title: In vivo CRISPR screens reveal SCAF1 and USP15 as novel drivers of pancreatic cancer

abstract: Functionally characterizing the genetic alterations that drive pancreatic cancer progression is a prerequisite for Precision Medicine. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to assess the transforming potential of 125 recurrently mutated  long-tail pancreatic cancer genes, which revealed USP15 and SCAF1 as novel and potent Pancreatic ductal adenocarcinoma PDAC tumor suppressors, with USP15 functioning in a haplo-insufficient manner. Mechanistically, we found that loss of USP15 leads to reduced inflammatory responses associated with TNF, TGF-{beta} and IL6 signaling and sensitizes pancreatic cancer cells to PARP inhibition and gemcitabine. Similarly, genetic ablation of SCAF1 reduced inflammatory responses linked to TNF, TGF-{beta} and mTOR signaling and increased sensitivity to PARP inhibition. Furthermore, we identified that loss of SCAF1 resulted in the formation of a truncated inactive USP15 isoform at the expense of full length USP15, functionally coupling SACF1 and USP15. Notably, USP15 and SCAF1 mutations or copy number losses are observed in 31% of PDAC patients. Together, our results demonstrate the utility of in vivo CRISPR to integrate human cancer genomics with mouse modeling to delineate novel cancer driver genes USP15 and SCAF1 such as with potential prognostic and therapeutic implications.


title: In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer

abstract: How the genetic landscape of a tumor governs the tumors response to immunotherapy remains largely elusive. Here, we established a direct in vivo CRISPR/Cas9 gene editing methodology to assess the immune-modulatory capabilities of 573 putative cancer genes associated with altered cytotoxic activity in human cancers. Using KrasG12D- and BrafV600E-driven mouse lung cancer models, we identify Serpinb9 and Adam2 as our top immune suppressive and immune enhancing genes, respectively. Mechanistically, we show that Serpinb9 ablation in KrasG12D- and BrafV600E-mutant lung tumor cells greatly enhances the efficacy of cytotoxic T-cells in vitro and in vivo. ADAM2 is a cancer testis antigen broadly expressed in human cancers such as lung adenocarcinoma (13.9%), renal (74.7%), prostate (72.4%), uterine (28.6%) and invasive breast (9.5%) cancer. In our mouse models, we show that Adam2 expression is induced in KrasG12D- but not BrafV600E-driven murine lung tumors and that its expression is further enhanced by immunotherapy. We show that loss of Adam2 significantly decreases KrasG12D-lung tumor burden but blocks the efficacy of cytotoxic T-cells. Consistently, Adam2 overexpression dramatically increases tumor growth and enhances immunotherapy efficacy. Mechanistically, we find that Adam2s oncogenic function depends on modulating the tumor immune microenvironment by restraining productive type I and type II interferon responses as well as cytokine signaling, reducing the presentation of tumor-associated antigen, and modulating surface expression of several immunoregulatory receptors within Kras-driven lung tumors. Adam2 expression also leads to reduced levels of immune checkpoint inhibitors such as Pd-l1, Lag3, Tigit and Tim3. This reduced exhaustion within the tumor microenvironment may explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy against Adam2 overexpressing lung tumors. Together, our study highlights the power of integrating cancer genomic with in vivo CRISPR/Cas9 screens to uncover how cancer-associated genetic alterations control responses to immunotherapies.

category: cancer biology


title: Dbx1 controls the development of astrocytes of the intermediate spinal cord by modulating Notch signaling

abstract: Significant progress has been made in elucidating the basic principles that govern neuronal specification in the developing central nervous system. In contrast, much less is known about the origin of astrocytic diversity. Here we demonstrate that a restricted pool of progenitors in the mouse spinal cord, expressing the transcription factor Dbx1, produces a subset of astrocytes, in addition to interneurons. Ventral p0-derived astrocytes (vA0) exclusively populate intermediate regions of spinal cord with extraordinary precision. Postnatal vA0 population comprises gray matter protoplasmic and white matter fibrous astrocytes and a group of cells with strict radial morphology contacting the pia. We identified that vA0 cells in the lateral funiculus are distinguished by the expression of Reelin and Kcnmb4. We show that Dbx1 mutants have increased vA0 cells at the expense of p0-derived interneurons. Manipulation of the Notch pathway, together with the alteration in their ligands seen in Dbx1 knock-outs, suggest that Dbx1 controls neuron-glial balance by modulating Notch-dependent cell interactions. In summary, this study highlights that restricted progenitors in dorsal-ventral neural tube produce region-specific astrocytic subgroups and that progenitor transcriptional programs highly influence glial fate and are instrumental in creating astrocyte diversity.

category: developmental biology


title: Wnt and BMP signaling enhance melanocyte regeneration and suppress melanoma cell migration

abstract: Tissue regeneration and cancer share remarkable features including activation of cell proliferation and migration. Yet, tumors considerably differ from the regenerating tissue with respect to abnormal proliferation, invasive growth and metastasis. Thus, it is likely that cancer resembles early stages of regeneration with increased proliferation, but separates from the later stages with reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration, and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers opposite regulation of Wnt and BMP signaling pathways between regeneration and cancer. Functional inhibition of canonical Wnt or BMP pathways during melanocyte regeneration impeded the regenerative capacity of the melanocytes. In contrast, activation of either pathway significantly promoted melanocyte regeneration and potently suppressed migration of human melanoma cells. Therefore, mechanisms of regeneration can be exploited to correct dysregulated molecular pathways and malignant transformation in cancer.


title: Genome-resolved metaproteomics decodes the microbial and viral contributions to coupled carbon and nitrogen cycling in river sediments

abstract:
Rivers have a significant role in global carbon and nitrogen cycles, serving as a nexus for nutrient transport between terrestrial and marine ecosystems. Although rivers have a small global surface area, they contribute substantially to global greenhouse gas emissions through microbially mediated processes within the river hyporheic zone. Despite this importance, microbial roles in these climatically relevant systems are mostly inferred from 16S rRNA amplicon surveys, which are not sufficiently resolved to inform biogeochemical models. To survey the metabolic potential and gene expression underpinning carbon and nitrogen biogeochemical cycling in river sediments, we collected an integrated dataset of over 30 metagenomes, metaproteomes, and paired metabolomes. We reconstructed over 500 microbial metagenome assembled genomes (MAGs), which we dereplicated into 55 unique genomes spanning 12 bacterial and archaeal phyla. We also reconstructed 2482 viral genomic contigs, which were dereplicated into 111 viral MAGs >10kb in size. As a result of integrating gene expression data with geochemical and metabolite data, we created a conceptual model that uncovers new roles for microorganisms in organic matter decomposition, carbon sequestration, nitrogen mineralization, nitrification, and denitrification. Integrated through shared resource pools of ammonium, carbon dioxide, and inorganic nitrogen we show how these metabolic pathways could ultimately contribute to carbon dioxide and nitrous oxide fluxes from hyporheic sediments. Further, by linking viral genomes to these active microbial hosts, we provide some of the first insights into viral modulation of river sediment carbon and nitrogen cycling.

ImportanceHere we created HUM-V (Hyporheic Uncultured Microbial and Viral), an annotated microbial and viral genome catalog that captures the strain and functional diversity encoded in river sediments. Demonstrating its utility, this genomic inventory encompasses multiple representatives of the most dominant microbial and archaeal phyla reported in river sediments and provides novel viral genomes that can putatively infect these. Furthermore, we used HUM-V to recruit gene expression data to decipher the functional activities of these genomes and reconstruct their active roles in river sediment biogeochemical cycling. We show the power of genome resolved, multi-omics to uncover the organismal interactions and chemical handoffs shaping an intertwined carbon and nitrogen metabolic network and create a framework that can be extended to other river sediments. The accessible microbial and viral genomes in HUM-V will serve as a community resource to further advance more untargeted, activity-based measurements in these and related freshwater terrestrial-aquatic ecosystems.

category: microbiology


title: Metal Coordinating Inhibitors of Rift Valley Fever virus Replication

abstract: Rift Valley Fever Virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the Bunyavirales order, and replication of these viruses depends on the viral endonuclease activity of the viral L protein. Screening for RVFV replication inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 31 novel RVFV inhibitors with selective indexes from 5 - 402 and 50% effective concentrations of 0.54 - 56 {micro}M in Vero cells, primarily -Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against another Bunyavirus, La Crosse Virus (LACV). Conservation of the enzymatic activity such as the cap-snatching mechanism among the Bunyavirales implies that the -Hydroxytropolone and N-Hydroxypyridinedione chemotypes hold potential for development into treatments for related pathogens, including Hantaan Virus, Severe fever with thrombocytopenia syndrome virus, Crimean-Congo Hemorrhagic Fever Virus, and LACV. Keywords: Rift Valley Fever Virus 1, La Crosse virus 2, Cap-snatching endonuclease 3, Replication inhibitors 4, -Hydroxytropolones 5, N-Hydroxypyridinediones 6.


title: Synapse-type-specific competitive Hebbian learning forms functional recurrent networks

abstract: Cortical networks exhibit complex stimulus-response patterns. Previous work has identified the balance between excitatory and inhibitory currents as a central component of cortical computations, but has not considered how the required synaptic connectivity emerges from biologically plausible plasticity rules. Using theory and modeling, we demonstrate how a wide range of cortical response properties can arise from Hebbian learning that is stabilized by the synapse-type-specific competition for synaptic resources. In fully plastic recurrent circuits, this competition enables the development and decorrelation of inhibition-balanced receptive fields. Networks develop an assembly structure with stronger connections between similarly tuned neurons and exhibit response normalization and surround suppression. These results demonstrate how neurons can self-organize into functional circuits and provide a foundational understanding of plasticity in recurrent networks.

