title: The RNA-binding protein EIF4A3 promotes axon development by direct control of the cytoskeleton

abstract:
The exon junction complex (EJC), nucleated by EIF4A3, is indispensable for mRNA fate and function throughout eukaryotes. Unexpectedly, we discover that EIF4A3 directly controls microtubules independent of RNA, and this is critical for neural wiring. While neuronal survival in the developing mouse cerebral cortex depends upon an intact EJC, axonal tract formation requires only Eif4a3. Using human cortical organoids, we demonstrate that EIF4A3 disease mutations also impair neuronal maturation, highlighting conserved functions relevant for neurodevelopmental pathology. Employing biochemistry and molecular modeling we discover that EIF4A3 directly binds to microtubules, mutually exclusive of the RNA-binding complex. In growing neurons, EIF4A3 is essential for microtubule dynamics, and sufficient to promote microtubule polymerization and stability in vitro. Together, our data show that tubulin-bound EIF4A3 orchestrates microtubule dynamics, underlying key events of neuronal development. This reveals a new mechanism by which neurons re-utilize core gene expression machinery to rapidly and directly control the cytoskeleton.

HighlightsO_LIThe Exon Junction Complex controls neuronal survival but only EIF4A3 directs axonal growth
C_LIO_LIEIF4A3 controls axonal tract formation in vivo.
C_LIO_LIHuman EIF4A3 deficient iPSC-derived cortical organoids recapitulate neuronal defects.
C_LIO_LIEIF4A3 directly binds to microtubules to control their growth and stability in neurons.
C_LI


title: Inducible depletion of Scleraxis-lineage cells during tendon healing impairs multi-scale restoration of tendon structure

abstract: Tendons are composed of a heterogeneous cell environment, with Scleraxis-lineage (ScxLin) cells being the predominant population. Although ScxLin cells are required for maintenance of tendon homeostasis, their functions during tendon healing are unknown. To this end, we first characterized the spatiotemporal dynamics of ScxLin cells during tendon healing, and identified that the overall ScxLin pool continuously expands up to early remodeling healing phase. To better define the function of ScxLin cells during the late proliferative phase of healing, we inducibly depleted ScxLin cells from day 14-18 post-surgery using the Scx-Cre; Rosa-DTR mouse model, with local administration of diphtheria toxin inducing apoptosis of ScxLin cells in the healing tendon. At D28 post-surgery, ScxLin cell depleted tendons (DTR) had substantial impairments in structure and function, relative to WT, demonstrating the importance of ScxLin cells during tendon healing. Next, bulk RNAseq was utilized to identify the underlying mechanisms that were impaired with depletion and revealed that ScxLin depletion induced molecular and morphological stagnation of the healing process at D28. However, this stagnation was transient, such that by D56 tendon mechanics in DTR were not significantly different than wildtype repairs. Collectively, these data offer fundamental knowledge on the dynamics and roles of ScxLin cells during tendon healing.

category: cell biology


title: Coverage-preserving sparsification of overlap graphs for long-read assembly

abstract:
Read-overlap-based graph data structures play a central role in computing de novo genome assembly using long reads. Many assembly tools use the string graph model [Myers, Bioinformatics 2005] to sparsify overlap graphs. Graph sparsification improves accuracy by removing spurious and redundant connections. However, a graph model must be coverage-preserving, i.e., it must ensure that each chromosome can be spelled as a walk in the graph, given sufficient sequencing coverage. This property becomes even more important for diploid genomes, polyploid genomes and metagenomes where there is a risk of losing haplotype-specific information.

We develop a novel theoretical framework under which the coverage-preserving properties of a graph model can be analysed. We first prove that de Bruijn graph and overlap graph models are guaranteed to be coverage-preserving. We also prove that the standard string graph model lacks this guarantee. The latter result is consistent with the observation made in [Hui et al., 2016; Nurk et al., 2021] that removal of contained reads during string graph construction can lead to coverage gaps. To remedy this, we propose practical heuristics that are well-supported by our theoretical results to sparsify overlap graphs. In our experiments using simulated long reads from HG002 human diploid genome, we find that 98 and 5 coverage gaps are introduced by ignoring contained reads from nanopore and HiFi long-read datasets respectively. We test the proposed heuristics for deciding which contained reads should be retained to avoid the coverage gaps. The proposed method retains a small fraction of contained reads (1 - 2%) and closes all coverage gaps. This compares favorably to other known solutions for this problem.

category: bioinformatics


title: Geology and discovery record of the Trinil Pithecanthropus erectus site, Java

abstract:
The scientific utility of Eugene Dubois Pithecanthropus erectus (P.e.) Skullcap (Trinil 1), Femur I (Trinil 3) and associated paleontological specimens has been impaired for over a century by questions about their provenience. Firsthand accounts and contemporaneous field photographs, presented here, extensively document the site geology and discovery history.

The P.e. specimens and numerous-other fossils were unearthed in 1891-1893 from small excavations dug into a flat-lying bonebed exposed near the seasonal low-water level of the Solo River along its incised left embankment. Dubois on-site supervisors specified that the two P.e. fossils came from a [~]0.2-m-thick bonebed subunit traced at a single elevation for [~]12m from the 1891 Skullcap pit ([~]30m2) to the 1892 Femur-discovery excavation and across an enlarged 1892-1893 trench ([~]170m2). The depositional co-occurrence of the finds is supported by key documentation: the supervisors letters to Dubois about Femur I; his initial reporting to the Indies government; 1892-1893 accounts about expanding excavation of the Femur I stratum; Dubois 1891-1893 government submissions and 1894-1896 publications; confirmation by the Selenka Expedition in 1907-1908; Dubois annotations on unpublished site photographs; and a letter he wrote the year he died. Field studies in the 1930s to 1970s confirmed the essential aspects of the site geology.

The bonebed of 1891-1893 contained fossils referable to the extinct Trinil fauna species Axis lydekkeri, Duboisia santeng and Stegodon trigonocephalus. The Selenka Expedition excavations had a similar assemblage in the same stratigraphic position which they named the Hauptknochenschicht. The bonebed was thin bioclast-rich gravelly volcaniclastic sandstone with taphonomic and sedimentary features indicating an unusual origin. Bioclasts range from proboscidean craniums and logs to rat teeth, freshwater mollusc shells and leaves. The terrestrial-vertebrate skeletal elements are overwhelmingly disarticulated and frequently broken. Their surfaces are little-abraded by fluvial transport. The bone fossilization is quite uniform. More than one-hundred ungulate individuals perished. No evidence has been found of hominin- or terrestrial-carnivore involvement. The bioclasts varied in density from place-to-place and vertically, and were matrix supported in the bonebed. No substantial internal depositional hiatus was reported. In combination with Trinils paleogeographic context, these features implicate a catastrophic mortality of ungulates in a population aggregation along the floodplain of a perennial paleo-river, followed by lahar-flood transport and deposition of gravel-size lithic- and biotic-materials.

Trinil provides evidence favoring a broad archaic-hominin presence in southern Sundaland. The Trinil fauna is a lynch-pin in a long-lasting paleobiogeographic association between H. erectus and certain lineages of large bovids, cervids, proboscideans, rhinoceros, suids and tiger. The bonebeds paleogeographic setting exemplifies the stratovolcanic drainages that H. erectus occupied for >0.8 million years in Java, including the watershed of a marine delta [~]150km east of Trinil, a volcanic island [~]100km north of Trinil, and areas to its west for 500km (where species associated with Trinil H. erectus occur). In the Java Sea (Sunda Shelf), seismic data image immense Pleistocene river- and coastal-terranes which archaic hominins and other large-mammals, like those at Trinil, might have inhabited.

category: paleontology


title: The rate of information transmission through the MAPK/ERKsignaling pathway stimulated in a pulsatile manner

abstract: Many intracellular signaling pathways, including the MAPK/ERK cascade, respond to an external stimulus in a yes-or-no manner. This has been reflected in estimates of the amount of information a single cell can transmit about the amplitude of an applied (and sustained) input signal, which turns out to only slightly exceed 1 bit. More information, however, can potentially be transmitted in response to time-varying stimulation. In this work, we find a lower bound of the MAPK/ERK signaling channel capacity. We use an epithelial cell line expressing an ERK activity reporter and an optogenetically modified fibroblast growth factor receptor, which allows triggering eventual ERK activity by short light pulses. We observe that it is possible to reconstruct the stimulatory input pattern with five-minute delay and one-minute resolution. By stimulating the cells with random pulse trains we demonstrate that the information transmission rate through the MAPK/ERK pathway can exceed 6 bits per hour. Such high information transmission rate allows the MAPK/ERK pathway to coordinate multiple processes including cell movement.

category: systems biology


title: Gene Co-expression Connectivity Predicts Gene Targets Underlying High Ionic Liquid Tolerance in Yarrowia lipolytica

abstract: Microbial tolerance to organic solvents such as ionic liquids (ILs) is a robust phenotype beneficial for novel biotransformation. While most microbes become inhibited in 1%-5% (v/v) IL (e.g., 1-ethyl-3-methylimidazolium acetate), we engineered a robust Yarrowia lipolytica (YlCW001) that tolerates a record high of 18% (v/v) IL via adaptive laboratory evolution. Yet, genotypes conferring high IL tolerance in YlCW001 remain to be discovered. Using dynamic RNA-Seq data, we shed light on the underlying cellular processes that Y. lipolytica responds to IL. We introduced Gene Co-expression Connectivity (GeCCo) to discover genotypes conferring desirable phenotypes that might not be found by the conventional differential expression (DE) approaches. GeCCo selects genes based on their number of co-expressed genes in a sub-network of upregulated genes by the target phenotype. We experimentally validated GeCCo by reversely engineering high IL-tolerant phenotype in wildtype Y. lipolytica. We found that gene targets selected by both DE and GeCCo exhibited the best statistical chance at increasing IL tolerance when individually overexpressed. Remarkably, the best combination of dual-overexpressed genes were genes selected by GeCCo alone. This non-intuitive combination of genes, BRN1 and OYE2, are involved in guiding/regulating mitotic cell division, chromatin segregation/condensation, microtubule and cytoskeletal organization, and Golgi vesicle transport.


title: Diminished distractor filtering with increased perceptual load and sustained effort explains attention deficit in post-stroke fatigue

abstract:
ObjectivesPost-stroke fatigue (PSF) is a prevalent symptom associated with attention deficits. However, it is currently unclear what drives these. Here we applied Load Theory of Attention to investigate the role of perceptual load in the relationship between attention, distraction, and fatigue levels in PSF.

