation trials (designated leaders) presented an increased activation of D1-containing neurons in the PrL during cooperation. The PrL and NAc electrical activity increased when rats were cooperating, while the BLA activity increased before cooperation. The PrL and NAc showed increased functional connectivity at the moment of cooperation on the platform, whereas during the individual phase the highest connectivity was found before the animals climbed individually onto the platform.


title: SLDP and LIPA mediate lipid droplet-plasma membrane tethering in Arabidopsis thaliana

abstract:
Membrane contact sites (MCS) are inter-organellar connections that allow for the direct exchange of molecules, such as lipids or Ca2+ between organelles, but can also serve to tether organelles at specific locations within cells. Here we identified and characterised three proteins that form a lipid droplet (LD)-plasma membrane (PM) tethering complex in plant cells, namely LD-localised SEED LD PROTEIN (SLDP) 1 and 2 and PM-localised LD-PLASMA MEMBRANE ADAPTOR (LIPA). Using proteomics and different protein-protein interaction assays, we show that both SLDPs associate with LIPA. Disruption of either SLDP1 and 2 expression, or that of LIPA, leads to an aberrant clustering of LDs in Arabidopsis seedlings. Ectopic co-expression of one of the SLDPs with LIPA on the other hand is sufficient to reconstitute LD-PM tethering in Nicotiana tabacum pollen tubes, a cell type characterised by dynamically moving LDs in the cytosolic streaming. Further, confocal laser scanning microscopy revealed both SLDP2.1 and LIPA to be enriched at LD-PM contact sites in seedlings. These and other results suggest that SLDP and LIPA interact to form a tethering complex that anchors a subset of LDs to the PM during post-germinative seedling growth in Arabidopsis thaliana.

One-sentence summarySEED LIPID DROPLET PROTEIN1 and 2 and LIPID DROPLET PLASMA MEMBRANE ADAPTOR tether lipid droplets to the plasma membrane in seedlings of Arabidopsis thaliana.


title: In vivo growth of Staphylococcus lugdunensis is facilitated by the concerted function of heme and non-heme iron acquisition mechanisms

abstract:
Acquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Here we show that S. lugdunensis utilizes diverse genome encoded iron acquisition mechanisms to satisfy its need for this nutrient. Indeed, S. lugdunensis can usurp hydroxamate siderophores, and staphyloferrin A and B from S. aureus, using the fhuC ATPase-encoding gene. Acquisition of catechol siderophores and catecholamine stress hormones necessitates the presence of the sst-1 transporter-encoding locus, but not the sst-2 locus. Iron-dependent growth in acidic culture conditions necessitates the feoAB locus. Heme iron is acquired via expression of the iron-regulated surface determinant (isd) locus. During systemic infection of mice we demonstrate that while S. lugdunensis does not cause overt illness, it does colonize and proliferate to high numbers in the kidneys. By combining mutations in the various iron acquisition loci, we further demonstrate that only a strain mutated for all of isd, fhuC, sst-1, and feo, versus combination mutants carrying wild type copies of any one of those loci, was attenuated in its ability to proliferate to high numbers in kidneys. Taken together our data reveal that S. lugdunensis requires a repertoire of both heme and non-heme iron acquisition mechanisms to proliferate during systemic infection of mammals.

ImportanceAcquisition of iron underpins the ability of pathogens to cause disease and Staphylococcus lugdunensis has increasingly been recognized as a pathogen that can cause serious infection. In this study, we sought to address the knowledge gap that exists regarding the iron acquisition mechanisms employed by S. lugdunensis, especially during infection of the mammalian host. Owing to an inability to synthesize siderophores, growth of S. lugdunensis is dramatically impaired in the presence of transferrin or serum, yet S. lugdunensis nonetheless uses several other genome-encoded iron acquisition mechanisms, in concert, to proliferate within the mammalian host. Therefore, the development of interventions that target bacterial iron acquisition systems should consider the overlapping function of distinct metal acquisition strategies deployed by bacterial pathogens.


title: Seasonality and competition select for variable germination behavior in perennials

abstract: The common occurrence of within-population variation in germination behavior and associated traits such as seed size has long fascinated evolutionary ecologists. In annuals, unpredictable environments are known to select for bet-hedging strategies causing variation in dormancy duration and germination strategies. Variation in germination timing and associated traits is also commonly observed in perennials, and often tracks gradients of environmental predictability. Although bet-hedging is thought to occur less frequently in long-lived organisms, these observations suggest a role of bet-hedging strategies in perennials occupying unpredictable environments. We use complementary numerical and evolutionary simulation models of within- and among-individual variation in germination behavior in seasonal environments to show how bet-hedging interacts with density dependence, life-history traits, and priority effects due to competitive differences among germination strategies. We reveal substantial scope for bet-hedging to produce variation in germination behavior in long-lived plants, when "false starts" to the growing season results in either competitive advantages or increased mortality risk for alternative germination strategies. Additionally, we find that two distinct germination strategies can evolve and coexist through negative frequency-dependent selection. These models extend insights from bet-hedging theory to perennials and explore how competitive communities may be affected by ongoing changes in climate and seasonality patterns.

category: evolutionary biology


title: Rat leukocyte population dynamics predicts a window for intervention in aging.

abstract: Age-associated changes in human hematopoiesis have been mostly recapitulated in mouse models; but not much has been explored in rats, a physiologically closer model to humans. To establish whether rat hematopoiesis closely mirrors humans, we examined the peripheral blood of rats throughout their lifespan. Significant age-associated changes showed distinctive population shifts predictive of age. A divergence between predicted versus chronological age changes was indicative of fragility; thus, these data may be a valuable tool to identify underlying diseases or as a surrogate predictor for intervention efficacy. Notably, several blood parameters and DNA methylation alterations defined specific leverage points during aging, supporting non-linear aging effects and highlighting a roadmap for interventions at these junctures. Overall, we present a simple set of rat blood metrics that can provide a window into their health and inform the implementation of interventions in a model system physiologically relevant for humans.


title: ACDC: Analysis of Congruent Diversification Classes

abstract:
1. Diversification rates inferred from phylogenies are not identifiable. There are infinitely many combinations of speciation and extinction rate functions that have the exact same likelihood score for a given phylogeny, building a congruence class. The specific shape and characteristics of such congruence classes have not yet been studied. Whether speciation and extinction rate functions within a congruence class share common features is also not known.