category: neuroscience


title: A robust Reeb graph model of white matter fibers with application to Alzheimer's disease progression

abstract: Tractography generates billions of complex curvilinear fibers (streamlines) in 3D that exhibit the geometry of white matter pathways. Analysis of raw streamlines on such a large scale is time-consuming and intractable. Further, it is well known that tractography computations produce noisy streamlines, and this in turn severely affect their use in structural brain connectivity analysis. Prompted by these challenges, we propose a novel method to model the bundling structures of streamlines using the construct of a Reeb graph. Three key parameters in our method capture the geometry and topology of the streamlines: (i){epsilon} - distance between a pair of streamlines in a bundle that defines its sparsity; (ii)  - spatial length of the bundle that introduces persistence; and (iii){delta} - the bundle thickness. Together, these parameters control the robustness and granularity of the model to provide a compact signature of the streamlines and their underlying anatomic fiber structure. We validate the robustness of the bundling structure using synthetic and ISMRM datasets. Next, we demonstrate the potential of this approach as a tool for efficient tractogram comparison by quantifying the fiber densities in the progression of Alzheimers disease. Our results on ADNI data localize the maximal bundles of various brain regions and show a significant depletion in the fiber density as Alzheimers disease progresses. The source code for the implementation is available on GitHub.


title: Patterned apoptosis modulates local growth and tissue shape in a fast-growing epithelium

abstract: What regulates organ size and shape remains one of the fundamental mysteries of modern biology. So far, research in this area has primarily focused on deciphering the regulation in time and space of growth and cell division, while the contribution of cell death has been much more neglected. This includes studies of the Drosophila wing imaginal disc, the prospective fly wing which undergoes massive growth during larval stage, and represents one of the best characterised systems for the study of growth and patterning. So far, it has been assumed that cell death was relatively neglectable in this tissue and as a result the pattern of growth was usually attributed to the distribution of cell division. Here, using systematic mapping and registration combined with quantitative assessment of clone size and disappearance, we show for the first time that cell death is not neglectable, and outline a persistent pattern of cell death and clone elimination in the disc. Local variation of cell death is associated with local variation of clone size, pointing to an impact of cell death on local growth which is not fully compensated by proliferation. Using morphometric analyses of adult wing shape and genetic perturbations, we provide evidence that patterned death affects locally and globally adult wing shape and size. This study describes a roadmap for accurate assessment of the contribution of cell death to tissue shape, and outlines for the first time an important instructive role of cell death in modulating quantitatively local growth and the morphogenesis of a fast-growing tissue.


title: Patterned apoptosis has an instructive role for local growth and tissue shape in a fast-growing epithelium


title: The extinction of threatened species by anthropogenic threats endangers the functional diversity of turtles and crocodiles

abstract: The Anthropocene is tightly associated with a drastic loss of species worldwide, and consequently, with the disappearance of key ecosystem functions. The on-going reduction in species functionality is driven by global and local threats. The orders Testudines (turtles and tortoises) and Crocodilia (crocodilians and alligators) contain numerous threatened, long-lived species for which their functional diversity and potential erosion by anthropogenic impacts remains unknown. Here, we examine 259 of the existing 375 species of Testudines and Crocodilia quantifying their life history strategies (i.e., schedules of survival, development, and reproduction) from open-access data on their demography, ancestry, and threats. We find that the loss of functional diversity in simulated extinction scenarios of threatened species is greater than expected by chance. Moreover, the effects of unsustainable local consumption, diseases, and pollution are associated to specific functional strategies. Meanwhile climate change, habitat disturbance, and global trade affect all species independent of their life history strategy. Importantly, the loss of functional diversity for threatened species by habitat disturbance is twice greater than for all other threats. Our findings highlight the key importance of conservation programmes focused on preserving the functional diversity of life history strategies jointly with the phylogenetic representativity of these highly threatened groups.

category: ecology


title: Improved basic cytogenetics challenges holocentricity of butterfly chromosomes

abstract: Mitotic chromosomes of butterflies, which look like dots or short filaments in most published data, are generally considered to lack localised centromeres and thus to be holokinetic. This particularity, observed in a number of other invertebrates, is associated with meiotic particularities known as "inverted meiosis", in which the first division is equational, i.e., centromere splitting-up and segregation of sister chromatids instead of that of homologous chromosomes. However, the accurate analysis of butterfly chromosomes is difficult. 1) Their size is very small, equivalent to a single band of a mammalian metaphase chromosome. 2) They lack satellite DNA/heterochromatin in putative centromere regions and therefore marked primary constrictions. Our improved conditions for chromosome preparations in six butterfly species belonging to the Nymphalidae and Pieridae families challenges the holocentricity of their chromosomes: in spite of the absence of primary constriction, sister chromatids are recurrently held together at definite positions during mitotic metaphase, which makes possible to establish karyotypes composed of acrocentric and sub-metacentric chromosomes. The total number of chromosomes per karyotype is roughly inversely proportional to that of non-acrocentric chromosomes, which suggests the occurrence of frequent Robertsonian-like fusions or fissions during evolution. Furthermore, the behaviour and morphological changes of chromosomes along the various phases of meiosis do not differ much from those of canonical meiosis. In particular at metaphase II, chromosomes clearly have two sister chromatids, which refutes that anaphase I was equational. Thus, we propose an alternative mechanism to holocentricity for explaining the large variations in chromosome numbers in butterflies: 1) in the ancestral karyotype, composed of about 60-62 acrocentric chromosomes, the centromeres, devoid of centromeric heterochromatin/satellite DNA, were located at contact with telomeric heterochromatin; 2) the instability of telomeric heterochromatin largely contributed to drive the multiple chromosome rearrangements, which occurred during butterfly evolution.

category: genetics


title: Assessment of genetic diversity and SNP marker development within peanut germplasm in Taiwan by RAD-seq

abstract: The cultivated peanut (Arachis hypogaea L.) is an important oil crop but has a narrow genetic diversity. Molecular markers can be used to probe the genetic diversity of various germplasm. In this study, the restriction site associated DNA (RAD) approach was utilized to sequence 31 accessions of Taiwanese peanut germplasm, leading to the identification of a total of 17,610 single nucleotide polymorphisms (SNPs). The origin of these 31 accessions is contrasted so the global subset (n = 17) has greater genetic diversity than the local subset (n = 14). Concerning botanical varieties, the var. fastigiata subset has greater genetic diversity than the other two subsets of var. vulgaris and var. hypogaea, suggesting that novel genetic resources should be introduced into breeding programs to enhance genetic diversity. Principal component analysis (PCA) using genotyping data separated the 31 accessions into three clusters largely according to the botanical varieties, consistent with the PCA result for 282 accessions genotyped by 14 kompetitive allele-specific PCR (KASP) markers developed in this study. The SNP markers identified in this work not only revealed the genetic relationship and population structure of current germplasm in Taiwan, but also offer an efficient tool for breeding and further genetic applications.


title: High-frame-rate analysis of knee cartilage deformation by spiral dualMRI and relaxation mapping

abstract:
PurposeDaily activities including walking impose high frequency cyclic forces on cartilage and repetitive compressive deformation. Analyzing cartilage deformation during walking would provide spatial maps of displacement, strain, and enable viscoelastic characterization, which may serve as imaging biomarkers for early cartilage degeneration when the damage is still reversible. However, the time-dependent biomechanics of cartilage is not well described, and how defects in the joint impact the viscoelastic response is unclear.

MethodsWe used spiral acquisition with displacement encoding MRI to quantify displacement and strain maps at a high frame rate (40 ms; 25 frames/sec) in tibiofemoral joints. We also employed relaxometry methods (T1, T1{rho}, T2, T2*) on the cartilage.

ResultsNormal and shear strains were concentrated on the tibiofemoral contact area during loading, and the defected joint exhibited larger compressive strains. We also determined a positive correlation between the change of T1{rho} in cartilage after cyclic loading and increased compressive strain on the defected joint. Viscoelastic behavior was quantified by the time-dependent displacement, where the damaged joint showed increased creep behavior compared to the intact.