MethodsThirty-two chronic stroke survivors performed a selective attention task under different perceptual load levels. Neural responses to targets and distractors were measured with frequency-tagged EEG responses.

ResultsWe showed that Fatigue Severity Scale-7 (FSS-7) scores are predictive of slower responses, irrespective of the task level of perceptual load. Although average distractor frequency (10Hz) power was reduced with higher perceptual load, the reduction in 10Hz power with increasing task load, was smaller in those with higher FSS-7 scores. Higher FSS-7 scores were also associated with increased 10Hz distractor response as time progressed, both within task-trials and across the experiment duration.

ConclusionThe results are consistent with previous reports of slower processing speed and sustained selective attention deficits. Importantly they demonstrate that higher fatigue severity is associated with a reduced ability to suppress neural response to irrelevant distractors stimuli when the task demands more attention due to its increased perceptual load. An account for attention deficit in PSF based on a distractor filtering deficit that emerges with increased perceptual load and sustained effort can explain a myriad of PSF symptoms (e.g. sensory perceptual overload, and difficulties to concentrate).

Key messagesO_LIWhat is already known on this topic
[tpltrtarr]Post-stroke fatigue involves mental fatigue which is exacerbated in cognitively demanding task, as well as difficulties in concentrating and sustaining attention on a task.
[tpltrtarr]However previous research has not converged on a clear account of the nature of attention deficits in post-stroke fatigue, as well as on how these relate to the level of perceptual demand in a cognitive task

C_LIO_LIWhat this study adds
[tpltrtarr]The study suggests that attention deficits in post-stroke fatigue are attributed to a failure to attenuate neural responses to distractors with increased perceptual load in the task, as well as with increased demands on sustained attention with a longer task engagement
[tpltrtarr]This pattern points to a distractor filtering deficit that is magnified by perceptual load and sustained mental effort as main drivers of attention deficits in post-stroke fatigue
How this study might affect research, practice or policy
[tpltrtarr]This study enhances our understanding of attentional deficit in post-stroke fatigue, within an integrative account that explains mental fatigue symptomology

C_LI

category: neuroscience


title: The combination of Hebbian and predictive plasticity learns invariant object representations in deep sensory networks

abstract: Discriminating distinct objects and concepts from sensory stimuli is essential for survival. Our brains accomplish this feat by forming meaningful internal representations in deep sensory networks with plastic synaptic connections. Experience-dependent plasticity presumably exploits temporal contingencies between sensory inputs to build these internal representations. However, the precise mechanisms underlying plasticity remain elusive. We derive a local synaptic plasticity model inspired by self-supervised machine learning techniques that shares a deep conceptual connection to Bienenstock-Cooper-Munro (BCM) theory and is consistent with experimentally observed plasticity rules. We show that our plasticity model yields disentangled object representations in deep neural networks without the need for supervision and implausible negative examples. In response to altered visual experience, our model qualitatively captures neuronal selectivity changes observed in the monkey inferotemporal cortex in-vivo. Our work suggests a plausible learning rule to drive learning in sensory networks while making concrete testable predictions.


title: EXONIZATION BY THE EMERGENCE OF A CLEAVAGE-POLYADENYLATION SITE

abstract: Exonization is the evolutionary process of recruitment of new exonic regions from previously intronic regions. It is a major contributor to the increased complexity of alternative splicing. Here, we explore exonization mediated by the emergence of a novel cleavage-polyadenylation site in an intron. In Xenopus laevis, the tpm1 gene, which encodes muscular tropomyosin, contains alternative terminal exons. In adult muscles and embryonic hearts, exon 9A is joined to the terminal exon 9B. In embryonic somites, it is joined to the exonic region 9, which is transcribed from the intron immediately downstream of exon 9A. Consequently, exon 9A is either an internal exon when ligated to exon 9B, or a part of a terminal exon along with region 9. We show here that region 9 is present only in amphibians and coelacanths. This suggests that it emerged in sarcopterygians and was lost in amniotes. We used antisense morpholino oligonucleotides to mask the regions of tpm1 pre-mRNA that potentially regulate the inclusion of exon 9A9. This revealed that the definition of exon 9A9 relies on a weak cleavage-polyadenylation site and an intronic enhancer, but is independent of the 3 splice site. We demonstrate that RNAs containing exon 9B are toxic in somites. This may have contributed to the evolutionary pressure that led to the exonization of region 9 in sarcopterygians. These findings reveal the emergence of a novel cleavage-polyadenylation site that avoids the accumulation of a toxic RNA as a novel mechanism for exonization-mediated diversification of terminal exons.

category: evolutionary biology


title: Transcellular chaperone signaling is an intercellular stress-response distinct from the HSF-1 mediated HSR

abstract: Organismal proteostasis is maintained by intercellular signaling processes including cell nonautonomous stress responses such as transcellular chaperone signaling (TCS). When TCS is activated upon tissue-specific knockdown of hsp-90 in the C. elegans intestine, heat-inducible hsp-70 is induced in muscle cells at the permissive temperature resulting in increased heat stress resistance and lifespan extension. However, our understanding of the molecular mechanism and signaling factors mediating transcellular activation of hsp-70 expression from one tissue to another is still in its infancy. Here we conducted a combinatorial approach using transcriptome RNA-Seq profiling and a forward genetic mutagenesis screen to elucidate how stress-signaling from the intestine to the muscle is regulated. We find that the TCS-mediated "gut-to-muscle" induction of hsp-70 expression is suppressed by HSF-1 and instead relies on transcellular-X-cross-tissue (txt) genes. We identify a key role for the PDZ-domain guanylate cyclase txt-1 and the homeobox transcription factor ceh-58 as signaling hubs in the stress receiving muscle cells to initiate hsp-70 expression and facilitate TCS-mediated heat stress resistance and lifespan extension. Our results provide a new view on cell-nonautonomous regulation of "inter-tissue" stress responses in an organism that highlight a key role for the gut. Our data suggest that the HSF-1-mediated HSR is switched off upon TCS activation, in favor of an intercellular stress-signaling-route to safeguard survival.

category: genetics


title: Plasmid characterization in bacterial isolates of public health relevance in a tertiary healthcare facility in Kilimanjaro, Tanzania

abstract:
Plasmids are infectious double stranded DNA molecules that are found within bacteria. Horizontal gene transfer promotes successful spread of different types of plasmids within or among bacteria species, making their detection an important task for guiding clinical treatment. We used whole genome sequenced data to determine the prevalence of plasmid replicons in clinical bacterial isolates, the presence of resistance and virulence genes in plasmids, and the relationship between resistance and virulence genes within each plasmid. All bacterial sequences were de novo assembled using Unicycler before extraction of plasmids. Assembly graphs were submitted to Gplas+plasflow for plasmid prediction. The predicted plasmid components were validated using PlasmidFinder.

A total of 159 (56.2%) out of 283 bacterial isolates were found to carry plasmids, with E. coli, K. pneumoniae and S. aureus being the most prevalent plasmid carriers. A total of 27 (87.1%) combined plasmids were found to carry both resistance and virulence genes compared to 4 (12.9%) single plasmids. No statistically significant correlation was found between the number of antimicrobial resistance and virulence genes in plasmids (r =-0.25, p > 0.05). Our findings show a relatively high proportion of plasmid-carrying isolates suggesting selection pressure due to antibiotic use in the hospital. Co-occurrence of antibiotic resistance and virulence genes in clinical isolates is a public health relevant problem needing attention.

category: genomics


title: Towards reliable quantification of cell state velocities

abstract:
A few years ago, it was proposed to use the simultaneous quantification of unspliced and spliced messenger RNA (mRNA) to add a temporal dimension to high-throughput snapshots of single cell RNA sequencing data. This concept can yield additional insight into the transcriptional dynamics of the biological systems under study. However, current methods for inferring cell state velocities from such data (known as RNA velocities) are afflicted by several theoretical and computational problems, hindering realistic and reliable velocity estimation. We discuss these issues and propose new solutions for addressing some of the current challenges in consistency of data processing, velocity inference and visualisation. We translate our computational conclusion in two velocity analysis tools: one detailed method{kappa} -velo and one heuristic method eco-velo.