2. Instead of striving to make the diversification rates identifiable, we can embrace their inherent non-identifiable nature. We use two different approaches to explore a congruence class: (i) testing of specific alternative hypotheses, and (ii) randomly sampling alternative rate function within the congruence class.

3. Our methods are implemented in the open-source R package ACDC (https://github.com/afmagee/ACDC). ACDC provides a flexible approach to explore the congruence class and provides summaries of rate functions within a congruence class. The summaries can highlight common trends, i.e. increasing, flat or decreasing rates.

Although there are infinitely many equally likely diversification rate functions, these can share common features. ACDC can be used to assess if diversification rate patterns are robust despite non-identifiability. In our example, we clearly identify three phases of diversification rate changes that are common among all models in the congruence class. Thus, congruence classes are not necessarily a problem for studying historical patterns of biodiversity from phylogenies.


title: Single cell mutant selection for metabolic engineering of actinomycetes

abstract: Actinomycetes are important producers of pharmaceuticals and industrial enzymes. However, wild type strains require laborious development prior to industrial usage. Here we present a generally applicable reporter-guided metabolic engineering tool based on random mutagenesis, selective pressure, and single-cell sorting. We developed fluorescence-activated cell sorting (FACS) methodology capable of reproducibly identifying high-performing individual cells from a mutant population directly from liquid cultures. Genome-mining based drug discovery is a promising source of bioactive compounds, which is complicated by the observation that target metabolic pathways may be silent under laboratory conditions. We demonstrate our technology for drug discovery by activating a silent mutaxanthene metabolic pathway in Amycolatopsis. We apply the method for industrial strain development and increase mutaxanthene yields 9-fold to 99 mg l-1 in a second round of mutant selection. Actinomycetes are an important source of catabolic enzymes, where product yields determine industrial viability. We demonstrate 5-fold yield improvement with an industrial cholesterol oxidase ChoD producer Streptomyces lavendulae to 20.4 U g-1 in three rounds. Strain development is traditionally followed by production medium optimization, which is a time-consuming multi-parameter problem that may require hard to source ingredients. Ultra-high throughput screening allowed us to circumvent medium optimization and we identified high ChoD yield production strains directly from mutant libraries grown under preset culture conditions. In summary, the ability to screen tens of millions of mutants in a single cell format offers broad applicability for metabolic engineering of actinomycetes for activation of silent metabolic pathways and to increase yields of proteins and natural products.

category: bioengineering


title: m6A-TSHub: unveiling the context-specific m6A methylation and m6A-affecting mutations in 23 human tissues

abstract: As the most pervasive epigenetic marker present on mRNA and lncRNA, N6-methyladenosine (m6A) RNA methylation has been shown to participate in essential biological processes. Recent studies revealed the distinct patterns of m6A methylome across human tissues, and a major challenge remains in elucidating the tissue-specific presence and circuitry of m6A methylation. We present here a comprehensive online platform m6A-TSHub for unveiling the context-specific m6A methylation and genetic mutations that potentially regulate m6A epigenetic mark. m6A-TSHub consists of four core components, including (1) m6A-TSDB: a comprehensive database of 184,554 functionally annotated m6A sites derived from 23 human tissues and 499,369 m6A sites from 25 tumor conditions, respectively; (2) m6A-TSFinder: a web server for high-accuracy prediction of m6A methylation sites within a specific tissue from RNA sequences, which was constructed using multi-instance deep neural networks with gated attention; (3) m6A-TSVar: a web server for assessing the impact of genetic variants on tissue-specific m6A RNA modification; and (4) m6A-CAVar: a database of 587,983 TCGA cancer mutations (derived from 27 cancer types) that were predicted to affect m6A modifications in the primary tissue of cancers. The database should make a useful resource for studying the m6A methylome and genetic factor of epitranscriptome disturbance in a specific tissue (or cancer type). m6A-TSHub is accessible at: www.xjtlu.edu.cn/biologicalsciences/m6ats.

category: bioinformatics


title: PolarMorphism enables discovery of shared genetic variants across multiple traits from GWAS summary statistics

abstract: Pleiotropic SNPs are associated with multiple traits. Such SNPs can help pinpoint biological processes with an effect on multiple traits or point to a shared etiology between traits. We present PolarMorphism, a new method for the identification of pleiotropic SNPs from GWAS summary statistics. PolarMorphism can be readily applied to more than two traits or whole trait domains. PolarMorphism makes use of the fact that trait-specific SNP effect sizes can be seen as Cartesian coordinates and can thus be converted to polar coordinates r (distance from the origin) and theta (angle with the Cartesian x-axis). r describes the overall effect of a SNP, while theta describes the extent to which a SNP is shared. r and theta are used to determine the significance of SNP sharedness, resulting in a p-value per SNP that can be used for further analysis. We apply PolarMorphism to a large collection of publicly available GWAS summary statistics enabling the construction of a pleiotropy network that shows the extent to which traits share SNPs. This network shows how PolarMorphism can be used to gain insight into relationships between traits and trait domains. Furthermore, pathway analysis of the newly discovered pleiotropic SNPs demonstrates that analysis of more than two traits simultaneously yields more biologically relevant results than the combined results of pairwise analysis of the same traits. Finally, we show that PolarMorphism is more efficient and more powerful than previously published methods.