ConclusionsOur results indicate that spiral scanning with displacement encoding can quantitatively differentiate the damaged from intact joint using the strain and creep response. The viscoelastic response identified with this methodology could serve as biomarkers to detect defects in joints in vivo and facilitate the early diagnosis of joint diseases such as osteoarthritis.

category: bioengineering


title: cgRNASP: coarse-grained statistical potentials with residue separation for RNA structure evaluation

abstract: Knowledge-based statistical potentials are very important for RNA 3-dimensional (3D) structure prediction and evaluation. In recent years, various coarse-grained (CG) and all-atom models have been developed for predicting RNA 3D structures, while there is still lack of reliable CG statistical potentials not only for CG structure evaluation but also for all-atom structure evaluation at high efficiency. In this work, we have developed a series of residue-separation-based CG statistical potentials at different CG levels for RNA 3D structure evaluation, namely cgRNASP, which is composed of long-ranged and short-ranged interactions by residue separation. Compared with the newly developed all-atom rsRNASP, the short-ranged interaction in cgRNASP was involved more subtly and completely through explicitly adding the interactions between nearest neighbor residues and between next-nearest ones. Our examinations show that, the performance of cgRNASP varies with CG levels and compared with rsRNASP, cgRNASP can have similarly good performance for extensive test datasets and slightly better performance for the realistic RNA-Puzzles dataset. Furthermore, cgRNASP is strikingly more efficient than all-atom potentials such as rsRNASP, and can be apparently superior to other all-atom statistical potentials and scoring functions trained from neural networks for the RNA-Puzzles dataset. cgRNASP is available at https://github.com/Tan-group/cgRNASP.

category: biophysics


title: Profiling Mouse Brown and White Adipocytes to Identify Metabolically Relevant Small ORFs and Functional Microproteins

abstract: The absence of thousands of recently annotated small open reading frame (smORF)-encoded peptides and small proteins (microproteins) from databases has precluded their analysis in metabolism and metabolic disease. Given the outsized importance of small proteins and peptides such as insulin, leptin, amylin, glucagon, and glucagon-like peptide-1 (GLP-1) in metabolism, microproteins are a potentially rich source of uncharacterized metabolic regulators. Here, we annotate smORFs in primary differentiated brown, white, and beige mouse adipose cells. Ribosome profiling (Ribo-Seq) detected a total of 3,877 unannotated smORFs. Analysis of RNA-Seq datasets revealed diet-regulated smORF expression in adipose tissues, and validated the adipose translation of the feeding-neuron marker gene Gm8773. Gm8773 encodes the mouse homolog of FAM237B, a neurosecretory protein that stimulates food intake and promotes weight gain in chickens. Testing of recombinant mFAM237B produced similar orexigenic activity in mice further supporting a role for FAM237B as a metabolic regulator and potentially part of the brain-adipose axis. Furthermore, we demonstrated that data independent acquisition mass spectrometry (DIA-MS) proteomics can provide a sensitive, flexible, and quantitative platform for identifying microproteins by mass spectrometry. Using this system led to the detection of 58 microproteins from cell culture and an additional 33 from mouse plasma. The proteomics data established the anti-inflammatory microprotein AW112010 as a circulating factor, and found that plasma levels of a microprotein translated from a FRS2 uORF is elevated in older obese mice. Together, the data highlight the value of this database in examining understudied smORFs and microproteins in metabolic research and identifying additional regulators of metabolism.

category: systems biology


title: Rhythm of relationships in a social fish over the course of a full year in the wild

abstract: Animals are expected to adjust their social behaviour to cope with challenges in their environment. Therefore, for fish populations, in temperate regions with seasonal and daily environmental oscillations, characteristic rhythms of social relationships should be pronounced. To date, most research concerning fish social networks and biorhythms has occurred in artificial laboratory environments or over confined temporal scales of days to weeks. By contrast, little is known about the social networks of wild, freely roaming fish, including how seasonal and diurnal rhythms modulate social networks over the course of a full year. The advent of high-resolution acoustic telemetry enables us to quantify detailed social interactions in the wild over time-scales sufficient to examine seasonal rhythms at whole-ecosystems scales. Our objective was to explore the rhythms of social interactions in a social fish population at various time-scales over one full year in the wild by examining high-resolution snapshots of dynamic social network. To that end, we tracked the behaviour of 36 adult common carp, Cyprinus carpio, in a 25 ha lake and constructed temporal social networks among individuals across various time-scales, where social interactions were defined by proximity. We compared the network structure to a temporally shuffled null model to examine the importance of social attraction, and checked for persistent characteristic groups ("friendships") over time. The clustering within the carp social network tended to be more pronounced during daytime than nighttime throughout the year. Social attraction, particularly during daytime, was a key driver for interactions. Shoaling behavior substantially increased during daytime in the wintertime, whereas in summer carp interacted less frequently, but the interaction duration increased. Characteristic groups were more common in the summer months and during nighttime, where the social memory of carp lasted up to two weeks. We conclude that social relationships of carp change diurnally and seasonally. These patterns were likely driven by predator avoidance, seasonal shifts in lake temperature, visibility, forage availability and the presence of anoxic zones. The techniques we employed can be applied generally to high-resolution biotelemetry data to reveal social structures across other fish species at ecologically realistic scales.

category: animal behavior and cognition


title: Wireless networks of injectable microelectronic stimulators based on rectification of volume conducted high frequency currents

abstract:
ObjectiveTo develop and in vivo demonstrate threadlike wireless implantable neuromuscular microstimulators that are digitally addressable.

ApproachThese devices perform, through its two electrodes, electronic rectification of innocuous high frequency current bursts delivered by volume conduction via epidermal textile electrodes. By avoiding the need of large components to obtain electrical energy, this approach allows the development of thin devices that can be intramuscularly implanted by minimally invasive procedures such as injection. For compliance with electrical safety standards, this approach requires a minimum distance, in the order of millimeters or a very few centimeters, between the implant electrodes. Additionally, the devices must cause minimal mechanical damage to tissues, avoid dislocation and be adequate for long-term implantation. Considering these requirements, the implants were conceived as tubular and flexible devices with two electrodes at opposite ends and, at the middle section, a hermetic metallic capsule housing the electronics.

Main resultsThe developed implants have a submillimetric diameter (0.97 mm diameter, 35 mm length) and consist of a microcircuit, which contains a single custom-developed integrated circuit, housed within a titanium capsule (0.7 mm diameter, 6.5 mm length), and two platinum-iridium coils that form two electrodes (3 mm length) located at opposite ends of a silicone body. These neuromuscular stimulators are addressable, allowing to establish a network of microstimulators that can be controlled independently. Their operation was demonstrated by injecting a few of them in the hind limb of anesthetized rabbits and inducing controlled and independent contractions.

SignificanceThese results show the feasibility of manufacturing threadlike wireless addressable neuromuscular stimulators by using fabrication techniques and materials well established for chronic electronic implants. This paves the way to the clinical development of advanced motor neuroprostheses formed by dense networks of such wireless devices.


title: dialogi: Utilising NLP with chemical and disease similarities to drive the identification of Drug-Induced Liver Injury literature

abstract: Drug-Induced Liver Injury (DILI), despite its low occurrence rate, can cause severe side effects or even lead to death. Thus, it is one of the leading causes for terminating the development of new, and restricting the use of already-circulating, drugs. Moreover, its multifactorial nature, combined with a clinical presentation that often mimics other liver diseases, complicate the identification of DILI-related literature, which remains the main medium for sourcing results from the clinical practice and experimental studies. In this work- contributing to the  Literature AI for DILI Challenge of the Critical Assessment of Massive Data Analysis (CAMDA) 2021- we present an automated pipeline for distinguishing between DILI-positive and negative papers. We used Natural Language Processing (NLP) to filter out the uninformative parts of a text, and identify and extract mentions of chemicals and diseases. We combined that information with small-molecule and disease embeddings, which are capable of capturing chemical and disease similarities, to improve classification performance. The former are directly sourced from the Chemical Checker (CC). For the latter, we collected data that encode different aspects of disease similarity from the National Library of Medicines (NLM) Medical Subject Headings (MeSH) thesaurus and the Comparative Toxicogenomics Database (CTD). Following a similar procedure as the one used in the CC, vector representations for diseases were learnt and evaluated. Two Neural Network (NN) classifiers were developed: one that only accepts texts as input (baseline model) and an augmented classifier that also utilises chemical and disease embeddings (extended model). We trained, validated, and tested the models through a Nested Cross-Validation (NCV) scheme with 10 outer and 5 inner folds. During this, the baseline and extended models performed virtually identically, with macro F1-scores of 95.04 {+/-} 0.61% and 94.80 {+/-} 0.41%, respectively. Upon validation on an external, withheld, dataset, representing imbalanced data, the extended model achieved an F1-score of 91.14 {+/-} 1.62%, outperforming its baseline counterpart, which got a lower score of 88.30 {+/-} 2.44%. We make further comparisons between the classifiers and discuss future improvements and directions, including utilising chemical and disease embeddings for visualisation and exploratory analysis of the DILI-positive literature.

category: bioinformatics


title: FPGA Acceleration of GWAS Permutation Testing

abstract:
MotivationGenome-wide association studies (GWASs) analyse genetic variation over the genomes of many individuals in an attempt to identify single nucleotide polymorphisms (SNPs) associated with complex phenotypes. To capture a large amount of genetic variation and increase the chance of detecting associated SNPs, modern GWASs include millions of SNPs sampled from thousands of individuals. The cumulative probability of false associations increases with the number of SNPs included in the analysis. A GWAS, therefore, needs to control the number of false associations. Permutation testing is a straightforward and accurate method of controlling the false positive rate, but it is very computationally expensive (and slow) so there is a need for a permutation testing accelerator that can process modern GWAS datasets in reasonable time.

ResultsFPGAs (Field-Programmable Gate Arrays) are reconfigurable integrated circuits which provide a high level of parallelisation that can be harnessed to accelerate GWAS permutation testing. This work presents an accessible FPGA-based tool (designed to run on a cloud-based AWS EC2 FPGA instance) that accelerates GWAS permutation testing for continuous phenotypes. The tool implements two known GWAS permutation testing algorithms: maxT permutation testing and adaptive permutation testing. The speed of the FPGA-based tool was compared to the speed of PLINK (a popular CPU-based tool) running on 40 Intel Xeon 4114 CPU cores using an imputed breast cancer dataset of 13.7 million SNPs sampled from 3652 individuals. For 1000 maxT permutations, the FPGA-based algorithms run time was 22 minutes while PLINKs run time was almost 7 days; for 100 million adaptive permutations, the FPGA-based algorithms run time was 325 minutes and PLINKs run time was about 8.5 days. For 700 million adaptive permutations of the same dataset (an almost unfeasible workload for PLINK running on a 40-core CPU) the run time of the FPGA-accelerated algorithm was 33 hours.

