Biology subjects

Kuhn, J.

Publications and source records attributed to Kuhn, J..

At least 19 recordsLinked to original sources

bioRxiv2026

The Human Bindome: A Proteome-scale Atlas of Designed Binder Candidates

Affinity reagents such as antibodies are indispensable for interrogating proteins biological function. Yet they are costly and frequently unreliable, with unknown sequences, posing challenges to reproducible experimental research. Deep learning-based protein design can now in silico generate affinity reagents achieving reliable experimental success rates, but has remained largely confined to specialist laboratories. Here we present the Human Bindome, a proteome-scale atlas of high-confidence in silico protein binder candidates. By embedding the experimentally benchmarked BindCraft method in an accelerated, parallelized framework with automated domain-level target selection, we generated 306,146 binder candidates covering 8,296 human proteins (40.9% of the full proteome). Every candidate carries a defined sequence, a predicted binder-target structure model, and in silico confidence metrics. We characterize proteome-wide coverage and show that binder epitopes frequently overlap functional sites. This positions the Bindome as a resource of genetically encodable perturbagens for site-specific, modular control of protein function. The Bindome is freely available through a web interface (https://bindome.epfl.ch), with agentic, natural-language querying and as data splits for machine-learning model development. We anticipate that the Bindome will be valuable for the scientific community by providing affinity and perturbation reagents with broad applications in dissecting biological mechanisms as well as in drug and target discovery.

synthetic biology↗

bioRxiv2026

Delivery of defective interfering RNA antivirals to the lungs using hyperbranched poly(beta-amino ester) nanoparticles

Hyperbranched poly(beta-amino ester) (hPBAE) nanoparticles represent a promising platform for nucleic acid delivery, particularly to the lungs. In this study, we evaluate the potential of hPBAE nanoparticles to deliver defective interfering RNA (diRNA) antivirals targeting betacoronaviruses under a range of formulations and storage conditions. hPBAE-diRNA nanoparticles demonstrated efficient cellular uptake of functional diRNA across diverse cell types, conferred protection against nuclease-mediated degradation, and exhibited low in vitro cytotoxicity. In vivo, these nanoparticles enabled effective delivery of functional diRNA to the lungs of golden hamsters without inducing adverse physiological effects. Collectively, these findings support hPBAE nanoparticles as a safe and effective platform for diRNA delivery for the treatment of respiratory viral infections. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=66 SRC="FIGDIR/small/721911v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@2fc386org.highwire.dtl.DTLVardef@1cda4f9org.highwire.dtl.DTLVardef@9f61borg.highwire.dtl.DTLVardef@1fc8461_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO Defective interfering RNA was mixed with hyperbranched poly(beta-amino ester) nanoparticles and delivered to cells in vitro and to golden hamsters in vivo, to measure toxicity and the replication potential of the RNA. C_FIG

microbiology↗

bioRxiv2026

A 667-nucleotide sequence in the SARS-CoV-2 nsp15 coding region promotes genome encapsidation

Coronavirus genome encapsidation depends on cis-acting RNA elements that interact with viral structural proteins. While such packaging signals have been characterized in several coronaviruses, their definition in SARS-CoV-2 remains incomplete. Using synthetic defective SARS-CoV-2 genomes, we identify a 667-nucleotide region within the nsp15 coding sequence that preferentially binds SARS-CoV-2 nucleoprotein and enhances the accumulation of defective viral genomes both in vitro and in vivo. Sequential and targeted deletion analyses further delineate candidate RNA secondary structures within this region that contribute to this enrichment. These structures show similarity to elements within the putative packaging signal of SARS-CoV but are not conserved across other coronaviruses. Together, these findings support the presence of a structured RNA element within nsp15 that contributes to SARS-CoV-2 genome encapsidation and provide a framework for further structural and functional dissection of coronavirus packaging signals. IMPORTANCEThis study identifies a 667-nt region within the SARS-CoV-2 nsp15 coding sequence that binds nucleoprotein and promotes accumulation of defective viral genomes, revealing a previously unrecognized contributor to genome encapsidation. Mapping of candidate RNA structures within this region links SARS-CoV-2 packaging activity to conserved structural features observed in SARS-CoV, while highlighting key differences from other coronaviruses. These findings refine understanding of cis-acting packaging signals in SARS-CoV-2 and provide a foundation for further structural and functional analysis of coronavirus genome encapsidation. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/721935v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1b64611org.highwire.dtl.DTLVardef@1b21b7borg.highwire.dtl.DTLVardef@2a68b5org.highwire.dtl.DTLVardef@405fe1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO A part of the nsp15 coding sequence of SARS-CoV-2 promotes efficient transmission of defective viral genomes in vitro and in vivo. Using a sequential deletion library and targeted deletions within this region we identify RNA structures that may function as packaging signals. C_FIG

microbiology↗

bioRxiv2026

Regulation of trehalose biosynthesis and thermotolerance by the Cryptococcus neoformans HECT E3 ubiquitin ligase Rsp5