Author summarySingle cell transcriptomics has been used to study dynamical biological processes such as cell differentiation or disease progression. An ideal study of these systems would track individual cells in time but this is not directly feasible since cells are destroyed as part of the sequencing protocol. Because of asynchronous progression of cells, single cell snapshot datasets often capture cells at different stages of progression. The challenge is to infer both the overall direction of progression (pseudotime) as well as single cell specific variations in the progression. Computational methods development for inference of the overall direction are well advanced but attempts to address the single cell level variations of the dynamics are newer. La Manno et al. [1] proposed that simultaneous measurement of abundances of new (unspliced) and older (spliced) mRNA in the same single cell adds a temporal dimension to the data which can be used to infer the time derivative of single cells progression through the dynamical process. State-of-the-art methods for inference of cell state velocities from RNA-seq data (also known as RNA velocity) have multiple unaddressed issues. In this manuscript, we discuss these issues and propose new solutions. In previous works, agreement of RNA velocity estimations with pseudotime has been used as validation. We show that this in itself is not proof that the method works reliably and the overall direction of progression has to be distinguished from individual cells behaviour. We propose two new methods (one detailed and one cost efficient heuristic) for estimation and visualisation of RNA velocities and show that our methods faithfully capture the single-cell variances and overall trend on simulation. We further apply the methods to a dataset of developing mouse pancreas and show how the method can help us gain biological insight from real data.


title: DENVIS: scalable and high-throughput virtual screening using graph neural networks with atomic and surface protein pocket features

abstract: Computational methods for virtual screening can dramatically accelerate early-stage drug discovery by identifying potential hits for a specified target. Docking algorithms traditionally use physics-based simulations to address this challenge by estimating the binding orientation of a query protein-ligand pair and a corresponding binding affinity score. Over the recent years, classical and modern machine learning architectures have shown potential for outperforming traditional docking algorithms. Nevertheless, most learning-based algorithms still rely on the availability of the protein-ligand complex binding pose, typically estimated via docking simulations, which leads to a severe slowdown of the overall virtual screening process. A family of algorithms processing target information at the amino acid sequence level avoid this requirement, however at the cost of processing protein data at a higher representation level. We introduce deep neural virtual screening (DENVIS), an end-to-end pipeline for virtual screening using graph neural networks (GNNs). By performing experiments on a benchmark database, we show that our method performs at least competitively or outperforms several docking-based, machine learning-based, and hybrid docking/machine learning-based algorithms. By avoiding the intermediate docking step, DENVIS exhibits several orders of magnitude faster screening times (i.e., higher throughput) than both docking-based and hybrid models. When compared to an amino acid sequence-based machine learning model with comparable screening times, DENVIS achieves dramatically better performance. Some key elements of our approach include protein pocket modelling using a combination of atomic and surface features, the use of model ensembles, and data augmentation via artificial negative sampling during model training. In summary, DENVIS achieves state-of-the-art virtual screening performance, while offering the potential to scale to billions of molecules using minimal computational resources.


title: Complementing machine learning-based structure predictions with native mass spectrometry

abstract: The advent of machine learning-based structure prediction algorithms such as AlphaFold2 (AF2) has moved the generation of accurate structural models for the entire cellular protein machinery into the reach of the scientific community. However, structure predictions of protein complexes are based on user-provided input and may therefore require experimental validation. Mass spectrometry (MS) is a versatile, time-effective tool that provides information on post-translational modifications, ligand interactions, conformational changes, and higher-order oligomerization. Using three protein systems, we show that native MS experiments can uncover structural features of ligand interactions, homology models, and point mutations, that are undetectable by AF2 alone. We conclude that machine learning can be complemented with MS to yield more accurate structural models on the small and the large scale.

category: biophysics


title: MINSTED nanoscopy enters the Angstrom localization range

abstract: We report all-optical, room-temperature localization of fluorophores with precision in the [A]ngstrom range. These precisions are attained in a STED microscope, by encircling the fluorophore with the low-intensity edge of the STED donut beam, while constantly increasing the absolute donut power. Individual fluorophores bound to a DNA strand are localized with{sigma} = 4.7 [A], corresponding to a fraction of the fluorophore size, with only 2,000 detected photons. MINSTED fluorescence nanoscopy with single-digit nanometer resolution is exemplified by imaging nuclear pore complexes and the distribution of nuclear lamin in mammalian cells labeled by transient DNA hybridization. Since our experiments yield a localization precision{sigma} = 2.3 [A], estimated for 10,000 detected photons, we anticipate that MINSTED will open up entirely new areas of application in the study of macromolecular complexes in cells.


title: Proteomic profiling identifies co-regulated expression of splicing factors as a characteristic feature of intravenous leiomyomatosis

abstract: Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbours unique genomic and transcriptomic alterations when compared to uterine leiomyoma (uLM), which may account for their distinct clinical behaviour. Here we undertake the first comparative proteomic analysis of IVLM and other smooth muscle tumours (comprising uLM, soft tissue leiomyoma and benign metastasising leiomyoma) utilising data-independent acquisition mass spectrometry. We show that, at the protein level, IVLM is defined by the unique co-regulated expression of splicing factors. In particular, IVLM is enriched in two clusters composed of co-regulated proteins from the hnRNP, LSm, SR and Sm classes of the spliceosome complex. One of these clusters (Cluster 3) is associated with key biological processes including nascent protein translocation and cell signalling by small GTPases. Taken together, our study provides evidence of co-regulated expression of splicing factors in IVLM compared to other smooth muscle tumours which suggests a possible role for alternative splicing in the pathogenesis of IVLM.

category: cancer biology


title: KAT5 activity regulates G0-like states in human gliomas

abstract: In solid tumors, G0-like cell populations likely play important roles in maintaining cellular heterogeneity and promoting recurrence after standard of care. However, little is known about the mechanisms of tumor cell G0 ingress and egress. To discover regulators of G0-like states for glioblastoma (GBM), we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) for genes that trap cells in G0-like states when inhibited. We identify the protein acetyltransferase KAT5 as a key regulator of G0 and cell cycle dynamics in GSCs and GSC-derived tumors. In primary gliomas, KAT5low cells display G0-like properties, while overall KAT5 activity increases from low to high grade tumors. Further, we find that KAT5 activity suppresses the emergence of non-dividing subpopulations with oligodendrocyte progenitor and radial glial cell characteristics both in vitro and in a GSC tumor model. These results reveal that KAT5 activity regulates transitions between non-dividing/slow cycling, neurodevelopmental, and proliferative states in GBM tumors.


title: Dietary Induced Dynamic Plasticity of Intestinal Stem Cells and the Mucosa in Elevating Risk for Tumor Development

abstract: NWD1, a mouse purified western diet uniquely relevant to human nutritional exposures elevating risk for human sporadic colon cancer rapidly and reversibly altered the stem cell signature and transcriptome of Lgr5hi intestinal stem cells. Down-regulated Ppargc1a expression altered mitochondrial structure and function, metabolically reprogramming Lgr5hi cells, suppressing developmental maturation of their progeny as they progress through progenitor cell compartments. This recruited Bmi1+, Ascl2 cells, remodeling the mucosa, including cell adaptation to the altered nutritional environment and elevated pathways of antigen processing and presentation, especially in mature enterocytes, a pathogenic mechanism in human Inflammatory Bowel Disease resulting in chronic low-level pro-tumorigenic inflammation. Plasticity of intestinal cells to function as stem-like cells encompasses a physiological and continual response to changing nutritional environments, supporting historic concepts of tissue homeostasis as a process of continual adaptation to the environment, with important consequences for mechanisms establishing probability for tumor development. The data emphasize importance of better reflecting human nutritional exposures in mouse models of development and disease.


title: Toxicological Analysis of Poly-Lactide Co-Glycolide Microparticles, Chitosan Nanoparticles and Poly(Anhydride) Nanoparticles in Vero Cell

abstract: The present study was carried out to evaluate in-vitro toxicity associated with chitosan nanoparticles, poly(anhydride) nanoparticles and poly-lactide co-glycolide (PLG) microparticle in Vero cell line. The cytotoxicity of all three micro/nano-particles was assessed using different concentration. For each concentration, the confluent monolayer was treated for a period of 36-48 hours and studied for morphological alteration, live and death count etc. after the treatment. It was observed that the different concentrations of chitosan nanoparticles and Gantrez(R) nanoparticles did not have significant effect on the cell viability as evident from the non-significant difference between the OD540 of formazan product formed from MTT in treated and untreated cells. The concentration of chitosan nanoparticles and Gantrez(R) nanoparticles up to 1000 g/ml did not have any influence in cellular metabolic activities and viability. However, a reduction in the cellular viability and metabolic activities were observed when PLG microparticles were used at 1000 g/ml. At concentrations below 1000 g/ml, all the nanoparticles/microparticles were found to be safe in terms of cytotoxicity.

category: pharmacology and toxicology


title: Single-nucleotide substitution determines pollen production in Japanese cedar

abstract: Pollinosis, also known as pollen allergy or hay fever, is a global problem caused by pollen produced by various plant species1-6. The wind-pollinated Japanese cedar (Cryptomeria japonica) is the largest contributor to severe pollinosis in Japan, where increasing proportions of people have been affected in recent decades7. The MS4 (MALE STERILITY 4) locus of Japanese cedar controls pollen production, and its homozygous mutants (ms4/ms4) show abnormal pollen development after the tetrad stage and produce no mature pollen. In this study, we narrowed down the MS4 locus by fine mapping in Japanese cedar and found TKPR1 (TETRAKETIDE -PYRONE REDUCTASE) gene in this region. Transformation experiments using Arabidopsis thaliana showed that single-nucleotide substitution of CjTKPR1 determines pollen production. Broad conservation of TKPR1 beyond plant division could lead to the creation of pollen-free plant not only for Japanese cedar but also for broader plant species.

category: plant biology


title: Generalized Method of Moments improves parameter estimation in biochemical signaling models of time-stamped single-cell snapshot data

abstract:
MotivationOrdinary differential equations are commonly used to model the sub-cellular dynamics of average values of proteins and mRNAs. New single-cell technologies provide cell-to-cell differences in protein/mRNA abundances that allow for the evaluation of higher order moments. However, using this additional information to improve parameter estimation can be challenging since the magnitudes of single-cell abundances can vary widely between proteins/mRNA.

ResultsWe employ Generalized Method of Moments (GMM) and Particle Swarm Optimization to address the above challenges in mechanistic modeling of signaling kinetics data. Using synthetic data from linear and non-linear models, we show that the proposed method improves parameter estimation and enables construction of approximate confidence intervals. Furthermore, our approach exploits parallel computation to scale with increasing data size and dimensions. We apply our software CyGMM to estimate parameters in a linear ODE model for publicly available longitudinal single-cell cytometry data for CD8+ T cells. Our results demonstrate substantial improvements for modeling data from single-cell cytometry and RNA-seq experiments.