AvailabilityAn EC2 AMI (FPGA_perm) in the us-east-1 region is available. Instructions, source code and sample data are available at https://github.com/witseie/fpgaperm.


title: Selective Control of Parasitic Nematodes Using Bioactivated Nematicides

abstract: Parasitic nematodes are a major threat to global food security, particularly as the world amasses 10 billion people amidst limited arable land. Most traditional nematicides have been banned due to poor nematode-selectivity, leaving farmers with inadequate controls. Here, we use the model nematode Caenorhabditis elegans to identify a family of selective imidazothiazole nematicides, called selectivins, that undergo cytochrome p450-dependent bioactivation exclusively in nematodes. At low parts-per-million concentrations, selectivins perform comparably well with commercial nematicides to control root infection by Meloidogyne incognita - the worlds most destructive plant-parasitic nematode. Tests against a wide range of phylogenetically diverse non-target systems demonstrate that selectivins are more nematode-selective than nearly all marketed nematicides. Thus, selectivins are first-in-class bioactivated nematode controls that provide efficacy as well as much-needed nematode selectivity.

category: pharmacology and toxicology


title: A fungal endophyte-generated nucleoside signal regulates host cell death and promotes root colonization

abstract:
SummaryIntracellular colonization of plant roots by the beneficial fungal endophyte Serendipita indica follows a biphasic strategy. After an early biotrophic phase, the interaction switches to a host cell death phase restricted to the root epidermis and cortex layers. Host cell death contributes to successful fungal accommodation during beneficial interaction in Arabidopsis thaliana. How the host cell death is initiated and controlled is largely unknown. Here we show that two fungal enzymes, the ecto-5-nucleotidase SiE5NT and the nuclease SiNucA, act synergistically in the plant apoplast at the onset of cell death to produce deoxyadenosine (dAdo), a potent cell death inducer in animal systems. Uptake of extracellular dAdo, but not of the structurally related adenosine (Ado), activates a previously undescribed cell death mechanism in A. thaliana and the basal land plant Marchantia polymorpha, suggesting a conserved cell death response to dAdo across land plant lineages. Mutation of the A. thaliana equilibrative nucleoside transporter ENT3 confers resistance to extracellular dAdo-triggered cell death and leads to decreased fungal-mediated cell death during root colonization. A library screen of A. thaliana T-DNA insertion lines identified a nucleotide-binding leucine-rich repeat protein (NLR) as an additional intracellular component in dAdo-triggered cell death. Our data show that the combined activity of two apoplast-resident fungal enzymes leads to the production of a metabolite, which induces an NLR-modulated plant host cell death upon uptake.

In briefRegulated host cell death is part of a plant defense strategy against pathogens but it is also involved in accommodating certain beneficial root microbes. We have identified extracellular metabolites and intracellular metabolic signals that contribute to beneficial root fungal endophyte colonization, and uncovered a conserved cell death mechanism likely co-opted for establishing plant-endophyte symbiosis.

category: plant biology


title: BrainQCNet: a Deep Learning attention-based model for multi-scale detection of artifacts in brain structural MRI scans

abstract: Analyses of structural MRI (sMRI) data depend on robust upstream data quality control (QC). It is also crucial that researchers retain the maximum amount of usable data to ensure reproducible, generalisable models. The time-consuming task of manual QC evaluation has prompted the development of tools for the automatic assessment of brain sMRI scans. Such tools are particularly valuable in this age of big data. One limitation of the most commonly used tools is that execution time is long, which poses a challenge in terms of duration and resource usage, particularly when processing large datasets. Further, evaluation is global (pass/fail) rather than localized. Having a tool that localizes areas of low quality could prevent unnecessary data loss. To address these issues, we trained a Deep Learning model, ProtoPNet, to classify minimally preprocessed 2D slices of scans that were manually annotated with a refined quality assessment (ABIDE 1 n = 980 scans). To validate the best model, we assessed 2141 ABCD scans for which gold-standard manual QC annotations were available. We obtained excellent accuracy: 82.4% for good quality scans (Pass), 91.4% for medium to low quality scans (Fail). Further validation using 799 scans from ABIDE 2 and 751 scans from ADHD-200 confirmed the reliability of our model. Accuracy was comparable to or exceeded that of another commonly used tool (MRIQC), but with dramatically reduced processing and prediction time (1 min per scan, GPU machine, CUDA-compatible). To facilitate faster and more accurate QC prediction for the neuroimaging community, we have shared the model that returned the most reliable global quality scores, local predictions of quality, and maps and prototypes of local artifacts as a BIDS-app (https://github.com/garciaml/BrainQCNet).


title: A novel automated morphological analysis of microglia activation using a deep learning assisted model

abstract: There is growing evidence for the key role of microglial activation in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements, and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools (Aiforia(R) Cloud (Aifoira Inc., Cambridge, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinsons disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are shared within the Aiforia(R) platform and are available for study-specific adaptation and validation.


title: Synapse type-specific molecular nanoconfigurations of the presynaptic active zone in the hippocampus identified by systematic nanoscopy

abstract: Neurotransmitters are released by exocytosis from synaptic vesicles at the active zone in the presynaptic terminal. The scaffold of the active zone consists of only a few evolutionarily conserved proteins, including RIM, CAST/ELKS, and RIM-BP, and tethers Munc13 and Ca2+ channels. The molecular principles that enable these proteins to mediate synaptic diversity have remained unclear. Here, we identified synapse type-specific molecular nanoconfigurations in the active zone by systematic quantification of active zone proteins using nanoscopy at two types of excitatory synapses and two types of inhibitory synapses in the rat hippocampal CA3 region. Quantitative analysis revealed that Munc13 content was particularly varied among the various synapse types and that the physical proximity of Ca2+ channels to the active zone scaffolds correlated with the efficacy of neurotransmitter release. We propose that the active zone is a flexible supramolecular assembly that can tune its composition and spatial configuration to adjust neurotransmitter release.


title: Coherent network oscillations regulate quiescence and behavioral responsiveness in Drosophila

abstract: Quiescent states such as sleep restore vital physiological functions across phyla and are characterized by reduced locomotion and diminished behavioral responsiveness to external stimuli. In humans, synchronous activity across cortical networks is a hallmark of deep sleep, but how network coherence elevates arousal thresholds to maintain quiescent states remains largely unclear. Here, we build on our recent discovery of slow wave activity (SWA) mediating sleep need in the R5 ring network of Drosophila and investigate interactions across sleep- and arousal mediating networks. We demonstrate that information of sleep need travels across a recently described recurrent network for sleep regulation (dFSB-helicon-R5) and elicits oscillatory Ca2+ signatures in the presynaptic terminals of the interconnected networks. Subject to circadian modulation, the sleep need mediating circuits within this network (dFSB and R5) reciprocally promote these oscillatory signatures. Optogenetically imposing slow rhythms (1 Hz) on R5 and dFSB induces entrainable quiescent states while high-frequency stimulation of R5 (10 Hz) leads to flies losing postural control. We further discover that increased excitability in the master sleep homeostat (dFSB) likely acts as a switch that synchronizes the presynaptic electrical patterns of R5 and arousal mediating neurons (helicon) at night. Exposing the behavioral significance by optogenetically mimicking coherent activity we show that R5/helicon synchronization facilitates suppression of responsiveness to visual stimuli in sleeping flies. Moreover, neural activity in downstream head-direction neurons targeted by both helicon and R5 can be completely inhibited through activation of the R5 network. We therefore propose that sleep need mediating circuits promote coherent SWA to induce quiescent states by rhythmically associating neural networks that mediate locomotion, arousal and postural control.


title: B cells are addicted to immunoglobulin production in the ER

abstract: Resting B cell dependence on the B cell antigen receptor (BCR) has been attributed solely to its signaling competence. We have recently shown that the presence of the BCR is vital for endoplasmic reticulum (ER) homeostasis and mitochondrial function both in primary B cells and Burkitt lymphoma (BL) cell lines. Unexpectedly, in BL Ramos cells this role has been shown to be independent of BCR signals from the cell membrane. Now, we provide evidence that also in mouse resting B cells ER-resident immunoglobulin (Ig) heavy chains control ER homeostasis, calcium storage and mitochondrial homeostasis through ER-mitochondria contacts. These findings demonstrate that BCR expression shapes cellular fitness already at the stage of assembly in the ER and uncover a new layer of B cell dependence on the production of Ig heavy chains in the ER. Sensing protein expression in the ER, with counterselection of compromised cells, might well operate also in other differentiated cells.

category: immunology


title: The AppNL-G-F mouse model of Alzheimer's disease is refractory to regulatory T cell treatment

abstract:
BackgroundAlzheimers Disease is a neurodegenerative disease with a neuroinflammatory component. Due to the multifunctional capacity of regulatory T cells to prevent and reverse inflammation, regulatory T cells have been proposed as a potential therapeutic in Alzheimers Disease, either as a direct cell therapy or through the use of IL2 as a biologic to expand the endogenous population.

MethodsHere we characterize the longitudinal immunological changes occurring in T cells in the AppNL-G-F mouse model of Alzheimers disease.

ResultsAge-dependent immunological changes, in both the brain and periphery, occurred in parallel in both AppNL-G-F mice and control AppNL mice. As the endogenous IL2 axis was disturbed with age, we sought to determine the effect of IL2 supplementation on disease progression. Using a genetic model of IL2 provision in the periphery or in the brain, we found that expanding regulatory T cells in either location was unable to alter the progression of key pathological events or behavioral changes.