category: genetics


title: Impaired spatial memory in adult vitamin D deficient BALB/c mice is associated with reductions in spine density, nitric oxide, and neural nitric oxide synthase in the hippocampus

abstract: Vitamin D deficiency is prevalent in adults and is associated with cognitive impairment. However, the mechanism by which adult vitamin D (AVD) deficiency affects cognitive function remains unclear. We examined spatial memory impairment in AVD-deficient BALB/c mice and its underlying mechanism by measuring spine density, long term potentiation (LTP), nitric oxide (NO), neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS) in the hippocampus. Adult male BALB/c mice were fed a control or vitamin D deficient diet for 20 weeks. Spatial memory performance was measured using an active place avoidance (APA) task, where AVD-deficient mice had reduced latency entering the shock zone compared to controls. We characterised hippocampal spine morphology in the CA1 and dentate gyrus (DG) and made electrophysiological recordings in the hippocampus of behaviourally naive mice to measure LTP. We next measured NO, as well as glutathione, lipid peroxidation and oxidation of protein products and quantified hippocampal immunoreactivity for nNOS and eNOS. Spine morphology analysis revealed a significant reduction in the number of mushroom spines in the CA1 dendrites but not in the DG. There was no effect of diet on LTP. However, hippocampal NO levels were depleted whereas other oxidation markers were unaltered by AVD deficiency. We also showed a reduced nNOS, but not eNOS, immunoreactivity. Finally, vitamin D supplementation for 10 weeks to AVD-deficient mice restored nNOS immunoreactivity to that seen in in control mice. Our results suggest that lower levels of NO, reduced nNOS immunostaining contribute to hippocampal-dependent spatial learning deficits in AVD-deficient mice.

category: animal behavior and cognition


title: APOE ε4 effects on hippocampal atrophy in the healthy elderly reflect future cognitive decline

abstract: The APOE {varepsilon}4 allele is the primary genetic risk factor for late onset Alzheimers disease (AD). A cardinal problem in determining APOE {varepsilon}4s effect on cognition and brain structure in older individuals is dissociating prodromal changes - linked to increased AD risk - from potential phenotypic differences. To address this, we used cognitive and neuroimaging data from a large cohort of cognitively normal 69-86 year-olds with up to 8 yearly follow-ups to investigate cross-sectional and longitudinal differences between APOE {varepsilon}3/{varepsilon}3 homozygotes and {varepsilon}3/{varepsilon}4 heterozygotes. Although we found a significant age-by-genotype interaction in right hippocampal volume, once our analyses were conditionalised by future diagnosis to account for prodromal mild cognitive impairment (MCI) and AD, this effect was no longer observed. Likewise, longitudinally, rate of hippocampal atrophy was determined not by genotype, but by future diagnosis. Thus, we provide direct evidence in support of the prodromal hypothesis of APOE {varepsilon}4 on brain structure.


title: qEEG Analysis in the Diagnosis of Alzheimers Disease; a Comparison of Functional Connectivity and Spectral Analysis

abstract: Alzheimers disease (AD) is a brain disorder that is mainly characterized by a progressive degeneration of neurons in the brain, causing a decline in cognitive abilities and difficulties in engaging in day-to-day activities. This study compares an FFT-based spectral analysis against a functional connectivity analysis based on phase synchronization, for finding known differences between AD patients and Healthy Control (HC) subjects. Both of these quantitative analysis methods were applied on a dataset comprising bipolar EEG montages values from 20 diagnosed AD patients and 20 age-matched HC subjects. Additionally, an attempt was made to localize the identified AD-induced brain activity effects in AD patients. The obtained results showed the advantage of the functional connectivity analysis method compared to a simple spectral analysis. Specifically, while spectral analysis could not find any significant differences between the AD and HC groups, the functional connectivity analysis showed statistically higher synchronization levels in the AD group in the lower frequency bands (delta and theta), suggesting that the AD patients brains are in a  phase-locked state. Further comparison of functional connectivity between the homotopic regions confirmed that the traits of AD were localized in the centro-parietal and centro-temporal areas in the theta frequency band (4-8 Hz). The contribution of this study is that it applies a neural metric for Alzheimers detection from a data science perspective rather than from a neuroscience one. The study shows that the combination of bipolar derivations with phase synchronization yields similar results to comparable studies employing alternative analysis methods.


title: Lateral entorhinal cortex inputs modulate hippocampal dendritic excitability by recruiting a local disinhibitory microcircuit

abstract:
The lateral entorhinal cortex (LEC) provides information about multi-sensory environmental cues to the hippocampus through direct inputs to the distal dendrites of CA1 pyramidal neurons. A growing body of work suggests that LEC neurons perform important functions for episodic memory processing, coding for contextually-salient elements of an environment or the experience within it. However, we know little about the functional circuit interactions between LEC and the hippocampus. In this study, we combine functional circuit mapping and computational modeling to examine how long-range glutamatergic LEC projections modulate compartment-specific excitation-inhibition dynamics in hippocampal area CA1. We demonstrate that glutamatergic LEC inputs can drive local dendritic spikes in CA1 pyramidal neurons, aided by the recruitment of a disinhibitory vasoactive intestinal peptide (VIP)-expressing inhibitory neuron microcircuit. Our circuit mapping further reveals that, in parallel, LEC also recruits cholecystokinin (CCK)-expressing inhibitory neurons, which our model predicts act as a strong suppressor of dendritic spikes. These results provide new insight into a cortically-driven GABAergic microcircuit mechanism that gates non-linear dendritic computations, which may support compartment-specific coding of multi-sensory contextual features within the hippocampus.