AvailabilityWe also make freely available our estimation software CyGMM written in C++ on github (https://github.com/jhnwu3/CyGMM).

Contactjayajit@gmail.com

Supplementary informationSupplementary data are available at Bioinformatics online.


title: Sparse coding models predict a spectral bias in the development of primary visual cortex (V1) receptive fields

abstract:
It is well known that sparse coding models trained on natural images learn basis functions whose shapes resemble the receptive fields (RFs) of simple cells in the primary visual cortex (V1). However, few studies have considered how these basis functions develop during training. In particular, it is unclear whether certain types of basis functions emerge more quickly than others, or whether they develop simultaneously. In this work, we train an overcomplete sparse coding model (Sparsenet) on natural images and find that there is indeed order in the development of its basis functions, with basis functions tuned to lower spatial frequencies emerging earlier and higher spatial frequency basis functions emerging later. We observe the same trend in a biologically plausible sparse coding model (SAILnet) that uses leaky integrate-and-fire neurons and synaptically local learning rules, suggesting that this result is a general feature of sparse coding. Our results are consistent with recent experimental evidence that the distribution of optimal stimuli for driving neurons to fire shifts towards higher frequencies during normal development in mouse V1. Our analysis of sparse coding models during training yields an experimentally testable prediction for V1 development that this shift may be due in part to higher spatial frequency RFs emerging later, as opposed to a global shift towards higher frequencies across all RFs, which may also play a role. We also find that at least two explanations could account for the order of RF development: 1) high frequency RFs require more information to be specified accurately, and thus may require more visual experience in order to learn, and 2) early development of low frequency RFs improves the sparseness and fidelity of the visual representation more than early development of high frequency RFs.

Author summaryWe are interested in how visual neurons learn representations of the natural world. In particular, we want to know whether certain visual features are learned by the visual cortex earlier in development than others. To address this question, we turn to a class of algorithms that can learn to represent natural scenes in a sparse fashion, with only a few neurons active at any given time (population sparseness). While sparse coding has been used extensively to model the response properties of neurons in the visual cortex, we use it here to arrive at a quantitative description of the way neurons might learn to encode visual information during development. We find that receptive fields (RFs) tuned to lower spatial frequencies develop earlier in our sparse coding models compared to high frequency RFs. If our prediction is accurate, such a description would provide a general framework for understanding the development of the functional properties of V1 neurons and serve as a guide for future experimental studies. It could also lead to new computational models that learn from input statistics, as well as advances in the design of devices that can augment or replace human vision.


title: Reproducible Tract Profiles (RTP2): from diffusion MRI acquisition to clinical practice and research

abstract:
Diffusion MRI is a complex technique, where new discoveries and implementations occur at a fast pace. The expertise needed for data analyses and accurate and reproducible results is increasingly demanding and requires multidisciplinary collaborations. In the present work we introduce Reproducible Tract Profiles (RTP2): a set of flexible and automated methods to analyze anatomical MRI and diffusion weighted imaging (DWI) data for reproducible tractography. The tools read structural MRI data and process them through a succession of serialized containerized analyses. We describe the DWI algorithms used to identify white-matter tracts and their summary metrics, the flexible architecture of the platform, and the tools to programmatically access and control the computations. The combination of these three components provides an easy-to-use automatized tool developed and tested over 20 years, to obtain usable and reliable state-of-the-art diffusion metrics at the individual and group levels for basic research and clinical practice.

HighlightsO_LIAutomated, flexible and reproducible protocol for white-matter tractography and tractometry.
C_LIO_LIHigh computational (same data, different computations) and test-retest reproducibility (data from different sessions, different computations).
C_LIO_LIOpen-source code and publicly available containers.
C_LI


title: Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats

abstract: Oxytocinergic actions within the hippocampal CA2 are important for neuromodulation, memory processing and social recognition. However, the source of the OTergic innervation, the cellular targets expressing the OT receptors (OTRs) and whether the PVN-to-CA2 OTergic system is altered during heart failure (HF), a condition recently associated with cognitive and mood decline, remains unknown. Using immunohistochemistry along with retrograde monosynaptic tracing, RNAscope and a novel OTR-Cre rat line, we show that the PVN (but not the supraoptic nucleus) is an important source of OTergic innervation to the CA2. These OTergic fibers were found in many instances in close apposition to OTR expressing cells within the CA2. Interestingly, while only a small proportion of neurons were found to express OTRs ([~]15%), this expression was much more abundant in CA2 astrocytes ([~]40%), an even higher proportion that was recently reported for astrocytes in the central amygdala. Using an established ischemic rat heart failure (HF) model, we found that HF resulted in robust changes in the PVN-to-CA2 OTergic system, both at the source and target levels. Within the PVN, we found an increased OT immunoreactivity, along with a diminished OTR expression in PVN neurons. Within the CA2 of HF rats, we observed a blunted OTergic innervation, along with a diminished OTR expression, which appeared to be restricted to CA2 astrocytes. Taken together, our studies highlight astrocytes as key cellular targets mediating OTergic PVN inputs to the CA2 hippocampal region. Moreover, provides the first evidence for an altered PVN-to-CA2 OTergic system in HF rats, which could potentially contribute to previously reported cognitive and mood impairments in this animal model.


title: A murine model of hnRNPH2-related neurodevelopmental disorder recapitulates clinical features of human disease and reveals a mechanism for genetic compensation of HNRNPH2

abstract: Mutations in HNRNPH2 cause an X-linked neurodevelopmental disorder with a phenotypic spectrum that includes developmental delay, intellectual disability, language impairment, motor function deficits, and seizures. More than 90% of patients with this disorder have a missense mutation within or adjacent to the nuclear localization signal (NLS) of hnRNPH2, although the specific pathogenic consequences of these mutations have not been examined. Here we found that hnRNPH2 NLS mutations result in reduced interaction with the nuclear transport receptor Kap{beta}2 in vitro and in cultured human cells. These mutations also cause modest accumulation of hnRNPH2 in the cytoplasm, suggesting that mislocalization of the protein might contribute to pathogenesis. We generated two knock-in mouse models with human-equivalent mutations in the endogenous mouse gene Hnrnph2, as well as Hnrnph2 knockout (KO) mice, and subjected them to extensive, deep phenotyping. Mutant knock-in mice displayed a spectrum of phenotypes that recapitulated aspects of the human disorder, including reduced survival in males, craniofacial abnormalities, impaired motor functions, and increased susceptibility to audiogenic seizures. Mutant knock-in male mice developed more severe phenotypes than female mice, likely due to differences in X-chromosome gene dosage. In contrast, two independent lines of Hnrnph2 KO mice showed no detectable phenotypes. Notably, KO mice had upregulated expression of Hnrnph1, a close paralog of Hnrnph2, whereas mutant Hnrnph2 knock-in mice failed to upregulate Hnrnph1. Thus, genetic compensation by Hnrnph1 might be sufficient to counteract the loss of hnRNPH2. These findings suggest that the pathogenesis of HNRNPH2-related disorder in humans may be driven by a toxic gain of function or a complex loss of HNRNPH2 function with impaired compensation by HNRNPH1. The carefully phenotyped mutant knock-in mice described here are an important resource for preclinical studies to assess the potential benefit of either gene replacement or therapeutic knockdown of mutant hnRNPH2.


title: Hyper-adaptation in the Human Brain: Functional and structural changes in the foot section of the primary motor cortex in a top wheelchair racing Paralympian

abstract: The human brain has the capacity to drastically alter its somatotopic representations in response to congenital or acquired limb deficiencies and dysfunctions. The main purpose of the present study was to elucidate such extreme adaptability in the brain of an active top wheelchair racing Paralympian (participant P1) who has congenital paraplegia (dysfunction of bilateral lower limbs). Participant P1 has undergone long-term wheelchair racing training using bilateral upper limbs and has won a total of 19 medals in six consecutive summer Paralympic games as of 2021. We examined the functional and structural changes in the foot section of the primary motor cortex (M1) in participant P1 as compared to able-bodied control participants. We also examined the functional and structural changes in three other individuals (participants P2, P3, and P4) with acquired paraplegia, who also had long-term non-use period of the lower limbs and had undergone long-term training for wheelchair sports (but not top athletes at the level of participant P1). We measured brain activity in all the participants using functional magnetic resonance imaging (MRI) when bimanual wrist extension-flexion movement was performed, and the structural MRI images were collected. Compared to 37 control participants, participant P1 showed significantly greater activity in the M1 foot section during the bimanual task, and significant local GM expansion in this section. Significantly greater activity in the M1 foot section was also observed in participant P4, but not in P2 and P3, and the significant local GM expansion was observed in participant P2, but not in P3 and P4. Thus, functional or structural change was observed in an acquired paraplegic participant, but was not observed in all the paraplegic participants. The functional and structural changes typically observed in participant P1 may represent extreme adaptability of the human brain. We discuss the results in terms of a new idea of hyper-adaptation.


title: Fine oculomotor knowledge enhances high-acuity vision

abstract: It has long been debated how humans resolve fine details and perceive a stable visual world despite the fixational motion of their eyes, the incessant ocular jitter that occurs in the intervals between voluntary gaze shifts. Current theories assume these processes to rely solely on the visual input to the retina, without contributions from motor and/or proprioceptive sources. Here we show that contrary to this widespread assumption, the visual system has access to high-resolution extra-retinal knowledge of fixational eye motion and uses it to deduce spatial relations. Building on recent advances in gaze-contingent display control, we created a spatial discrimination task in which the stimulus configuration was entirely determined by oculomotor activity. Our results show that humans correctly infer geometrical relations even when no spatial information is delivered to the retina and accurately combine high-resolution extraretinal monitoring of gaze displacement with retinal signals. These findings reveal a multimodal strategy for encoding spatial details, in which fine oculomotor knowledge is used to interpret the fixational input to the retina.