ConclusionThese results suggest that either the AppNL-G-F mouse model does not recapitulate key regulatory T cell-dependent process of Alzheimers disease, or that regulatory T cell therapy is not a promising candidate for APP-mutation-driven Alzheimers disease.


title: The asymmetric ABA response on both sides of root tip is important for tomato root hydrotropism by mediating proton efflux and cell elongation

abstract:
Hydrotropism is an important adaptation of plant roots to the uneven distribution of water, and the current research on hydrotropism is mainly focused on Arabidopsis thaliana. We examined hydrotropism in tomato (Solanum lycopersicum) primary roots. We used RNA sequencing to detect the gene expression on both sides (dry and wet side) of root tips (5 mm from the root cap junction) by splitting root tips longitudinally into two halves. We found that hydrostimulation induced the asymmetric cell elongation between the dry side (lower water potential) and wet side of root tips (higher water potential). ABA biosynthesis gene ABA4 was induced on the dry side as compared to the wet side of root tips. Chemical inhibitors that block ABA biosynthesis can disrupt hydrotropism, and ABA biosynthesis mutant not showed significantly reduced hydrotropism. Furthermore, asymmetric H+ efflux was found in wild-type but not in root tips of ABA biosynthesis mutant not after hydrostimulation. Our results suggest that the asymmetric ABA response on both sides of root tip mediate asymmetric H+ efflux, and then drive the asymmetric cell elongation, which allows the root to bend towards the wet side to take up more water.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/483958v1_ufig1.gif" ALT="Figure 1">
View larger version (56K):
org.highwire.dtl.DTLVardef@1f8132dorg.highwire.dtl.DTLVardef@1b30b09org.highwire.dtl.DTLVardef@199955corg.highwire.dtl.DTLVardef@1cfd13_HPS_FORMAT_FIGEXP  M_FIG Involvement of ABA-mediated asymmetric H+ efflux in root hydrotropism.

Compared to the wet side of root tip (higher water potential), the dry side (lower water potential) induces the expression of ABA biosynthesis gene ABA4, thus enhancing proton efflux to promoting cell elongation on the dry side. Because H+ efflux and cell elongation on the dry side of the root tip are higher than that on the wet side, the asymmetric growth of cells on both sides allows the root to bend towards the wet side for taking up more water.

C_FIG In BriefThe asymmetric ABA response on both sides of root tip (dry side and wet side) sequently mediates root asymmetric H+ efflux, and then drives the asymmetric cell elongation on both sides of root tip, which allows the root to bend towards the wet side for absorbing more water.

HighlightsHydrotropic bending requires asymmetric cell elongation on the root two sides.

Asymmetric expression of ABA biosynthesis gene ABA4 is required for root hydrotropism.

The H+ efflux on the dry side of the root is increased.

ABA-associated asymmetric H+ efflux driven root hydrotropic bending.


title: Elevated human footprint on islands promotes both introduction and extinction probability of insular reptiles at opposite ends of geographic, evolutionary and ecological continua

abstract: The Anthropocene is marked by unprecedented changes to species ranges worldwide. Introduced species expand their native range into new geographic regions while extinction-prone species experience severe native range contraction. Introductions and extinctions are both caused by how species respond to human influence within their native ranges. The question arises if the opposite response in distributional change is due to introduced and extinction-prone species falling at opposite ends of geographic, evolutionary and ecological trait continua. Here, we assess the factors that explain the introduction and extinction-prone status for 3111 squamate reptile species native to the western hemisphere, of which 142 species have been introduced elsewhere and 483 species are threatened with extinction. We first asked what geographic regions contained the most introduced and extinction-prone species and if these species are evolutionarily related. We then tested the opposite ends hypothesis for several species characteristics. Our results show that the native ranges of introduced and extinction-prone reptiles are skewed towards island regions and that significant phylogenetic signal exists for these two groups, indicating they are not a random selection of the reptiles that have evolved in the western hemisphere. Species whose native ranges were more insular and were more influenced by humans were more likely to be introduced or extinction-prone. Evolutionary factors did not explain species status, but multiple geographic and ecological factors supported the opposite ends hypothesis. Introduced species were positively associated with herbivory and omnivory and had large and complex ranges, whereas extinction-prone species were generally carnivorous with small and simple ranges. In addition, introduced species produced larger clutches and extinction-prone species had relatively small body sizes. In the Anthropocene, the naive ranges of introduced and extinction-prone species are situated in the same human-impacted regions, but species range characteristics and functional traits determine whether species ranges expand or contract in the continuing face of global change.


title: Positive selection of senescence through increased evolvability: ageing is not a by-product of evolution.

abstract:
The possibility of ageing being directly selected through evolution has been discussed for the past hundred years. As ageing is occurring, by definition, only late in life - i.e. after the organismal development is finalized -, many think that it cannot be actively selected for as a process. In addition, by decreasing an individuals fitness, it is thought unlikely to be selected for. In order to explain the observation of its broad presence in the realm of life, numerous theories have been proposed in the past 75 years, in agreement with this view.

Here, building upon a simple life-history trait model that we recently introduced and that summarizes the life of an organism to its two core abilities - reproduce and thrive -, we discuss the possibility of ageing being selected for through evolution.

Our model suggests that senescence can be positively selected through evolution thanks to the higher evolvability it confers to organisms, not through a given mechanism but through a function "ageing", limiting organismal maintenance and ability to reproduce. It provides an elegant explanation for the apparent tradeoff between longevity and fertility that led to the disposable soma theory without requiring an energy tradeoff while confirming the substrate for mutation accumulation and antagonistic pleiotropy theories. In addition, it predicts that the Lansing effect should be present in organisms showing rapid post-reproductive senescence. This formal and numerical modeling of ageing evolution also provides new hints to test the validity of existing theories.

category: evolutionary biology


title: Black Queen Hypothesis, partial privatization, andquorum sensing evolution

abstract: Microorganisms produce costly cooperative goods whose benefit is partially shared with nonproducers, called  mixed goods. The Black Queen Hypothesis predicts that partially privatization of benefits from the mixed goods has two major evolutionary implications. First, to favor strains producing several mixed goods over nonproducing strains. Second, to favor the maintenance of cooperative traits through different strains instead of having all cooperative traits present in a single strain (metabolic specialization). Despite the importance of quorum sensing regulation of mixed goods, it is not clear how partial privatization of benefits affects quorum sensing evolution. Here, we studied the influence of partial privatization of benefits on the evolution of quorum sensing. We developed a mathematical population genetics model of an unstructured microbial population considering four strains that differ in their ability to produce an autoinducer (quorum sensing signaling molecule) and a mixed good. Our model assumes that the production of the autoinducers and the mixed goods is constitutive and/or depends on quorum sensing. Our results suggest that partially privatized benefits cannot foster quorum sensing. This result occurs because: (1) a strain that produces both autoinducer and good (fully producing strain) cannot persist in the population; (2) the strain only producing the autoinducer and the strain producing mixed goods in response to the autoinducers cannot coexist, i.e., metabolic specialization cannot be fostered.


title: A re-emerging arbovirus in livestock in China: Early genomic surveillance and phylogeographic analysis

abstract: Viruses in livestock represent a great risk to public health due to the close contact of their hosts with humans and the potential long-range transportation though animal trade. Here, we show how to predict outbreaks of potential zoonotic pathogens and use spatially-explicit phylogeographic and phylodynamic approaches to provide estimates of key epidemiological parameters. First, we use metagenomic next generation sequencing (mNGS) to identify a Getah virus (GETV) as the pathogen responsible for a re-emerging swine disease in China. The GETV isolate is able to replicate in a variety of cell lines including human cells and shows high pathogenicity in a mouse model suggesting a potential public health risk. We obtained 16 complete genomes and 78 E2 gene sequences from viral strains collected within China from 2017 to 2021 through large-scale surveillance among livestock, pets and mosquitoes. Moreover, phylogenetic analysis reveals that three major GETV lineages are responsible for the current epidemic in livestock in China. We identify three potential positively selected sites and mutations of interest in E2, which may impact the transmissibility and pathogenicity of the virus. We then reconstruct the evolutionary and dispersal history of the virus and test the impact of several environmental factors on the viral genetic diversity through time and on the dispersal dynamic of viral lineages. Of note, we identify temporal variation in livestock meat consumption as a main predictor of viral genetic diversity through time. Finally, phylogeographic analyses indicate that GETV preferentially circulates within areas associated with relatively higher mean annual temperature and pig population density. Our results highlight the importance of continuous surveillance of GETV among livestock in southern Chinese regions associated with relatively high temperatures, and the need to control mosquitoes in the livestock farms. Our analyses of GETV also provide a baseline for future studies of the molecular epidemiology and early warning of emerging arboviruses in China.


title: Sulfur-mediated chalcogen versus hydrogen bonds in proteins: a seesaw effect in the conformational space

abstract: Divalent sulfur (S) form chalcogen bond (Ch-bond) via its {sigma}-holes and hydrogen bond (H-bond) via its lone-pairs. Relevance of these interactions and their interplay for protein structure and function is unclear. Based on the analyses of the crystal structures of small organic/organometallic molecules and proteins, and their Molecular Electrostatic Surface Potential, we show that the reciprocity of the substituent-dependent strength of the {sigma}-holes and lone-pairs correlate with the formation of either Ch-bond or H-bond. In proteins, disulfide-bonded cystine preferentially forms Ch-bond, metal-chelated cysteine forms H-bond, while methionine forms either of them with comparable frequencies. This has implications to the positioning of these residues and their role in protein structure and function. Computational analyses reveal that the S-mediated interactions stabilize protein secondary structures by mechanisms such as helix capping, protecting free {beta}-sheet edges by negative-design, and augmenting the stability of {beta}-turns. We find that Ch-bond can be as strong as H-bond. The study highlights the importance of S-mediated Ch-bond and H-bond for understanding protein folding and function, development of improved strategies for protein/peptide structure prediction and design, and structure-based drug discovery.