HIGHLIGHTSO_LISlice electrophysiology experiments investigate how lateral entorhinal cortex influences hippocampal area CA1
C_LIO_LILEC drives local spikes in distal dendrites but not in somata of CA1 pyramidal neurons
C_LIO_LILEC inputs recruit VIP IN and CCK IN populations in CA1, but not SST INs
C_LIO_LIComputational modeling and circuit manipulation experiments identify a VIP IN-mediated disinhibitory microcircuit for gating local dendritic spike generation
C_LI

IN BRIEFBilash et al. found that a distal cortical input is capable of driving local dendritic spikes in hippocampal pyramidal neurons. This dendritic spike generation is promoted by cortical recruitment of a local VIP interneuron-mediated disinhibitory microcircuit. Their results highlight new circuit mechanisms by which dynamic interaction of excitation, inhibition, and disinhibition support supralinear single-cell computations.


title: Parallel molecular mechanisms underlie convergent evolution of the exaggerated snout phenotype in East African cichlids

abstract:
Studying instances of convergent evolution of novel phenotypes can shed light on the evolutionary constraints that shape morphological diversity. Cichlid fishes from the East African Great Lakes are a prime model to investigate convergent adaptations. However, most studies on cichlid craniofacial morphologies have primarily considered bony structures, while soft tissue adaptations have been less intensely scrutinised. A rare example of an exaggerated soft tissue phenotype is the formation of a snout flap. This tissue flap develops from the upper lip and has evolved in only one cichlid genus from Lake Malawi and one genus from Lake Tanganyika. To investigate the molecular basis of snout flap convergence, we used mRNA sequencing to compare two species with snout flap (Labeotropheus trewavasae and Ophthalmotilapia nasuta) to their close relatives without snout flaps (Tropheops tropheops and Ophthalmotilapia ventralis) from Lake Tanganyika and Malawi. Our analysis revealed a greater complexity of differential gene expression patterns underlying the snout flap in the younger adaptive radiation of Lake Malawi than in the older Lake Tanganyika radiation. We identified 201 genes that were repeatedly differentially expressed between species with and without the snout flap in both lakes, suggesting that the pathway that gives rise to snout flaps is evolutionarily constrained, even though the flaps play very different functions in each species. The convergently expressed genes are involved in proline and hydroxyproline metabolism, which have been linked to human skin and facial deformities. Additionally, we also found enrichment for transcription factor binding sites upstream of differentially expressed genes such as members of the FOX transcription factor family, especially foxf1 and foxa2, which also showed an increased expression in the flapped snout and are linked to nose morphogenesis in mammals, as well as ap4 (tfap4), a transcription factor showing reduced expression in the flapped snout with an unknown role in the development of craniofacial soft tissues. As genes involved in cichlids snout flap development are associated with many human mid-line facial dysmorphologies, our findings imply a conservation of genes involved in mid-line patterning across vastly distant evolutionary lineages of vertebrates.

Significance statementThe study of the evolution of similar physical traits across taxa can give insight into the molecular architecture underlying shared phenotypes. This has mostly been studied in bony structures, while soft tissue traits have been less intensely covered. We investigated the exaggerated snout in cichlid species from Lake Malawi and Lake Tanganyika and found that many genes involved in the development of the snout flap are also associated with mid-line dysmorphologies in humans, implying a conservation across distant vertebrate lineages.


title: Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

abstract: Transposable elements (TEs) contribute to the evolution of gene regulatory networks and are dynamically expressed throughout human brain development and disease. One gene regulatory mechanism influenced by TEs is the miRNA system of post-transcriptional control. miRNA sequences frequently overlap TE loci and this miRNA expression landscape is crucial for control of gene expression in adult brain and different cellular contexts. Despite this, a thorough investigation of the spatiotemporal expression of TE-embedded miRNAs in human brain development is lacking. Here, we identify a spatiotemporally dynamic TE-embedded miRNA expression landscape between childhood and adolescent stages of human brain development. These miRNAs sometimes arise from two apposed TEs of the same subfamily, such as for L2 or MIR elements, but in the majority of cases stem from solo TEs. They give rise to in silico predicted high-confidence pre-miRNA hairpin structures, likely represent functional miRNAs and have predicted genic targets associated with neurogenesis. TE-embedded miRNA expression is distinct in the cerebellum when compared to other brain regions, as has previously been described for gene and TE expression. Furthermore, we detect expression of previously non-annotated TE-embedded miRNAs throughout human brain development, suggestive of a previously undetected miRNA control network. Together, as with non-TE-embedded miRNAs, TE-embedded sequences give rise to spatiotemporally dynamic miRNA expression networks, the implications of which for human brain development constitute extensive avenues of future experimental research. To facilitate interactive exploration of these spatiotemporal miRNA expression dynamics, we provide the "Brain miRTExplorer" web application freely accessible for the community.


title: Interaction between photoperiod and variation in circadian rhythms in tomato

abstract: Many biological processes follow circadian rhythmicity and are controlled by the circadian clock. Predictable environmental changes such as seasonal variation in photoperiod can modulate circadian rhythms, allowing organisms to adjust to the time of the year. Modification of circadian clocks is especially relevant in crops to enhance their cultivability in specific regions by changing their sensibility to photoperiod. In tomato, the appearance of mutations in EMPFINDLICHER IM DUNKELROTEN LICHT 1 (EID1, Solyc09g075080) and NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED GENE 2 (LNK2, Solyc01g068560) during domestication delayed its circadian rhythms, and allowed its expansion outside its equatorial origin. Here we study how variation in circadian rhythms in tomato affects its perception of photoperiod. To do this, we create near isogenic lines carrying combinations of wild alleles of EID1 and LNK2 and perform transcriptomic profiling under two different photoperiods. We observe that EID1, but not LNK2, has a large effect on the tomato transcriptome and its response to photoperiod. This large effect of EID1 is likely a consequence of the global phase shift elicited by this gene in tomatos circadian rhythms.