title: Characterizing brain imaging features associated with ADAS-Cog13 sub-scores with 3D convolutional neural networks

abstract: To date, few advanced machine learning models have been developed for investigating the associations between features from brain imaging and individual Alzheimers disease (AD) related cognitive functional changes. Additionally, how these associations differ among different imaging modalities is unclear. Here we investigated 3D convolutional neural network (CNN) models which were trained to predict sub-scores in 13-item Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) based on MRI and FDG-PET brain imaging data obtained from the ADNI database. We found that each key ADAS-Cog13 sub-score was associated with a specific set of brain features within an imaging modality. Overall, sub-scores were strongly associated with structural changes of subcortical regions including amygdala, hippocampus, and putamen, and were associated with metabolic changes of cortical regions including the cingulated gyrus, occipital cortex, middle front gyrus, precuneus cortex, and the cerebellum. Our findings provided insights into complex AD etiology. Our analytical pipeline can also be utilized to study other brain diseases.


title: The Cocktail Party Effect in Post-Stroke Fatigue: an EEG study

abstract:
ObjectiveAn inability to selectively attend away from task irrelevant stimuli is thought to drive post-stroke fatigue. In this study we investigated if neural processing of task relevant stimuli, in the presence of noise (task-irrelevant stimuli), is compromised in post-stroke fatigue.

MethodsAn auditory oddball task consisting of target, standard and novel tones was carried out with and without background noise while recording neural responses using electroencephalography. Participants responded to target tones with a button press. After each block, participants rated how effortful the block felt. Fatigue was measured using the fatigue severity scale. The effect of fatigue and noise on behaviour (response time, accuracy, and effort rating) and neural responses (amplitude and latency) was examined using mixed model ANOVAS.

ResultsThose with fatigue had slower responses both in  noise and  no noise conditions. The response amplitude to the novel tones in the  noise condition was smaller, than  no noise condition, which was modulated by fatigue. The latency of response was longer, in the  noise when compared to  no noise condition which was not modulated by fatigue. likewise, perceived effort was also greater in the  noise condition, but not modulated by fatigue.

InterpretationProcessing of novel stimuli in the presence of background noise is significantly altered in post-stroke fatigue, indicating a problem with attentional switching processes, one that selectively contributes to the feeling of fatigue without affecting performance.


title: pTDP-43 aggregates accumulate in the gut and other non-central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis

abstract:
ObjectiveNeurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and non-central nervous system (CNS) manifestations, particularly gastrointestinal (GI) symptoms, are common. Our objective was to understand the systemic distribution of pathology in archived non-CNS tissues, taken as part of routine clinical practice during life from people with ALS.

DesignWe requested all surgical specimens of non-CNS tissue taken during life from 48 people with ALS, for whom evidence of the characteristic proteinopathy associated with ALS had been identified in the CNS after death (i.e., the pathological cytoplasmic accumulation of phosphorylated TDP-43 (pTDP-43) aggregates). Of the 48 patients, 13 had sufficient tissue for evaluation: 12 patients with sporadic ALS and 1 patient with a C9orf72 hexanucleotide repeat expansion. The final cohort consisted of 68 formalin-fixed paraffin embedded tissue samples from 22 surgical cases (some patients having more than one case over their lifetimes), representing 8 organ systems, which we examined for evidence of pTDP-43 pathology. The median age of tissue removal was 62.4 years old and median tissue removal to death was 6.3 years.

ResultsWe identified pTDP-43 aggregates in multiple cell types of the GI tract (i.e., colon and gallbladder), including macrophages and dendritic cells within the lamina propria, as well as neuronal and glial cells of the myenteric plexus. Aggregates were also noted within lymph node parenchyma, blood vessel endothelial cells, and chondrocytes. We note that in all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis (median=3years) and, in some instances, preceded neurological symptom onset by more than 10 years.

ConclusionThese data imply that patients with non-CNS symptoms may have occult protein aggregation that could be detected many years prior to neurological involvement.

SummaryNeurodegenerative diseases such as Parkinsons disease (PD), Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS) are traditionally considered strictly neurological disorders. However, clinical presentation is not restricted to neurological systems, and non-central nervous system (CNS) manifestations, particularly gastrointestinal (GI) symptoms, are common. Our objective was to understand the systemic distribution of TDP-43 pathology in archived non-CNS tissues, taken as part of routine clinical practice during life from people with ALS. We identified pTDP-43 aggregates in multiple cell types of the GI tract (i.e., colon and gallbladder), and within lymph node parenchyma, blood vessel endothelial cells, and chondrocytes. We note that in all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis (median=24months) and, in some instances, preceded neurological symptom onset by more than 10years. These data imply that patients with non-CNS symptoms may have occult protein aggregation tha could be detected many years prior to neurological involvement.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=159 SRC="FIGDIR/small/484805v1_ufig1.gif" ALT="Figure 1">
View larger version (67K):
org.highwire.dtl.DTLVardef@1f568c6org.highwire.dtl.DTLVardef@b1d99dorg.highwire.dtl.DTLVardef@45e643org.highwire.dtl.DTLVardef@1106d29_HPS_FORMAT_FIGEXP  M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Ante-mortem tissue cohort comprised of tissue taken from people with ALS demonstrates non-CNS accumulation of pTDP-43 aggregates prior to symptom onset.

Schematic of workflow to identify pTDP-43 aggregates indicative of non-central nervous system (CNS) manifestations of ALS. Lower panel left: cartoon depicting organs and cell types that had evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue. Lower panel right: cartoon depicting organs with no evidence of pTDP-43 aggregation in ALS patient non-CNS ante-mortem tissue.

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title: Causal Inference on Neuroimaging Data with Mendelian Randomisation

abstract: While population-scale neuroimaging studies offer the promise of discovery and characterisation of subtle risk factors, massive sample sizes increase the power for both meaningful associations and those attributable to confounds. This motivates the need for causal modelling of observational data that goes beyond statements of association and towards deeper understanding of complex relationships between individual traits and phenotypes, clinical biomarkers, genetic variation, and brain-related measures of health. Mendelian randomisation (MR) presents a way to obtain causal inference on the basis of genetic data and explicit assumptions about the relationship between genetic variables, exposure and outcome. In this work, we provide an introduction to and overview of causal inference methods based on Mendelian randomisation, with examples involving imaging-derived phenotypes from UK Biobank to make these methods accessible to neuroimaging researchers. We motivate the use of MR techniques, lay out the underlying assumptions, introduce common MR methods and focus on several scenarios in which modelling assumptions are potentially violated, resulting in biased effect estimates. Importantly, we give a detailed account of necessary steps to increase the reliability of MR results with rigorous sensitivity analyses.


title: A multi-scale fusion CNN model based on adaptive transfer learning for multi-class MI-classification in BCI system

abstract: Deep learning-based brain-computer interface (BCI) in motor imagery (MI) has emerged as a powerful method for establishing direct communication between the brain and external electronic devices. However, due to inter-subject variability, inherent complex properties, and low signal-to-noise ratio (SNR) in electroencephalogram (EEG) signal are major challenges that significantly hinders the accuracy of the MI classifier. To overcome this, the present work proposes an efficient transfer learning-based multi-scale feature fused CNN (MSFFCNN) which can capture the distinguishable features of various non-overlapping canonical frequency bands of EEG signals from different convolutional scales for multi-class MI classification. In order to account for inter-subject variability from different subjects, the current work presents 4 different model variants including subject-independent and subject-adaptive classification models considering different adaptation configurations to exploit the full learning capacity of the classifier. Each adaptation configuration has been fine-tuned in an extensively trained pre-trained model and the performance of the classifier has been studied for vast range of learning rates and degrees of adaptation which illustrates the advantages of using an adaptive transfer learning-based model. The model achieves an average classification accuracy of 94.06% ({+/-}2.29%) and kappa value of 0.88 outperforming several baseline and current state-of-the-art EEG-based MI classification models with fewer training samples. The present research provides an effective and efficient transfer learning-based end-to-end MI classification framework for designing a high-performance robust MI-BCI system.


title: Beneficial effects of prolonged 2-phenylethyl alcohol inhalation on chronic distress-induced anxio-depressive-like phenotype in female mice

abstract: Chronic distress-induced hypothalamic-pituitary-adrenal axis deregulations have been associated with the development of neuropsychiatric disorders such as anxiety and depression. Currently available drugs treating such pathological conditions have limited efficacy and diverse side effects, revealing the need of new safer strategies. Aromatic plant-based compounds are largely used in herbal medicine due to their therapeutic properties on mood, physiology, and general well-being. The purpose of this study was to investigate the effects of 2-phenylethyl alcohol (PEA), one of the pharmacologically active constituents of rose essential oil, on chronic corticosterone (CORT)-induced behavioral and neurobiological changes in female mice. Animals followed a prolonged PEA inhalation exposure (30 min per day) for 15 consecutive days prior to behavioral evaluation with open-field, forced swim and novelty-suppressed feeding tests. CORT treatment induced an anxio-depressive-like phenotype, evidenced by a reduced locomotor activity in the open-field, and an increased latency to feed in the novelty-suppressed feeding paradigms. To elucidate the neural correlates of our behavioral results, cerebral cFos expression analysis was further performed to provide a global map of neuronal activity. The altered feeding behavior was accompanied by a significant decrease in the number of cFos-positive cells in the olfactory bulb, and altered brain connectivity as shown by cross-correlation-based network analysis. CORT-induced behavioral and neurobiological alterations were reversed by prolonged PEA inhalation, suggesting a therapeutic action that allows regulating the activity of neural circuits involved in sensory, emotional and feeding behaviors. These findings might contribute to better understand the therapeutic potential of PEA on anxio-depressive symptoms.


title: Condensin positioning at telomeres by Taz1 promotes telomere disjunction in anaphase

abstract:
The localization of condensin along chromosome arms is crucial for chromosome segregation in anaphase. Condensin is also enriched at telomeres but how and for what function remains elusive. Here we show that Taz1, the main component of the Shelterin complex that ensures telomeric functions, acts as a positioning device to enrich condensin at telomeres in fission yeast. High condensin occupancy at telomeres is needed for their full disjunction in anaphase. Consistent with a cis-acting process, condensin drives telomere separation independently of the decatenation activity of Topoisomerase II also required for chromosome arm separation. Our results reveal a cis-acting pathway that enriches condensin at telomeres to promote their separation during mitosis.