category: biochemistry


title: Human myelin proteolipid protein structure and lipid bilayer stacking

abstract: The myelin sheath is an essential, multilayered membrane structure that insulates axons, enabling the rapid transmission of nerve impulses. The tetraspan myelin proteolipid protein (PLP) is the most abundant protein of compact myelin in the central nervous system (CNS). The integral membrane protein PLP adheres myelin membranes together and enhances the compaction of myelin, having a fundamental role in myelin stability and axonal support. PLP is linked to severe CNS neuropathies, including inherited Pelizaeus-Merzbacher disease and spastic paraplegia type 2, as well as multiple sclerosis. Nevertheless, the structure, lipid interaction properties, and membrane organization mechanisms of PLP have remained unidentified. We expressed, purified, and structurally characterized human PLP and its shorter isoform DM20. Synchrotron radiation circular dichroism spectroscopy and small-angle X-ray and neutron scattering revealed a dimeric, -helical conformation for both PLP and DM20 in detergent complexes, and pinpoint structural variations between the isoforms and their influence on protein function. In phosphatidylcholine membranes, reconstituted PLP and DM20 spontaneously induced formation of multilamellar myelin-like membrane assemblies. Cholesterol and sphingomyelin enhanced the membrane organization but were not crucial for membrane stacking. Electron cryomicroscopy, atomic force microscopy, and X-ray diffraction experiments for membrane-embedded PLP/DM20 illustrated effective membrane stacking and ordered organization of membrane assemblies with a repeat distance in line with CNS myelin. Our results shed light on the 3D structure of myelin PLP and DM20, their structure-function differences, as well as fundamental protein-lipid interplay in CNS compact myelin.


title: Tetrasulfide Bridge (TTSB) Formation: an Extraordinary Intermediate Structure in the Architecture and Dynamics of the HIV-1s gp120 molecule

abstract: Gp120, one of the molecules that execute HIV viral entry in CD4+ cells has a number of allosteric disulfide bridges. In this study we explore the dynamics of these potential disulfide (disulphide) bridges in the 3-D configuration (based on crystallography) and UNSW DBA analyses of various gp120 crystals. The data reveal the existence of a tetrasulfide (tetrasulphide) bridge (TTSB) which, together with a disulfide bridge, keeps two perpendicular beta sheets (namely V3 and V4) approximated in the architecture of the gp120 while allowing safe transfer of energy between the allosteric bonds. Analyses of multiple gp120 crystals reveal the existence of the TTSB to be more as an intermediate as opposed to a constant landmark, which implies more complex functions than just structural attributes. This TTSB, which is observed in various crystals of gp120, in various strains and clades of HIV-1, is demonstrated by various rendering software and some are also detected, reported and characterized by the UNSW Disulfide Bond Analysis (DBA) engine. This tetrasulfide bridge connects the allosteric bond Cys296-Cys331 to Cys385-Cys418, sometimes as CYS331:SG - CYS385:SG, and sometimes as CYS331:SG - CYS418:SG. Moreover in crystals 3TIH, 4LSR and 4R4N, we also observed an intermediate state of the TTSB where it presents a triangular formation in which the sulfur atom CYS331:SG binds to both CYS385:SG and CYS418:SG simultaneously, which represents an important intermediate in the functional dynamics of the gp120 molecule. The presence of this extraordinary structure (TTSB) does point to some intriguing insights in the multifunctional design and mechanics as well as some complex fragilities of the gp120 molecule, exposing a new target for antiviral therapy.


title: A low-power communication scheme for wireless, 1000 channel brain-machine interfaces

abstract:
ObjectiveBrain-machine interfaces (BMIs) have the potential to restore motor function but are currently limited by electrode count and long-term recording stability. These challenges may be solved through the use of free-floating "motes" which wirelessly transmit recorded neural signals, if power consumption can be kept within safe levels when scaling to thousands of motes. Here, we evaluated a pulse-interval modulation (PIM) communication scheme for infrared (IR)-based motes that aims to reduce the wireless data rate and system power consumption.

ApproachTo test PIMs ability to efficiently communicate neural information, we simulated the communication scheme in a real-time closed-loop BMI with non-human primates. Additionally, we performed circuit simulations of an IR-based 1000-mote system to calculate communication accuracy and total power consumption.

Main ResultsWe found that PIM at 1kb/s per channel maintained strong correlations with true firing rate and matched online BMI performance of a traditional wired system. Closed-loop BMI tests suggest that lags as small as 30 ms can have significant performance effects. Finally, unlike other IR communication schemes, PIM is feasible in terms of power, and neural data can accurately be recovered on a receiver using 3mW for 1000 channels.

SignificanceThese results suggest that PIM-based communication could significantly reduce power usage of wireless motes to enable higher channel-counts for high-performance BMIs.


title: OncoPubMiner: A platform for oncology publication mining

abstract:
Knowledge bases that are up-to-date and of expert quality are fundamental in biomedical research fields. A knowledge base established with human participation and subjected to multiple inspections is crucial for supporting clinical decision-making, especially in the exponentially growing field of precision oncology. The number of original publications in the field has skyrocketed with the advancement of technology and in-depth research evolved. It has become an increasingly pressing issue that researchers need to consider how to gather and mine these articles accurately and efficiently. In this paper, we present OncoPubMiner (https://oncopubminer.chosenmedinfo.com), a free and powerful system that combines text mining, data structure customization, publication search with online reading, project-centered and team-based data collection to realize a one-stop "keyword in, knowledge out" oncology publication mining platform. It was built by integrating all the open-access abstracts from PubMed and full-text articles from PubMed Central, and is updated on a daily basis. The system makes it straightforward to obtain precision oncology knowledge from scientific articles. OncoPubMiner will assist researchers in developing professional structured knowledge base systems efficiently, and bringing the oncology community closer to achieving precision oncology goals.

Graphical Abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/483968v1_ufig1.gif" ALT="Figure 1">
View larger version (64K):
org.highwire.dtl.DTLVardef@68235aorg.highwire.dtl.DTLVardef@e9256aorg.highwire.dtl.DTLVardef@9783daorg.highwire.dtl.DTLVardef@15193e2_HPS_FORMAT_FIGEXP  M_FIG OncoPubMiners one-stop "keyword in, knowledge out" workflow (A) is built on key features such as text mining (B), publication search (C), form customization (D), and team-based curation (E).

C_FIG


title: Testing microbiome associations with censored survival outcomes at both the community and individual taxon levels

abstract:
BackgroundFinding microbiome associations with possibly censored survival times is an important problem, especially as specific taxa could serve as biomarkers for disease prognosis or as targets for therapeutic interventions. The two existing methods for survival outcomes, MiRKAT-S and OMiSA, are restricted to testing associations at the community level and do not provide results at the individual taxon level. An ad hoc approach testing each taxon with a survival outcome using the Cox proportional hazard model may not perform well in the microbiome setting with sparse count data and small sample sizes.

MethodsWe have previously developed the linear decomposition model (LDM) that unifies community-level and taxon-level tests into one framework. Here we extend the LDM to test survival outcomes. We propose to use the Martingale residuals or the deviance residuals obtained from the Cox model as continuous covariates in the LDM. We further construct tests that combine the results of analyzing each set of residuals separately. Finally, we extend PERMANOVA, the most commonly used distance-based method for testing community-level hypotheses, to handle survival outcomes in a similar manner.

ResultsUsing simulated data, we showed that the LDM-based tests preserved the false discovery rate for testing individual taxa and had good sensitivity. The LDM-based community-level tests and PERMANOVA-based tests had comparable or better power than MiRKAT-S and OMiSA. An analysis of data on the association of the gut microbiome and the time to acute graft-versus-host disease revealed several dozen associated taxa that would not have been achievable by any community-level test, as well as improved community-level tests by the LDM and PERMANOVA over those obtained using MiRKAT-S and OMiSA.

Availability and ImplementationThe new methods described here have been added to our R package LDM, which is available on GitHub at https://github.com/yijuanhu/LDM.


title: AttnPacker: An end-to-end deep learning method for rotamer-free protein side-chain packing

abstract: Protein side-chain packing (PSCP), the task of determining amino acid side-chain conformations, has important applications to protein structure prediction, refinement, and design. Many methods have been proposed to resolve this problem, but their accuracy is still unsatisfactory. To address this, we present AttnPacker, an end-to-end, SE(3)-equivariant deep graph transformer architecture for the direct prediction of side-chain coordinates. Unlike existing methods, AttnPacker directly incorporates backbone geometry to simultaneously compute all amino acid side-chain atom coordinates without delegating to a rotamer library, or performing expensive conformational search or sampling steps. Tested on the CASP13 and CASP14 native and non-native protein backbones, AttnPacker predicts side-chain conformations with RMSD significantly lower than the best side-chain packing methods (SCWRL4, FASPR, Rosetta Packer, and DLPacker), and achieves even greater improvements on surface residues. In addition to RMSD, our method also achieves top performance in side-chain dihedral prediction across both data sets.