title: Deciphering the evolution of microbial interactions: in silico studies of two-member microbial communities

abstract: Microbes thrive in communities, embedded in a complex web of interactions. These interactions, particularly metabolic interactions, play a crucial role in maintaining the community structure and function. As the organisms thrive and evolve, a variety of evolutionary processes alter the interactions among the organisms in the community, although the community function remains intact. In this work, we simulate the evolution of two-member microbial communities in silico to study how evolutionary forces can shape the interactions between organisms. We employ genome-scale metabolic models of organisms from the human gut, which exhibit a range of interaction patterns, from mutualism to parasitism. We observe that the evolution of microbial interactions varies depending upon the starting interaction and also on the metabolic capabilities of the organisms in the community. We find that evolutionary constraints play a significant role in shaping the dependencies of organisms in the community. Evolution of microbial communities yields fitness benefits in only a small fraction of the communities, and is also dependent on the interaction type of the wild-type communities. The metabolites cross-fed in the wild-type communities appear in only less than 50% of the evolved communities. A wide range of new metabolites are cross-fed as the communities evolve. Further, the dynamics of microbial interactions are not specific to the interaction of the wild-type community but vary depending on the organisms present in the community. Our approach of evolving microbial communities in silico provides an exciting glimpse of the dynamics of microbial interactions and offers several avenues for future investigations.

category: systems biology


title: Impaired functional connectivity of the hippocampus in murine models of NMDA-receptor antibody associated pathology

abstract:
IntroductionWhile decreased hippocampal connectivity and disruption of functional networks are established MRI features in human anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, the underlying pathophysiology for brain network alterations remains poorly understood. Application of patient-derived monoclonal antibodies against the NR1 subunit of the NMDAR allows for the investigation of potential functional connectivity alterations in experimental murine NMDAR antibody disease models.

ObjectiveTo explore functional connectivity changes in NR1 antibody mouse models using resting-state functional MRI (rs-fMRI).

MethodsAdult C57BL/6J mice (n=10) were intrathecally injected with a recombinant human NR1 antibody over 14 days and then studied using rs-fMRI at 7 Tesla. In addition, a newly established mouse model with in utero exposure to a human recombinant NR1 antibody characterized by a neurodevelopmental disorder (NR1-offspring) was investigated with rs-fMRI at the age of 8 weeks (n=15) and 10 months (n=14). Mice exposed to isotype-matched control antibodies served as controls. Independent component analysis (ICA) and dual regression analysis were performed to compare functional connectivity between NMDAR antibody mouse models and control mice.

ResultsAdult NR1-antibody injected mice showed significantly impaired functional connectivity within the dentate gyrus of the left hippocampus in comparison to controls, resembling impaired hippocampal functional connectivity patterns observed in human patients with NMDAR encephalitis. Similarly, analyses showed significantly reduced functional connectivity in the dentate gyrus in NR1-offspring compared after 8 weeks, and impaired connectivity in the dentate gyrus and CA3 hippocampal subregion in NR1-offspring at the age of 10 months.

ConclusionFunctional connectivity changes within the hippocampus resulting from both direct application and in utero exposure to NMDAR antibodies can be modeled in experimental murine systems. With this translational approach, we successfully reproduced functional MRI alterations previously observed in human NMDAR encephalitis patients. Future experimental studies will identify the detailed mechanisms that cause functional network alterations and may eventually allow for non-invasive monitoring of disease activity and therapeutic effects in autoimmune encephalitis.


title: Harmonized-Multinational qEEG Norms (HarMNqEEG)

abstract:
This paper extends our frequency domain quantitative electroencephalography (qEEG) methods pursuing higher sensitivity to detect Brain Developmental Disorders. Prior qEEG work lacked integration of cross-spectral information omitting important functional connectivity descriptors. Lack of geographical diversity precluded accounting for site-specific variance, increasing qEEG nuisance variance. We ameliorate these weaknesses. i) Create lifespan Hermitian Riemannian multinational qEEG norms for cross-spectral tensors. These norms result from the HarMNqEEG project fostered by the Global Brain Consortium. We calculate the norms with data from 9 countries, 12 devices, and 14 studies, including 1564 subjects. Instead of raw data, only anonymized metadata and EEG cross-spectral tensors were shared. After visual and automatic quality control developmental equations for the mean and standard deviation of qEEG traditional and Hermitian Riemannian descriptive parameters were calculated using additive mixed-effects models. We demonstrate qEEG "batch effects" and provide methods to calculate harmonized z-scores. ii) We also show that the multinational harmonized Hermitian Riemannian norms produce z-scores with increased diagnostic accuracy to predict brain dysfunction at school-age produced by malnutrition only in the first year of life. We provide data and software for constructing norms. iii) We offer open code and data to calculate different individual z-scores from the HarMNqEEG dataset. These results contribute to developing bias-free, low-cost neuroimaging technologies applicable in various health settings.

HighlightsO_LIWe create lifespan Hermitian Riemannian qEEG norms for cross-spectral tensors.
C_LIO_LIThe norms are based on 9 countries, 12 devices, and 14 studies, with 1564 subjects.
C_LIO_LIWe demonstrate qEEG "batch effects", providing harmonization methods to remove them.
C_LIO_LIMultinational harmonized z-scores increase diagnostic accuracy of brain dysfunction.
C_LIO_LIData and software are available for norm and individual z-scores calculation.
C_LI


title: Using intracerebral microdialysis to probe the efficacy of repurposed drugs in Alzheimer's disease pathology

abstract:
All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimers disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-{beta}, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-{beta} in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-{beta}. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-{beta} than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-{beta} pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows.