One-Sentence SummaryThe telomeric protein Taz1 promotes the accumulation of condensin at telomeres that drives their disjunction in anaphase.


title: Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells

abstract: Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred as tauopathies, including Frontal Temporal Dementia and Alzheimers disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably report i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e. full-length or short fragments, wild-type or the disease-associated tau(P301L) variant) further insights in the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors are aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.


title: Towards understanding diversity, endemicity and global change vulnerability of soil fungi

abstract: Fungi play pivotal roles in ecosystem functioning, but little is known about their global patterns of diversity, endemicity, vulnerability to global change drivers and conservation priority areas. We applied the high-resolution PacBio sequencing technique to identify fungi based on a long DNA marker that revealed a high proportion of hitherto unknown fungal taxa. We used a Global Soil Mycobiome consortium dataset to test relative performance of various sequencing depth standardization methods (calculation of residuals, exclusion of singletons, traditional and SRS rarefaction, use of Shannon index of diversity) to find optimal protocols for statistical analyses. Altogether, we used six global surveys to infer these patterns for soil-inhabiting fungi and their functional groups. We found that residuals of log-transformed richness (including singletons) against log-transformed sequencing depth yields significantly better model estimates compared with most other standardization methods. With respect to global patterns, fungal functional groups differed in the patterns of diversity, endemicity and vulnerability to main global change predictors. Unlike -diversity, endemicity and global-change vulnerability of fungi and most functional groups were greatest in the tropics. Fungi are vulnerable mostly to drought, heat, and land cover change. Fungal conservation areas of highest priority include wetlands and moist tropical ecosystems.

category: ecology


title: A novel PLS1 c.981+1G>A variant causes autosomal-dominant hereditary hearing loss in a family via up-regulation of the PI3K-Akt signaling pathway

abstract:
BackgroundThe fimbrin protein family contains a variety of proteins, of which Plastin1 (PLS1) is an important member. The latest researches show that variations in the coding region of PLS1 gene is related to the development of deafness.

However, it remains unknown about the molecular mechanism of deafness caused by PLS1 gene variants.

Methodswhole exome sequencing was performed on the affected family members and healthy ones to identify the pathogenic variants, followed by sanger sequencing. Minigene assay was conducted to investigate the impact of the variant on PLS1 mRNA splicing. The pathogenicity of the variant was further investigated in zebrafish. RNA-sequencing (RNA-seq) was done for analyzing the dysregulated downstream signaling pathways caused by knockdown of PLS1 expression.

ResultsWe identified a novel variant PLS1 c.981+1G>A in a large Chinese family with hearing loss and demonstrated that the variant is responsible for the occurrence of hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). The variant caused abnormal inner ear phenotypes, characterized by decreased mean otolith distance, anterior otolith diameter, posterior otolith diameter, and cochlear diameter, swimming speed and distance in zebrafish. Furthermore, silencing PLS1 expression significantly upregulated genes in the PI3K-Akt signaling pathway, including Col6a3, Spp1, Itgb3 and Hgf.

ConclusionsPLS1 c.981+1G>A is a novel pathogenic variant for hearing loss by inducing Exon8 skipping or deletion of Exon8 (47bp). Up-regulation of the PI3K-Akt signaling pathway plays an important role in the pathogenesis of PLS-1 gene.


title: A novel class of long small RNAs associates with Argonaute1 and is up-regulated by nutrient deprivation in the alga Chlamydomonas

abstract: Small RNAs (sRNAs) associate with Argonaute (AGO) proteins forming effector complexes with key roles in gene regulation and defense responses against molecular parasites. In multicellular eukaryotes, extensive duplication and diversification of RNA interference (RNAi) components have resulted in intricate pathways for epigenetic control of gene expression. The unicellular alga Chlamydomonas reinhardtii also has a complex RNAi machinery, including three AGOs and three Dicer-like (DCL) proteins. However, little is known about the biogenesis and function of most endogenous sRNAs. We demonstrate here that Chlamydomonas contains uncommonly long sRNAs (>26 nt), which associate preferentially with AGO1. Somewhat reminiscent of animal PIWI-interacting RNAs, these long sRNAs are derived from moderately repetitive genomic clusters and their biogenesis appears to be Dicer-independent. Interestingly, long sRNA encoding sequences have been conserved and amplified in phylogenetically related Chlamydomonas species. Additionally, expression of several long sRNAs increases substantially under nutrient deprivation, correlating with the downregulation of predicted target transcripts. We hypothesize that the transposon-like sequences encoding long sRNAs might have been ancestrally targeted for silencing by the RNAi machinery but, during evolution, some long sRNAs might have fortuitously acquired endogenous target genes and become integrated into gene regulatory networks.


title: Tissue-adjusted pathway analysis of cancer (TPAC)

abstract: We describe a novel single sample pathway analysis method for cancer transcriptomics data named tissue-adjusted pathway analysis of cancer (TPAC). The TPAC method leverages information about the normal tissue-specificity of human genes to compute a robust multivariate distance score that quantifies pathway dysregulation in each profiled tumor. Because the null distribution of the TPAC scores has an accurate gamma approximation, both population and sample-level inference is supported. As we demonstrate through an analysis of gene expression data from The Cancer Genome Atlas (TCGA), TPAC pathway scores are more strongly associated with both patient prognosis and tumor stage than the scores generated by existing single sample pathway analysis methods.


title: Lack of self-medication by fungus infected Lasius platythorax ants in a multitrophic experiment

abstract: Ants live in dense colonies with low genetic diversity between nestmates, creating favourable conditions for the spread of diseases. Due to the constant pressure by infectious disease, ants have evolved different mechanisms to cope with it. One way to combat pathogens is via consumption of biologically active compounds, which can inhibit the growth of the microbes or eliminate them. Although ants are known to respond to pathogen infections by altering their foraging to incorporate reactive oxygen species (ROS) into their diet to successfully combat disease under laboratory conditions, it is still unknown how ants would self-medicate in the wild. By designing a multitrophic environment, we try for the first time to identify potential sources of medicinal compounds for ants to use against fungal infections under natural conditions to better understand how the behaviour is expressed in nature. We investigated whether a bean plant suffering from an infestation of Megoura viciae aphids would be a source of ROS which the ant could use for self-medication, and whether the ant Lasius platythorax changes its foraging behaviour on bean plants if exposed to infectious spores of the entomopathogenic fungus Beauveria bassiana. We found no clear evidence that the ants significantly change their foraging behaviour on extrafloral nectaries in response to the pathogen or that the nectar produced by aphid stressed plants contains ROS. The aphids contained ROS in levels which ants could potentially use, however Megoura viciae is considered unpalatable to ants and we saw no evidence of predation on the aphids. Our results mean that the combination of species of the ant - plant - aphid interactions which we studied does result in a detectable self-medication response in ants. Therefore, we suggest that alternative species of aphids as well as other natural sources of ROS should be studied for self-medication.

category: animal behavior and cognition


title: Characterization of Quantum Dots with Hyperspectral Fluorescence Microscopy for Multiplexed Optical Imaging of Biomolecules

abstract: The optical properties of quantum dots were extensively characterized using a hyperspectral fluorescence microscopy system. The system provides a single excitation wavelength in the ultraviolet and 311 emission wavelength channels in the visible. This allows detection of multiple fluorophores (e.g. different quantum dots) with a high spectral resolution in one go which is not achievable with a conventional fluorescence microscope where different filter sets have to be used. A spectral library was established based on the spectral profiles of six types of quantum dots. Notably, a slight spectral shift was observed for all samples while the sample was drying. Subsequently, two quantum dot mixture samples were studied. Using the spectral unmixing approach, the relative proportions of each quantum dot within a homogeneous mixture and the spatial distribution of each quantum dot within a heterogeneous mixture were calculated. The calculated values match well with the theoretical predictions. Hence, the analysis method presented here can be used for simultaneous imaging of multiple fluorophores using hyperspectral imaging technology. The results provide valuable information for the realization of real-time multi-channel in vivo fluorescent imaging of biomolecules.

category: bioengineering


title: Fragment-Based Ligand Generation Guided By Geometric Deep Learning On Protein-Ligand Structure

abstract: AO_SCPLOWBSTRACTC_SCPLOWComputationally-aided design of novel molecules has the potential to accelerate drug discovery. Several recent generative models aimed to create new molecules for specific protein targets. However, a rate limiting step in drug development is molecule optimization, which can take several years due to the challenge of optimizing multiple molecular properties at once. We developed a method to solve a specific molecular optimization problem in silico: expanding a small, fragment-like starting molecule bound to a protein pocket into a larger molecule that matches that physiochemical properties of known drugs. Using data-efficient E(3) equivariant based neural networks and a 3D atomic point cloud representation, our model learns how to attach new molecular fragments to a growing structure by recognizing realistic intermediates generated en route to a final ligand. This approach always generates chemically valid molecules and incorporates all relevant 3D spatial information from the protein pocket. This framework produces promising molecules as assessed by multiple properties that address binding affinity, ease of synthesis, and solubility. Overall, we demonstrate the feasibility of 3D molecular structure expansion conditioned on protein pockets while maintaining desirable drug-like physiochemical properties and developed a tool that could accelerate the work of medicinal chemists.