title: A method to predict 3D structural ensembles of chromatins from pairwise distances: Applications to Interphase Chromosomes and Structural Variants

abstract: The principles that govern the organization of genomes, which are needed for a deeper understanding of how chromosomes are packaged and function in eukaryotic cells, could be deciphered if the three dimensional (3D) structures are known. Recently, single-cell imaging experiments have determined the 3D coordinates of a number of loci in a chromosome. Here, we introduce a computational method (Distance Matrix to Ensemble of Structures, DIMES), based on the maximum entropy principle, with experimental pair-wise distances between loci as constraints, to generate a unique ensemble of 3D chromatin structures. Using the ensemble of structures, we quantitatively account for the distribution of pair-wise distances, three-body co-localization and higher-order interactions. We demonstrate that the DIMES method can be applied to both small length-scale and chromosome-scale imaging data to quantify the extent of heterogeneity and fluctuations in the shapes on various length scales. We develop a perturbation method that is used in conjunction with DIMES to predict the changes in 3D structures from structural variations. Our method also reveals quantitative differences between the 3D structures inferred from Hi-C and the ones measured in imaging experiments. Finally, the physical interpretation of the parameters extracted from DIMES provides insights into the origin of phase separation between euchromatin and heterochromatin domains.


title: DeepSCM: an efficient convolutional neural network surrogate model for the screening of therapeutic antibody viscosity

abstract: Predicting high concentration antibody viscosity is essential for developing subcutaneous administration. Computer simulations provide promising tools to reach this aim. One such model is the spatial charge map (SCM) proposed by Agrawal and coworkers (mAbs. 2015, 8(1):43-48). SCM applies molecular dynamics simulations to calculate a score for the screening of antibody viscosity at high concentrations. However, molecular dynamics simulations are computationally costly and require structural information, a significant application bottleneck. In this work, high throughput computing was performed to calculate the SCM scores for 6596 nonredundant antibody variable regions. A convolutional neural network surrogate model, DeepSCM, requiring only sequence information, was then developed based on this dataset. The linear correlation coefficient of the DeepSCM and SCM scores achieved 0.9 on the test set (N=1320). The DeepSCM model was applied to screen the viscosity of 38 therapeutic antibodies that SCM correctly classified and resulted in only one misclassification. The DeepSCM model will facilitate high concentration antibody viscosity screening. The code and parameters are freely available at https://github.com/Lailabcode/DeepSCM.


title: Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability

abstract: Tumour suppressor p53 (TP53) is the most frequently mutated gene in cancer. Several hotspot p53 mutants not only lose tumour suppressive capabilities, but also function in a dominant-negative manner, suppressing canonical wild-type p53 function. Furthermore, some hotspot p53 mutants promote oncogenesis by gain-of-function mechanisms. Levels of p53 are regulated predominantly through regulation of protein stability and while wild-type p53 is normally kept at very low levels at steady-state, p53 mutants are often stabilized in tumours, which may be vital for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. We found that most proteins that regulate wild-type p53 also regulate a subset of p53 mutants with the exception of p53 R337H regulators, which are largely private to this mutant. Mechanistically, we identified FBXO42 as novel positive regulator of a subset of mutant p53 comprising R273H, R248Q and R248W. We show that, FBXO42 acts together with CCDC6 to regulate USP28-mediated p53 stabilization. Our work also identifies C16orf72 as negative regulator of wild-type p53 stability as well as stability of all p53 mutants tested. C16orf72 is amplified in breast cancer, and we show that C16orf72 regulates p53 levels in mammary epithelium of mice and its overexpression can drive breast cancer formation. Together, this work provides a network view of the process that regulates p53 stability, which might provide clues for targeting of wild-type or mutant p53 in cancer.


title: Human endogenous retrovirus activation contributes to biliary atresia pathogenesis through re-education of resident macrophages

abstract: Biliary atresia (BA) is a life-threatening neonatal fibro-inflammatory disease characterized by hepatic fibrosis, cirrhosis, and end-stage liver failure. BA is also the most frequent indication of pediatric liver transplantation globally. Despite the devastating condition of BA, the pathogenesis mechanism is unknown. Viral infection has been suggested to be associated with BA, but definitive evidence to support this hypothesis is not available. To elucidate the virus-associated pathogenesis mechanism of BA and to understand the immune ecosystem, we performed single-cell transcriptomic and proteomic profiling of BA livers. We detected human endogenous virus (HERV) in infants with BA and their parents. HERV was mainly found in FOLR2+ resident macrophages, T cells, and NK cells. In addition, HERV activation re-educated the fetal-derived FOLR2+ resident macrophages, and reactive oxygen species scavenging neutrophil recruitment was impaired in patients with BA and HERV+, due to FOLR2+ resident macrophage re-education. Furthermore, we showed depletion of FOLR2+ resident macrophage and N-acetylcysteine treatment could rescue the liver damage in BA. Overall, our study revealed the HERV-associated immunopathology mechanism of BA. These results contribute to potential diagnosis and immunotherapy strategies for BA.

category: pathology


title: A Nematode-Selective Potentiator of Organophosphate and Carbamate Agrochemicals

abstract:
Nematode parasites of humans, livestock and crops pose a significant burden on human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we present a pipeline that exploits multiple motor outputs of the model nematode C. elegans for nematicide discovery. This pipeline yielded a compound, which we call Nementin, that selectively immobilizes diverse nematode parasites. We find that Nementin induces convulsions by agonizing neuronal dense core vesicle release, which in turn agonizes cholinergic signaling. Consequently, Nementin synergistically enhances the potency of acetylcholinesterase inhibitors that are restricted agrochemicals. Nementin therefore represents a novel candidate nematicide that may improve the selectivity of broad-acting pesticides.

One-Sentence SummaryA C. elegans-based screening pipeline identifies a selective nematicide that potentiates acetylcholinesterase inhibitors.


title: Comparing flickering and pulsed chromatic pupil light responses

abstract: Protocols for chromatic pupil light reflex (PLR) testing considered mostly pulsed stimulation (pPLR). A more sophisticated and promising technique is based on the PLR to flickering stimulation (fPLR). Our aim was to compare fPLR and pPLR parameters in order to validate fPLR paradigm. Two different experiments were carried out in young participants to compare parameters of chromatic pupillary measurements under flickering and pulsed conditions. We found that the fPLR amplitude parameter was significantly associated with pPLR transient constriction parameter. Also, for some conditions, typical pulse parameters can be identified directly in the fPLR recordings.

category: physiology


title: Physiological trait networks enhance understanding of crop growth and water use in contrasting environments

abstract:
Plant function arises from a complex network of structural and physiological traits. Explicit representation of these traits, as well as their connections with other biophysical processes, is required to advance our understanding of plant-soil-climate interactions. We used the Terrestrial Regional Ecosystem Exchange Simulator (TREES) to evaluate physiological trait networks in maize. Net primary productivity (NPP) and grain yield were simulated across five contrasting climate scenarios. Simulations achieving high NPP and grain yield in high precipitation environments featured trait networks conferring high water use strategies: deep roots, high stomatal conductance at low water potential ("risky" stomatal regulation), high xylem hydraulic conductivity, and high maximal leaf area index. In contrast, high NPP and grain yield was achieved in dry environments with low late-season precipitation via water conserving trait networks: deep roots, high embolism resistance, and low stomatal conductance at low leaf water potential ("conservative" stomatal regulation). We suggest that our approach, which allows for the simultaneous evaluation of physiological traits and their interactions (i.e., networks), has potential to improve crop growth predictions in different environments. In contrast, evaluating single traits in isolation of other coordinated traits does not appear to be an effective strategy for predicting plant performance.

Summary statementOur process-based model uncovered two beneficial but contrasting trait networks for maize which can be understood by their integrated effect on water use/conservation. Modification of multiple, physiologically aligned, traits were required to bring about meaningful improvements in NPP and yield.


title: A comprehensive mechanistic model of adipocyte signaling with layers of confidence

abstract: Adipocyte cellular signaling, normally and in type 2 diabetes, is far from fully studied. We have earlier developed detailed dynamic mathematical models for some well-studied, and partially overlapping, signaling pathways in adipocytes. Still, these models only cover a fraction of the total cellular response. For a broader coverage of the response, large-scale phosphoproteomic data is key. There exists such data for the insulin response of adipocytes, as well as prior knowledge on possible protein-protein interactions associated with a confidence level. However, methods to combine detailed dynamic models with large-scale data, using information about the confidence of included interactions, are lacking. In our new method, we first establish a core model by connecting our partially overlapping models of adipocyte cellular signaling with focus on: 1) lipolysis and fatty acid release, 2) glucose uptake, and 3) the release of adiponectin. We use the phosphoproteome data and prior knowledge to identify phosphosites adjacent to the core model, and then try to add the adjacent phosphosites to the model. The additions of the adjacent phosphosites is tested in a parallel, pairwise approach with low computation time. We then iteratively collect the accepted additions into a layer, and use the newly added layer to find new adjacent phosphosites. We find that the first 15 layers (60 added phosphosites) with the highest confidence can correctly predict independent inhibitor-data (70-90 % correct), and that this ability decrease when we add layers of decreasing confidence. In total, 60 layers (3926 phosphosites) can be added to the model and still keep predictive ability. Finally, we use the comprehensive adipocyte model to simulate systems-wide alterations in adipocytes in type 2 diabetes. This new method provide a tool to create large models that keeps track of varying confidence.


title: A Spatiotemporal Reconstruction of the C. elegans Pharyngeal Cuticle Reveals a Structure Rich in Phase-Separating Proteins

abstract: Roughly 4.5 million species of ecdysozoan animals repeatedly shed their old cuticle and construct a new one underneath to accommodate growth. How cuticles are constructed is not well understood. Here, we systematically mine gene expression datasets to uncover the spatiotemporal blueprint for how the chitin-based pharyngeal cuticle of the nematode Caenorhabditis elegans is built. We demonstrate that the blueprint correctly predicts expression patterns and functional relevance to cuticle development. We find that as larvae prepare to molt, catabolic enzymes are upregulated and the genes that encode chitin synthase, chitin cross-linkers, and homologs of amyloid regulators subsequently peak in expression. 48% of the gene products secreted during the molt are predicted to be intrinsically disordered proteins (IDPs), many of which belong to four distinct families that are expressed in overlapping waves. These include the IDPAs, IDPBs, and IDPCs that are introduced for the first time here. We find that all four families have sequence properties known to drive phase separation and show in vitro phase separation for one of these proteins. This systematic analysis reveals the massive contribution that IDPs make to the cuticle and highlights how reversibly phase-separating materials may facilitate cuticle disassembly and reassembly during the molt.


title: Comparative analysis of total alpha-synuclein (αSYN) immunoassays reveals that they do not capture the diversity of modified αSYN proteoforms

abstract:
BackgroundThe development of therapeutics for Parkinsons disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the -synuclein (SYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results.