One Sentence SummaryHere we circumvented the blood-brain barrier for drug delivery aimed at attenuating AD neuropathology.


title: White Matter Brain Structure Predicts Language Performance and Learning Success

abstract: Individual differences in the ability to deal with language have long been discussed. The neural basis of these, however, is yet unknown. Here we investigated the relationship between long-range white matter connectivity of the brain, as revealed by diffusion tractography, and the ability to process syntactically complex sentences in the participants native language as well as the improvement thereof by multi-day training. We identified specific network motifs that indeed related white matter tractography to individual language processing performance. First, for two such motifs, one in the left and one in the right hemisphere, their individual prevalence significantly predicted the individual language performance suggesting a predisposition for the individual ability to process syntactically complex sentences, which manifests itself in the white matter brain structure. Both motifs comprise a number of cortical regions, but seem to be dominated by areas known for the involvement in working memory rather than the classical language network itself. Second, we identified another left hemispheric network motif, whose change of prevalence over the training period significantly correlated with the individual change in performance, thus reflecting training induced white matter plasticity. This motif comprises diverse cortical areas including regions known for their involvement in language processing, working memory and motor functions. The present findings suggest that individual differences in language processing and learning can be explained, in part, by individual differences in the brains white matter structure. Brain structure may be a crucial factor to be considered when discussing variations in human cognitive performance, more generally.


title: Limb Specific Failure of Proliferation and Translation in the Mesenchyme Leads to Skeletal Defects in Diamond Blackfan Anemia

abstract: AbstractRibosomopathies are a class of disorders caused by defects in the structure or function of the ribosome and characterized by tissue-specific abnormalities. Diamond Blackfan anemia (DBA) arises from different mutations, predominantly in genes encoding ribosomal proteins (RPs). Apart from the anemia, skeletal defects are among the most common anomalies observed in patients with DBA, but they are virtually restricted to radial ray and other upper limb defects. What leads to these site-specific skeletal defects in DBA remains a mystery. Using a novel mouse model for RP haploinsufficiency, we observed specific, differential defects of the limbs. Using complementary in vitro and in vivo approaches, we demonstrate that reduced WNT signaling and subsequent increased {beta}-catenin degradation in concert with increased expression of p53 contribute to mesenchymal lineage failure. We observed differential defects in the proliferation and differentiation of mesenchymal stem cells (MSCs) from the forelimb versus the hind limbs of the RP haploinsufficient mice that persisted after birth and were partially rescued by allelic reduction of Trp53. These defects are associated with a global decrease in protein translation in RP haploinsufficient MSCs, with the effect more pronounced in cells isolated from the forelimbs. Together these results demonstrate translational differences inherent to the MSC, explaining the site-specific skeletal defects observed in DBA.

category: cell biology


title: The blowfly  Chrysomya latifrons  inhabits fragmented rainforests, but lacks genetic diversity and population structure

abstract:
Climate change and deforestation are causing rainforests to become increasingly fragmented, placing them at heightened risk of biodiversity loss. Invertebrates constitute the greatest proportion of this biodiversity, yet we lack basic knowledge of their population structure and ecology. It is not currently feasible to assess the population structure of every invertebrate species, so there is a compelling need to identify  indicator species that are broadly indicative of habitat-level patterns and processes. Blowflies are an ideal candidate, because they are widespread, abundant, and can be easily collected within rainforests.

Here, we present the first study of the blowfly Chrysomya latifrons, which is endemic to the rainforests of New South Wales, Australia. We genotyped 188 flies from 15 isolated rainforests and found low overall genetic diversity and a complete lack of genetic structure between populations - suggesting the presence of a single large panmictic population along ~1,000 km of the Australian east coast. This highlights that: (1) Ch. latifrons inhabits every rainforest in NSW and undoubtedly plays an important role in these ecosystems, but low genetic diversity may cause it to struggle to adapt to a changing climate; (2) strongly dispersing insects have the capacity to migrate between isolated rainforests, likely carrying pollen, parasites, phoronts, and pathogens with them to form crucial trophic networks; and (3) there is an urgent need for similar studies on poorly dispersing rainforest insects, as these may be the most fragmented and at highest risk of local extinction.


title: BlenderPhotonics - a versatile environment for 3-D complex bio-tissue modeling and light transport simulations based on Blender

abstract:
SignificanceRapid advances in biophotonics techniques require quantitative, model-based computational approaches to obtain functional and structural information from increasingly complex and multi-scaled anatomies. The lack of efficient tools to accurately model tissue structures and subsequently perform quantitative multi-physics modeling greatly impedes the clinical translation of these modalities.

AimWhile the mesh-based Monte Carlo (MMC) method expands our capabilities in simulating complex tissues by using tetrahedral meshes, the generation of such domains often requires specialized meshing tools such as Iso2Mesh. Creating a simplified and intuitive interface for tissue anatomical modeling and optical simulations is essential towards making these advanced modeling techniques broadly accessible to the user community.

ApproachWe responded to the above challenge by combining the powerful, open-source 3-D modeling software, Blender, with state-of-the-art 3-D mesh generation and MC simulation tools, utilizing the interactive graphical user interface (GUI) in Blender as the front-end to allow users to create complex tissue mesh models, and subsequently launch MMC light simulations.

ResultsHere we present a tutorial to our newly developed Python-based Blender add-on - BlenderPhotonics - to interface with Iso2Mesh and MMC, allowing users to create, configure and refine complex simulation domains and run hardware-accelerated 3-D light simulations with only a few clicks. We provide a comprehensive introduction to this new tool and walk readers through 5 examples, ranging from simple shapes to sophisticated realistic tissue models.

ConclusionBlenderPhotonics is user-friendly and open-source, leveraging the vastly rich ecosystem of Blender. It wraps advanced modeling capabilities within an easy-to-use and interactive interface. The latest software can be downloaded at http://mcx.space/bp.


title: BlenderPhotonics - an integrated open-source software environment for 3-D meshing and photon simulations in complex tissues


title: Integrative analysis of relative abundance data and presence-absence data of the microbiome using the LDM

abstract:
SummaryWe previously developed LDM for testing hypotheses about the microbiome that performs the test at both the community level and the individual taxon level. LDM can be applied to relative abundance data and presence-absence data separately, which work well when associated taxa are abundant and rare, respectively. Here we propose an omnibus test based on LDM that allows simultaneous consideration of data at different scales, thus offering optimal power across scenarios with different association mechanisms. The omnibus test is available for the wide range of data types and analyses that are supported by LDM.