title: Bioinformatics Analysis of next generation sequencing data for Risk Prediction in Patients with Type 1 diabetes mellitus

abstract: Type 1 diabetes mellitus (T1DM) comprise the most common forms of autoimmune disease. The aim of this investigation was to apply a bioinformatics approach to reveal related pathways or genes involved in the development of T1DM. The next generation sequencing (NGS) dataset GSE182870 was downloaded from the gene expression omnibus (GEO) database. Differentially expressed gene (DEG) analysis was performed using DESeq2. The g:Profiler was utilized to analyze the functional enrichment, gene ontology (GO) and REACTOME pathway of the differentially expressed genes. Protein-protein interaction (PPI) network, modules, miRNA- hub gene regulatory network, and TF-hub gene regulatory network were conducted via comprehensive target prediction and network analyses. Finally, hub genes were validated by using receiver operating characteristic curve analysis. A total of 860 DEGs were screened out from NGS dataset, among which 477 genes were up regulated and 383 genes were down regulated. GO enrichment analysis indicated that up regulated genes were mainly involved in cellular metabolic process, intracellular anatomical structure and catalytic activity, and the down regulated genes were significantly enriched in cellular nitrogen compound biosynthetic process, protein containing complex and heterocyclic compound binding. REACTOME pathway enrichment analysis showed that the up regulated genes were mainly enriched in metabolism of carbohydrates and the down regulated genes were significantly enriched in metabolism of RNA. A PPI network, modules, miRNA-hub gene regulatory network and TF - hub gene regulatory network were constructed, and hub genes (MAPK14, RHOC, MAD2L1, TAF1, TRAF2, HSP90AA1, TP53, HSP90AB1, UBA52 and RACK1) were identified. This study provides further insights into the underlying pathogenesis of T1DM.


title: Phenotype to genotype mapping using supervised and unsupervised learning

abstract: The relationship between the genotype, the genetic instructions encoded into a genome, and phenotype, the macroscopic realization of such instructions, remains mostly uncharted. In addition, tools able to uncover the connection between the phenotype with a specific set of responsible genes are still under definition. In this work, we focus on yeast organelles called vacuoles, which are cell membrane compartments that vary size and shape in response to various stimuli, and we develop a framework relating changes of cellular morphology to genetic modification. The method is a combination of convolutional neural network (CNN) and an unsupervised learning pipeline, which employs a deep-learning based segmentation, classification, and anomaly detection algorithm. From the live 3D fluorescence vacuole images, we observe that different genetic mutations generate distinct vacuole phenotypes and that the same mutation might correspond to more than one vacuole morphology. We trained a Unet architecture to segment our cellular images and obtain precise, quantitative information in 2D depth-encoded images. We then used an unsupervised learning approach to cluster the vacuole types and to establish a correlation between genotype and vacuole morphology. Using this procedure, we obtained 4 phenotypic groups. We extracted a set of 131 morphological features from the segmented vacuoles images, reduced to 50 after a tree-based feature selection. We obtained a purity of 85% adopting a Fuzzy K-Means based algorithm on a random subset of 880 images, containing all the detected phenotypic groups. Finally, we trained a CNN on the labels assigned during clustering. The CNN has been used for prediction of a large dataset (6942 images) with high accuracy (80%). Our approach can be applied extensively for live fluorescence image analysis and most importantly can unveil the basic principles relating genotype to vacuole phenotype in yeast cell, which can be thought as a first step for inferring cell designing principles to generate organelles with a specific, desired morphology.


title: Modeling of Aryl Hydrocarbon Receptor Pathway Intrinsic Immunometabolic Role using Glioblastoma Stem Cells and Patient-Derived Organoids

abstract: The intrinsic genetic program of glioblastoma (GBM) stem cells is critical for tumor evolution and recurrence. We recently identified intrinsic phenotypes and immune-like genetic programs of GBM organoids (GBMO)1 from patient derived glioblastoma stem cells (GSCs), replicating genomic, metabolic, and cellular aspects of GBM in vivo. Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is a key regulator of infiltrating immune cells in gliomas2, 3 and associated with poor prognosis, but its role in GSC biology is unknown2. Here, we show that AHR is a patient-specific regulator of the glioma intrinsic gene program in GSCs and GSC-derived GBMO that are enriched for AHR. We find that AHR is required for GSC self-renewal, GBMO expansion, radial glia-like cell proliferation, and expression of immune mediators seen in the mesenchymal subtype. CRISPR-Cas9 genetic ablation and pharmacological inhibition revealed that AHR regulates genes linked to intrinsic immunity, proliferation, and migration in GBMO. Genomic analysis of GBMO treated with AHR inhibitors identified expression signatures and candidate markers associated with survival of gliomas. Our work defines the glioma intrinsic function of AHR in a model of early GBM formation, offering a rationale for clinical exploration of a potential  two-hit target of both GBM cells and infiltrating immune cells in patients with GBM expressing high levels of AHR.


title: SPDEF promotes the classical subtype of pancreatic ductal adenocarcinoma.

abstract: Pancreatic ductal adenocarcinoma (PDA) samples reveal extensive cellular heterogeneity. Using single-cell RNA sequencing, we uncover multiple tumor cell populations distinguished by their differentiation state and associated with different stages of tumor progression in a mouse model of PDA. We identify Spdef as a factor required for tumorigenesis in pancreatic cancer cells of epithelial and mucinous nature. By comparative analysis of cell differentiation states in mice and humans, we find that the Spdef program is highly expressed by human PDAs of the classical subtype. Mouse and human PDA cells expressing elevated levels of Spdef are dependent upon this transcription factor for tumor progression in vivo. The tumor-promoting function of Spdef is recapitulated by two Spdef target genes that regulate protein folding and endoplasmic reticulum activity, Agr2 and Ern2/Ire1{beta}. These findings offer insights into the factors controlling differentiation states in PDA and identify new vulnerabilities in the most common subtype of pancreatic cancer.


title: Isoform-specific mutation in Dystonin-b gene causes late-onset protein aggregate myopathy and cardiomyopathy

abstract: Dystonin (DST), which encodes cytoskeletal linker proteins, express three tissue-selective isoforms: neural DST-a, muscular DST-b, and epithelial DST-e. DST mutations cause different disorders including hereditary sensory and autonomic neuropathy 6 (HSAN-VI) and epidermolysis bullosa simplex; however, etiology of the muscle phenotype in DST-related diseases has been unclear. Because DST-b contains all of the DST-a-encoding exons, known HSAN-VI mutations could affect both DST-a and DST-b isoforms. To investigate the specific function of DST-b in striated muscles, we generated a Dst-b-specific mutant mouse model harboring a nonsense mutation. Dst-b mutant mice exhibited late-onset protein aggregate myopathy and cardiomyopathy without neuropathy. We observed desmin aggregation, focal myofibrillar dissolution, and mitochondrial accumulation in striated muscles, which are common characteristics of myofibrillar myopathy. We also found nuclear inclusions containing p62, ubiquitin, and SUMO proteins with nuclear envelope invaginations as a unique pathological hallmark in Dst-b mutation-induced cardiomyopathy. RNA sequencing analysis revealed changes in expression of genes responsible for cardiovascular functions. In silico analysis identified DST-b alleles with nonsense mutations in populations worldwide, suggesting that some unidentified hereditary myopathy and cardiomyopathy are caused by DST-b mutations. Here, we demonstrate that the Dst-b isoform is essential for long-term maintenance of striated muscles.

category: pathology


title: Temporal integration of rod signals in luminance and chromatic pathways

abstract: We assessed how rod excitation (R) affects luminance (L+M+S) and chromatic [L/(L+M)] reaction times (RTs). A four-primary display based on the overlapped images of two spectrally-modified monitors, which allowed specific or combined [L+M+S+R, L/(L+M) + R] photoreceptor stimulation, was used to present a C-target stimulus differing from the background only by the selected stimulation. For the luminance pathway, rod input increased RTs, suggesting a suppressive rod-cone interaction. The responses of the chromatic pathway were faster when rods were involved, suggesting a major role of rods in mesopic color perception.

category: physiology


title: Novel diversity panel facilitates genomic dissection of lodging in tef (Eragrostis tef)

abstract:
Underutilized species that are not widely cultivated (known as orphan crops) present opportunities to increase crop diversity and food security. Tef [Eragrostis tef (Zucc.) Trotter] is known for its high-quality grain and forage. Root-borne lodging is a devastating problem in tef cultivation, leading to large economic losses and limiting its widespread adoption. The aim of this study was to identify genomic regions that are associated with tef lodging. A diversity panel comprised of 297 lines (TDP-300) was assembled, genotyped, and phenotyped across 4 field environments. Genome-wide association study identified 29 genomic regions associated with lodging; in all cases with a minor allele conferring reduced lodging. The eleven most prominent sites were located in or near genes, 5 of them with a putative role, of which 3 were to be associated with root development. The identification of lodging-related sites in the current study may advance understanding of the mechanisms underlying tef lodging and crop improvement. To the best of our knowledge, this is the first diversity panel developed for tef. This platform is expected to be useful for detecting genomic regions and markers associated with traits of interest in tef, as well as for breeding and molecular investigations.