ObjectiveTo determine whether the three commercial kits that have been extensively used for total SYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant SYN proteoforms.

MethodsWe investigated and compared the ability of the different assays to detect the diversity of SYN proteoform using a library of SYN proteins that compromise the majority of disease-relevant SYN variants and post-translational modification.

ResultsOur findings showed that none of the three tested immunoassays accurately capture the totality of relevant SYN species and are unable to recognize most disease-associated C-terminally truncated variants of SYN. Moreover, several N-terminal truncations and phosphorylation/nitration differentially modify the level of SYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the SYN proteoforms analyzed by the three immunoassays.

ConclusionsOur results showed that these immunoassays do not capture the totality of the relevant SYN species and therefore may not be appropriate tools to provide an accurate measure of total SYN levels in samples containing modified forms of the protein. This highlights the need for next-generation SYN immunoassays that capture the diversity of SYN proteoforms.


title: Chemogenetic enhancement of cAMP signaling renders hippocampal synaptic plasticity resilient to the impact of acute sleep deprivation

abstract:
Sleep facilitates memory storage and even brief periods of sleep loss lead to impairments in memory, particularly memories that are hippocampus dependent. In previous studies, we have shown that the deficit in memory seen after sleep loss is accompanied by deficits in synaptic plasticity. Our previous work has also found that sleep deprivation is associated with reduced levels of cyclic adenosine monophosphate (cAMP) in the hippocampus, and that the reduction of cAMP mediates the diminished memory performance. Based on these findings, we hypothesized that cAMP acts as a mediator for not only the cognitive deficits caused by sleep deprivation, but also the observed deficits in synaptic plasticity. In this study, we expressed the heterologous Drosophila melanogaster Gs-protein coupled octopamine receptor (DmOct{beta}1R) in mouse hippocampal neurons. This receptor is selectively activated by the systemically injected ligand (octopamine), thus allowing us to increase cAMP levels in hippocampal neurons during a five-hour sleep deprivation period. Our results show that chemogenetic enhancement of cAMP during the period of sleep deprivation prevents deficits in a persistent form of long-term potentiation (LTP) that is induced at the Schaffer collateral synapses in the hippocampal CA1 region. We also found that elevating cAMP levels only in the early or later half of sleep deprivation successfully prevented LTP deficits. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation at the synaptic level. Targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss.

Significance statementInsufficient sleep is an issue with significant health and socioeconomic implications. This includes a negative impact on memory consolidation. Previous studies in mice found that acute sleep deprivation leads to deficits in hippocampal synaptic plasticity and memory, which are associated with reduced levels of the signaling molecule cAMP. In this study, we used a chemogenetic strategy to enhance cAMP levels in specific hippocampal neurons during sleep deprivation. We found that this made synaptic plasticity resilient to the negative effects of sleep deprivation. These findings reveal that cAMP-dependent signaling pathways are key mediators of sleep deprivation and that targeting these pathways could be useful in designing strategies to prevent the impact of sleep loss.


title: Neurons in inferior temporal cortex are sensitive to motion trajectory during degraded object recognition

abstract: Our brains continuously acquire sensory information and make judgments even when visual information is limited. In some circumstances, an ambiguous object can be recognized from how it moves, such as an animal hopping or a plane flying overhead. Yet it remains unclear how movement is processed by brain areas involved in visual object recognition. Here we investigate whether inferior temporal cortex, an area traditionally known for shape processing, has access to motion information during degraded shape recognition. We developed a matching task that required monkeys to recognize moving shapes with variable levels of shape degradation. Neural recordings in area IT showed that, surprisingly, some IT neurons preferred blurry shapes over clear ones. Further, many of the neurons exhibited motion sensitivity at different times during the presentation of the blurry target. Population decoding analyses showed that motion pattern could be decoded from IT neuron pseudo-populations. Contrary to previous findings, these results suggest that neurons in IT can integrate visual motion and shape information, particularly when shape information is degraded, in a way that has been previously overlooked. Our results highlight the importance of using challenging multi-feature recognition tasks to understand the role of area IT in naturalistic visual object recognition. (Word count: 199)


title: Dimensionality reduction of calcium-imaged neuronal population activity

abstract: Calcium imaging has been widely adopted for its ability to record from large neuronal populations. To summarize the time course of neural activity, dimensionality reduction methods, which have been applied extensively to population spiking activity, may be particularly useful. However, it is unclear if the dimensionality reduction methods applied to spiking activity are appropriate for calcium imaging. We thus carried out a systematic study of design choices based on standard dimensionality reduction methods. We also developed a novel method to perform deconvolution and dimensionality reduction simultaneously (termed CILDS). CILDS most accurately recovered the single-trial, low-dimensional time courses from calcium imaging that would have been recovered from spiking activity. CILDS also outperformed the other methods on calcium imaging recordings from larval zebrafish and mice. More broadly, this study represents a foundation for summarizing calcium imaging recordings of large neuronal populations using dimensionality reduction in diverse experimental settings.


title: Implicit sensorimotor adaptation is preserved in Parkinson's Disease

abstract:
Our ability to enact successful goal-directed actions involves multiple learning processes. Among these processes, implicit motor adaptation ensures that the sensorimotor system remains finely tuned in response to changes in the body and environment. Whether Parkinsons Disease (PD) impacts implicit motor adaptation remains a contentious area of research: whereas multiple reports show impaired performance in this population, many others show intact performance. While there are a range of methodological differences across studies, one critical issue is that performance in many of the studies may reflect a combination of implicit adaptation and strategic re-aiming. Here, we revisited this controversy using a visuomotor task designed to isolate implicit adaptation. In two experiments, we found that adaptation in response to a wide range of visual perturbations (3{degrees} - 45{degrees}) was similar in PD and matched control participants. Moreover, in a meta-analysis of previously published work, we found that the mean effect size contrasting PD and controls across 16 experiments was not significant. Together, these analyses indicate that implicit adaptation is preserved in PD, offering a fresh perspective on the role of the basal ganglia in sensorimotor learning.

Significance statementAmong multiple motor learning processes, implicit adaptation ensures that our motor system remains exquisitely calibrated. Whether Parkinsons disease affects implicit motor adaptation has been a point of controversy. We revisited this issue using a visuomotor task designed to isolate implicit adaptation and found that individuals with PD and matched controls showed indistinguishable performance. A meta-analysis based on data from 16 previous experiments yielded a similar null result, strongly supporting the notion that implicit adaptation is preserved in PD.


title: Circuit analysis of the Drosophila brain using connectivity-based neuronal classification reveals organization of key information processing pathways

abstract:
We present a functionally relevant, quantitative characterization of the neural circuitry of Drosophila melanogaster at the mesoscopic level of neuron types as classified exclusively based on network connectivity. Starting from a large neuron-to-neuron brain-wide connectome of the fruit fly, we use stochastic block modeling and spectral graph clustering to group neurons together into a common "cell class" if they connect to neurons of other classes according to the same probability distributions. Thus, nodes of the identified circuit represent cell classes, while the directed edges represent the connection probabilities between neurons in those respective classes. We then characterize the connectivity-based cell classes with standard neuronal biomarkers, including neurotransmitters, developmental birthtimes, morphological features, spatial embedding, and functional anatomy. Mutual information indicates that connectivity-based classification reveals aspects of neurons that are not adequately captured by traditional classification schemes. Next, using graph-theoretic and random walk analyses to identify neuron classes as hubs, sources, or destinations, we detect patterns of directional connectivity and information flow that potentially underpin specific functional interactions in the Drosophila brain. We uncover a core of highly interconnected dopaminergic cell classes functioning as the backbone information highway for multisensory integration. We also recognize glutamatergic-dominant connections between the motor and optic regions, possibly facilitating circadian rhythmic activity. Additional predicted pathways pertain to spatial orientation, fight-or-flight response, and olfactory learning. Mapping the developmental birthtimes of neurons also pinpoints the temporal change of the circuit blueprint over the fly lifespan, revealing distinct critical growth periods of individual pathways. Our analysis provides experimentally testable hypotheses critically deconstructing complex brain function from organized connectomic architecture.

Significance StatementThe potential synaptic circuitry of a neural system constitutes the fundamental architectural underpinning of its in vivo dynamics, plasticity, and functions. The fruit fly neural circuit presented here captures the latent stochastic patterns of network connectivity and provides a fundamental parts list for reverse-engineering brain computation. Mapping the interactions among connectivity-based neuronal classes to development, morphology, physiology, and transcriptomics links connectomic structure with dynamic functional integration in the brain. These mappings result in testable hypotheses on the relationship between neural architecture and behavior.