Availability and ImplementationThe omnibus test has been added to the R package LDM, which is available on GitHub at https://github.com/yijuanhu/LDM.

Contactyijuan.hu@emory.edu

Supplementary informationSupplementary data are available at Bioinformatics online.


title: CCPLS reveals cell-type-specific spatial dependence of transcriptomes in single cells

abstract:
MotivationCell-cell communications regulate internal cellular states of the cell, e.g., gene expression and cell functions, and play pivotal roles in normal development and disease states. Furthermore, single-cell RNA sequencing methods have revealed cell-to-cell expression variability of highly variable genes (HVGs), which is also crucial. Nevertheless, the regulation on cell-to-cell expression variability of HVGs via cell-cell communications is still unexplored. The recent advent of spatial transcriptome measurement methods has linked gene expression profiles to the spatial context of single cells, which has provided opportunities to reveal those regulations. The existing computational methods extract genes with expression levels that are influenced by neighboring cell types based on the spatial transcriptome data. However, limitations remain in the quantitativeness and interpretability: it neither focuses on HVGs, considers cooperation of neighboring cell types, nor quantifies the degree of regulation with each neighboring cell type.

ResultsHere, we propose CCPLS (Cell-Cell communications analysis by Partial Least Square regression modeling), which isa statistical framework for identifying cell-cell communications as the effects of multiple neighboring cell types on cell-to-cell expression variability of HVGs, based on the spatial transcriptome data. For each cell type, CCPLS performs PLS regression modeling and reports coefficients as the quantitative index of the cell-cell communications. Evaluation using simulated data showed our method accurately estimated the effects of multiple neighboring cell types on HVGs. Furthermore, by applying CCPLS to the two real datasets, we demonstrate CCPLS can be used to extract biologically interpretable insights from the inferred cell-cell communications.

AvailabilityThe R package is available at https://github.com/bioinfo-tsukuba/CCPLS. The data are available at https://github.com/bioinfo-tsukuba/CCPLS_paper.

Contactharuka.ozaki@md.tsukuba.ac.jp

Supplementary informationSupplementary data are available at Bioinformatics online.


title: Griottes: a generalist tool for network generation from segmented tissue images

abstract: Microscopy techniques and image segmentation algorithms have improved dramatically this decade, leading to an ever increasing amount of biological images and a greater reliance on imaging to investigate biological questions. This has created a need for methods to extract the relevant information on the behaviors of cells and their interactions, while reducing the amount of computing power required to organize this information. This task can be performed by using a network representation in which the cells and their properties are encoded in the nodes, while the neighborhood interactions are encoded by the links. Here we introduce Griottes, an open-source tool to build the "network twin" of 2D and 3D tissues from segmented microscopy images. We show how the library can provide a wide range of biologically relevant metrics on individual cells and their neighborhoods, with the objective of providing multi-scale biological insights. The librarys capacities are demonstrated on different image and data types. This library is provided as an open-source tool that can be integrated into common image analysis workflows to increase their capacities.


title: In vitro Kinase-to-Phosphosite database (iKiP-DB) predicts kinase activity in phosphoproteomic datasets

abstract: Phosphoproteomics routinely quantifies changes in the levels of thousands of phosphorylation sites, but functional analysis of such data remains a major challenge. While databases like PhosphoSitePlus contain information about many phosphorylation sites, the vast majority of known sites are not assigned to any protein kinase. Assigning changes in the phosphoproteome to the activity of individual kinases therefore remains a key challenge.. A recent large-scale study systematically identified in vitro substrates for most human protein kinases. Here, we reprocessed and filtered these data to generate an in vitro Kinase-to-Phosphosite database (iKiP-DB). We show that iKiP-DB can accurately predict changes in kinase activity in published phosphoproteomic datasets for both well-studied and poorly characterized kinases. We apply iKiP-DB to a newly generated phosphoproteomic analysis of SARS-CoV-2 infected human lung epithelial cells and provide evidence for coronavirus-induced changes in host cell kinase activity. In summary, we show that iKiP-DB is widely applicable to facilitate the functional analysis of phosphoproteomic datasets.


title: A semi-supervised Bayesian mixture modelling approach for joint batch correction and classification

abstract: AO_SCPLOWBSTRACTC_SCPLOWSystematic differences between batches of samples present significant challenges when analysing biological data. Such batch effects are well-studied and are liable to occur in any setting where multiple batches are assayed. Many existing methods for accounting for these have focused on high-dimensional data such as RNA-seq and have assumptions that reflect this. Here we focus on batch-correction in low-dimensional classification problems. We propose a semi-supervised Bayesian generative classifier based on mixture models that jointly predicts class labels and models batch effects. Our model allows observations to be probabilistically assigned to classes in a way that incorporates uncertainty arising from batch effects. We explore two choices for the within-class densities: the multivariate normal and the multivariate t. A simulation study demonstrates that our method performs well compared to popular off-the-shelf machine learning methods and is also quick; performing 15,000 iterations on a dataset of 500 samples with 2 measurements each in 7.3 seconds for the MVN mixture model and 11.9 seconds for the MVT mixture model. We apply our model to two datasets generated using the enzyme-linked immunosorbent assay (ELISA), a spectrophotometric assay often used to screen for antibodies. The examples we consider were collected in 2020 and measure seropositivity for SARS-CoV-2. We use our model to estimate seroprevalence in the populations studied. We implement the models in C++ using a Metropolis-within-Gibbs algorithm; this is available in the R package at https://github.com/stcolema/BatchMixtureModel. Scripts to recreate our analysis are at https://github.com/stcolema/BatchClassifierPaper.


title: DeepGOZero: Improving protein function prediction from sequence and zero-shot learning based on ontology axioms

abstract:
MotivationProtein functions are often described using the Gene Ontology (GO) which is an ontology consisting of over 50,000 classes and a large set of formal axioms. Predicting the functions of proteins is one of the key challenges in computational biology and a variety of machine learning methods have been developed for this purpose. However, these methods usually require significant amount of training data and cannot make predictions for GO classes which have only few or no experimental annotations.