HighlightsHere we report on the assembly and genomic characterization of a tef diversity panel (TDP-300). This unique resource was used for GWAS to identify genomic regions associated with plant lodging.


title: Heterocyclic aromatic amines (HAAs) target mitochondrial physiology

abstract: Heterocyclic aromatic amines (HAA) may be found naturally in plants or are formed through the Maillard reaction when meat is cooked at high temperatures. Previous studies have indicated HAAs are especially toxic to dopaminergic neurons, whereas specific exposures may also affect other neuronal populations such as cholinergic neurons. Biochemical mechanisms of neurotoxic action implicate elevated oxidative stress and afflicted mitochondria. Notably, these mechanisms are of importance in Alzheimers disease (AD) and Parkinsons disease (PD). Most neurodegenerative disease cases are sporadic, where environmental and dietary factors may modulate risk. To further investigate HAA neurotoxicity, we tested the effect of common HAA (harmane, harmine, norharmane, PhIP, and HONH-PhIP) exposure on mitochondrial physiology, a key pathogenic target in AD and PD. Upon assessing mitochondrial bioenergetics, we observed a significant reduction in basal respiration, ATP production, maximal respiratory capacity, and non-mitochondrial respiration, indicating that HAA negatively impacts mitochondrial respiration. Followed by more specific studies on individual mitochondrial complexes, it was found that harmane, harmine, norharmane specifically inhibit complex I enzyme activity, whereas HONH-PhiP, a reactive metabolite of PhIP, inhibits Complex III enzyme activity. Our findings provide significant advancement with respect to underlying mechanisms of toxicity, though also validating HAA exposure as a potential risk factor for AD and PD.


title: Emotional intensity can enrich or degrade memories: impact of the amygdalar pathway on hippocampus through inhibitory neurons

abstract: The brains emotional system powerfully modulates processing of context and episodic memory. A key pathway that mediates these effects is the projection from the amygdala to the hippocampus. Wang and Barbas (1) uncovered a distinctive pattern in the pathways from amygdala to hippocampus in primates. In hippocampal CA3, a pathway from the amygdala innervated excitatory pyramidal neurons as well as parvalbumin (PV) and calretinin (CR) inhibitory neurons. In hippocampal CA1, amygdalar projections also innervated pyramidal neurons and CR interneurons, but not PV interneurons. The effects of these complex circuits can best be probed using computational simulations. We developed a model of spiking neurons to investigate the implications and significance of these amygdala-hippocampal circuits for affective influence on processing mnemonic context, and to test their effects as input from the amygdala gradually increased. Our simulations revealed that moderate input from the amygdala can enhance detail in CA3 representations that can correctly sort out contexts and episodes from memory. However, high amygdalar input suppressed CA3 responses to non-amygdalar inputs through powerful inhibitory neurons, leading to memory representations that lack detail. Moreover, high amygdalar input prematurely hastened the timing of responses in CA1 occurring when the current situation broadly and non-specifically matched a remembered context. Amygdalar pathways to hippocampus enable a mechanism whereby affective signaling appropriately enhances hippocampal representations of remembered context. However, when amygdalar input is excessive in high emotional arousal, there is loss of memory detail and overgeneralization, as seen in post-traumatic stress disorder or pathologic phobias.


title: Comparative developmental genomics of sex-biased gene expression in early embryogenesis across mammals

abstract: Mammalian gonadal sex is determined by the presence or absence of a Y chromosome. In males, the Y chromosome initiates male gonadogenesis and the subsequent production of male-specific hormones defines the male state of each cell in the organism. In females, the lack of a Y chromosome and the presence of two X chromosomes triggers the development of female gonads, hormones, and cellular identity. However, sex chromosome-linked genes encoding dosage-sensitive transcription and epigenetic factors are expressed well before gonad formation and have the potential to establish sex-biased expression. Here, we apply a comparative bioinformatics analysis on published single-cell datasets from mouse and human during very early embryogenesis-from two-cell to preimplantation stages-to characterize sex-specific signals and to assess the degree of conservation among early-acting sex-specific genes and pathways. Clustering and regression analyses of gene expression across samples reveal that sex initially plays a significant role in overall gene expression patterns at the earliest stages of embryogenesis. In addition, gene expression signals from male and female gametes during fertilization may still be present. Although these transcriptional sex effects rapidly diminish, the sex-biased expression of epigenetic enzymes has the potential to establish sex-specific patterns that persist beyond preimplantation. Sex-biased genes appear to form sex-specific protein-protein interaction networks across preimplantation stages in both mammals. While the distribution of sex-differentially expressed genes (sexDEGs) in early embryonic stages are similar in mice and humans, the genes involved are generally different. Non-negative matrix factorization (NMF) on male and female transcriptomes generated clusters of genes with similar expression patterns across sex and developmental stages including post-fertilization, epigenetic, and preimplantation ontologies conserved between mouse and human. This comparative study uncovers much earlier than expected sex-specific signals in mouse and human embryos that pre-date hormonal signaling from the gonads. These early signals are diverged with respect to orthologs yet conserved in terms of function with important implications in the use of genetic models for sex-specific disease.

category: developmental biology


title: Understandable Multifunctionality Measures Using Hill Numbers

abstract: In ecology, multifunctionality measures the simultaneous provision of multiple ecosystem functions. If species diversity describes the variety of species that together build the ecosystem, multifunctionality attempts to describe the variety of functions these species perform. A range of methods have been proposed to quantify multifunctionality, successively attempting to alleviate problems that have been identified with the previous methods. This has led to a proliferation of more-or-less closely related metrics which, however, lack an overarching theoretical framework. Here we borrow from the comprehensive framework of species diversity to derive a new metric of multifunctionality. Analogously to the effective number of species used to quantify species diversity, the metric we propose is influenced both by the number of functions as well as, crucially, the evenness of performance levels across functions. In addition, the effective multifunctionality also considers the average level at which the functions are performed. The result is a measure of the cumulative performance of the system were all functions provided equally. The framework allows for the inclusion of the correlation structure among functions, thus allowing to account for non-independence between functions. We show that the average metric is a special case of the newly proposed metric when all functions are uncorrelated and performed at equal levels. We hope that by providing a new metric of multifunctionality anchored in the rigorous framework of species diversity based on effective numbers, we will overcome the considerable skepticism that the larger community of ecologists has built against indices of multifunctionality. We thereby hope to help popularize this important concept which, as biological diversity, describes a fundamental property of ecosystems and thus lies at the heart of ecology.


title: Peripheral and central employment of acid-sensing ion channels during early bilaterian evolution

abstract: Acid-sensing ion channels (ASICs) are membrane proteins that endow vertebrate neurons with fast excitatory responses to decreases in extracellular pH. Although previous studies suggest that ASICs are found in certain invertebrates, the lineage in which ASICs emerged and the functional role of ASICs beyond the vertebrates is unknown. We reconstructed ASIC evolution by surveying metazoan ASICs and performing a phylogenetic analysis, which suggests that ASICs evolved in an early bilaterian. This was supported by electrophysiological measurements of proton-gated currents at heterologous channels from diverse bilaterians. This also revealed substantial variation in biophysical properties of broadly related ASICs, with selective sodium/potassium ion permeability ranging from 3-to 36-fold and half-maximal activating pH from 4.2 to 8.1. Furthermore, we studied the expression of ASICs in species outside the vertebrates and found expression in the central nervous system of certain bilaterian lineages but in the periphery, including nervous system, digestive system, and motile ciliated epithelia, of most lineages. The loss of such epithelial cells in Ecdysozoa might explain the loss of ASICs from this major animal lineage. Our results suggest that ASICs emerged in an early bilaterian, and expression in the central nervous system was accompanied or even pre-dated by expression in the periphery.


title: Standardization of cytological behavior of pollens in sorghum by Image analysis

abstract: The development of iso-nuclear male sterile (A) and maintainer (B) line along with male fertile (R) lines, referred to as fertility restorers, helped in cost-effective seed production and deployment of hybrids. The pollen viability/fertility for maintenance (B-line) and restoration (R-line) remains a significant phenotyping hurdle in developing new lines. We carried out the present investigation to evaluate the pollen fertility status of Cytoplasmic Genetic Male Sterility (CGMS) based hybrids in sorghum. The experimental material consisted of 238 CGMS based hybrids developed from the crossing of individuals of (296B xIS 188551) - based Recombinant Inbred Line (RIL) population (F7:F8) with male-sterile line (296A). The experiment was conducted in the rainy and post-rainy seasons during 2016 to evaluate pollen fertility. The authors illustrated the pollen fertility status by counting pollen counts using two methods: viz., visual counting by the naked eye, and image analysis using ImageJ (NIH, USA) software. We compared results between counts recorded visually and ImageJ reads for randomly selected 50 individuals each during the rainy and post-rainy seasons. The pollen counts from ImageJ were 95% efficient in detecting sterile vs. fertile counts. These results provide a better, efficient, and quick tool for characterizing the pollen behavior and also add value to the genetics studies by accounting for the quantitative variation encoded by multiple loci.


title: Symbolic quantitative cognition in wild zebrafish (Danio rerio)

abstract: Zebrafish (Danio rerio) constitute an excellent model system to investigate the neural and genetic basis of quantitative cognition because of the single neuron resolution of calcium imaging of awake, behaving fish. While nonsymbolic numerical cognition has been investigated across many taxa, symbolic numerical cognition has not been investigated among fish. We developed a novel quantitative symbolic test for zebrafish using an operant conditioning paradigm in which the number of horizontal lines zebrafish approached in a 2-alternative forced choice task predicted the number of food reward pellets they would receive. Zebrafish did not at the population level learn a preference for the 2-line stimulus predictive of receiving 2 food pellets. However, they performed significantly above chance in a nonsymbolic discrimination task with the same apparatus, in which the 2-line stimulus was associated with the same reward but the choice of the 1-line stimulus was not rewarded. We also explored the explanatory value of alternative spatial learning hypotheses such as a Win-Stay, Lose-Shift (WSLS) strategy at the individual level for fish in navigating these spatially randomised tasks. The implications of this for symbolic versus nonsymbolic quantitative cognition in this model system are discussed relative to reward type and stimulus modality.