ResultsWe developed DeepGOZero, a machine learning model which improves predictions for functions with no or only a small number of annotations. To achieve this goal, we rely on a model-theoretic approach for learning ontology embeddings and combine it with neural networks for protein function prediction. DeepGOZero can exploit formal axioms in the GO to make zero-shot predictions, i.e., predict protein functions even if not a single protein in the training phase was associated with that function. Furthermore, the zero-shot prediction method employed by DeepGOZero is generic and can be applied whenever associations with ontology classes need to be predicted.

Availabilityhttp://github.com/bio-ontology-research-group/deepgozero

Contactrobert.hoehndorf@kaust.edu.sa


title: Glucose-stimulated calcium dynamics in beta cells from C57BL/6J, C57BL/6N, and NMRI mice: A systematic comparison of activation, activity, and deactivation properties in tissue slices

abstract: Although mice are a very instrumental model in islet beta cell research, possible phenotypic differences between strains and substrains are largely neglected in the scientific community. In this study, we show important phenotypic differences in beta cell responses to glucose between NMRI, C57BL/6J, and C57BL/6N mice, i.e., the three most commonly used strains. High-resolution multicellular confocal imaging of beta cells in acute pancreas tissue slices was used to measure and quantitatively compare the calcium dynamics in response to a wide range of glucose concentrations. Strain- and substrain-specific features were found in all three phases of beta cell responses to glucose: a shift in the dose-response curve characterizing the delay to activation and deactivation in response to stimulus onset and termination, respectively, and distinct concentration-encoding principles during the plateau phase in terms of frequency, duration, and active time changes with increasing glucose concentrations. Our results underline the significance of carefully choosing and reporting the strain to enable comparison and increase reproducibility, emphasize the importance of analyzing a number of different beta cell physiological parameters characterizing the response to glucose, and provide a valuable standard for future studies on beta cell calcium dynamics in health and disease.

category: physiology


title: coveR: An R package for processing Digital Cover Photography images to retrieve forest canopy attributes

abstract:
O_LIDigital Cover Photography (DCP) is an increasingly popular tool for estimating canopy cover and leaf area index (LAI). However, existing solutions to process canopy images are predominantly tailored for fisheye photography, whereas open-access tools for DCP are lacking.
C_LIO_LIWe developed an R package (coveR) to support the whole processing of DCP images in an automated, fast, and reproducible way. The package functions, which are designed for step-by-step single-image analysis, can be performed sequentially in a pipeline, while also allowing simple implementation for batch-processing bunches of images.
C_LIO_LIA case study is presented to demonstrate the reliability of canopy attributes derived from coveR in pure beech (Fagus sylvatica L.) stands with variable canopy density and structure. Estimates of gap fraction and effective LAI from DCP were validated against reference measurements obtained from terrestrial laser scanning.
C_LIO_LIBy providing a simple, transparent, and flexible image processing procedure, coveR supported the use of DCP for routine measurements and monitoring of forest canopy attributes. This, combined with the implementability of DCP in many devices, including smartphones, micro-cameras, and remote trail cameras, can greatly expand the accessibility of the method also by non-experts.
C_LI


title: Functional resilience of mutually repressing motifs embedded in larger regulatory networks

abstract: Elucidating the design principles of regulatory networks driving cellular decision-making has important implications in understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between  master regulators of cell-fates can exhibit multistable dynamics, thus enabling multiple "single-positive" phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two network motifs has been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these network motifs in complex larger networks of varying sizes and connectivity and identify conditions under which these motifs maintain their canonical dynamical behavior, thus identifying hallmarks of their functional resilience. We show that an increased number of incoming edges onto a motif leads to a decay in their canonical stand-alone behaviors, as measured by multiple metrics based on pairwise correlation among nodes, bimodality of individual nodes, and the fraction of "single-positive" states. We also show that this decay can be exacerbated by adding self-inhibition, but not self-activation, loops on the  master regulators. These observations offer insights into the design principles of biological networks containing these motifs, and can help devise optimal strategies for integration of these motifs into larger synthetic networks.


title: Nicotinic signaling is required for motor learning but not rehabilitation after spinal cord injury

abstract: Currently, therapeutic intervention for spinal cord injury is limited. Many approaches rely on strengthening the remaining substrate and driving recovery through rehabilitative training. As compared to learning novel compensatory strategies, rehabilitation focuses on restoring movements lost to injury. Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning, or if it engages previously trained motor circuits without requiring novel learning. Our findings implicate the latter mechanism, as we demonstrate that nicotinic acetylcholine signaling is required for motor learning but is dispensable for the recovery of previously trained motor behavior after cervical spinal cord injury.


title: Contextual associations represented both in neural networks and human behavior

abstract: Contextual associations facilitate object recognition in human vision. However, the role of context in artificial vision remains elusive as does the characteristics that humans use to define context. We investigated whether contextually related objects (bicycle-helmet) are represented more similarly in convolutional neural networks (CNNs) used for image understanding than unrelated objects (bicycle-fork). Stimuli were of objects against a white background and consisted of a diverse set of contexts (N=73). CNN representations of contextually related objects were more similar to one another than to unrelated objects across all CNN layers. Critically, the similarity found in CNNs correlated with human behavior across three experiments assessing contextual relatedness, emerging significant only in the later layers. The results demonstrate that context is inherently represented in CNNs as a result of object recognition training, and that the representation in the later layers of the network tap into the contextual regularities that predict human behavior.