Microorganisms including fungi adapt to profound changes in their local environment during human infections. After exposure to high temperature and other stress conditions, the opportunistic fungal pathogen Cryptococcus neoformans enacts changes in metabolism, cell wall structure, and transmembrane transport that allow it to survive and proliferate in a mammalian host. This stress response program is regulated by the HECT E3-ubiquitin ligase Rsp5 which is required for growth at high salinity, pH and temperature. However, the complete set of Rsp5 substrates that direct these molecular changes remains incompletely understood. Here we demonstrate that C. neoformans Rsp5 confers increased tolerance to temperature and salt stress in part through regulation of the trehalose biosynthesis pathway. Two enzymes in the trehalose biosynthesis pathway, Tps1 and Tps2, are differentially ubiquitinated by Rsp5 after exposure to stress conditions. We directly measured trehalose production after exposure to high temperature and found that a C. neoformans strain lacking Rsp5 is unable to induce trehalose production. Quantitative proteomic analysis of the C. neoformans response to high salinity identified Rsp5-dependent and independent adaptations to osmotic stress, and that Rsp5-dependent ubiquitination does not alter the abundance of Tps1 or Tps2. These results demonstrate that regulation of trehalose biosynthesis is one of the cellular mechanisms by which Rsp5-dependent ubiquitination in C. neoformans facilitates survival in response to stressors encountered in the human infection environment. ImportanceCryptococcus neoformans is an opportunistic fungal pathogen that kills over 180,000 people every year with few effective treatment options. As a yeast that normally lives in the environment, C. neoformans has to survive large changes in its physical environment, including elevated body temperature, when it causes human infections. Here we show how C. neoformans uses a protein modification to regulate production of a fungal-specific metabolic pathway important for survival at human body temperature. Unraveling how environmental fungi tolerate and survive temperature and other stressors will help to understand how they cause disease and identify new and better ways to treat these deadly infections.

microbiology↗

bioRxiv2025

Spatial distribution of cytoskeleton-mediated feedback controls cell polarization: a computational study

In the social amoeba Dictyostelium, cell motility is regulated through a signal transduction excitable network that interfaces with the cytoskeleton to control actin polymerization patterns. In turn, the cytoskeleton influences the signaling machinery via several feedback loops, but the nature and function of this feedback remain poorly understood. In this study, we use computational models to discern the essential role of complementary positive and negative feedback loops in polarizing cells. We contrast two potential mechanisms for the negative feedback: local inhibition and global inhibition. Our results indicate that both mechanisms can stabilize the leading edge and inhibit actin polymerization in other sites, preventing multipolarity. While some experimental perturbations align more closely with the local inhibition model, statistical analyses reveal its limited polarization potential within a wide excitability range. Conversely, global inhibition more effectively suppresses secondary and tertiary leading-edge formation, making it a more robust polarization mechanism. This raises an intriguing question: if local inhibition better replicates experimental observations but is less effective for polarization than local excitation and global inhibition, could there be a supplementary mechanism enhancing its polarization potential? To address this, we propose a novel mechanism involving the dynamic partitioning of back molecules which enhances communication between the front and back of the cell and can be leveraged by local feedback interactions between the cytoskeleton and signal transduction to improve polarization efficiency.

cell biology↗

bioRxiv2024

The Alzheimers Disease Risk Genes MS4A4A And MS4A6A Cooperate to Negatively Regulate Trem2 and Microglia states

Genetic variations in MS4A4A and MS4A6A are linked to the regulation of cerebrospinal fluid soluble TREM2 (sTREM2) levels and are associated with Alzheimers disease (AD) risk and progression. Using CRISPR knockout and MS4A4A-degrading antibodies in primary human microglia, non-human primates (NHP), and a xenotransplantation model of amyloid pathology, we provide evidence that MS4A4A and MS4A6A are negative regulators of both the transmembrane and soluble TREM2 proteins. They also negatively regulate microglia proliferation, survival, metabolism, lysosomal function, energetics, phagocytosis, and disease-fighting states. Mechanistically, we find that MS4A4A exerts negative regulation by interacting with MS4A6A and protecting it from degradation. MS4A6A in turn forms a complex with and blocks the co-receptor DAP12, which is required for the stability, cell surface localization, and signaling of TREM2 and other receptors. Taken together, the data indicate that MS4A4A and MS4A6A are cooperating, post-transcriptional negative regulators of TREM2 and microglial function, and potential drug targets for AD.

neuroscience↗

bioRxiv2024

Thalamo-frontal connectivity patterns in Tourette Syndrome: Insights from combined intracranial DBS and EEG recordings

Thalamic deep brain stimulation (DBS) has shown clinical improvement for patients with treatment-refractory Tourette Syndrome (TS). Advancing DBS for TS requires identifying reliable electrophysiological markers. Recognising TS as a network disorder, we investigated thalamo-cortical oscillatory connectivity by combining local field potential (LFP) recordings from the DBS thalamic target region using the PerceptTM PC neurostimulator with high-density EEG in eight male TS patients (aged 27 to 38) while stimulation was off. We identified a spatially and spectrally distinct oscillatory network connecting the medial thalamus and frontal regions in the alpha band (8-12 Hz), with connectivity strength negatively correlated with TS symptom severity. Moreover, reduced thalamo-frontal alpha connectivity before tic onset, localised in sensorimotor regions and the inferior parietal cortex, suggests its direct role in tic generation. Importantly, associations with symptoms and pre-tic dynamics were specific to connectivity patterns and not evident in the pure power spectra. These findings underscore the importance of investigating electrophysiological oscillatory connectivity to characterise pathological network connections in TS, potentially guiding stimulation-based interventions and future research on closed-loop DBS for TS.

neuroscience↗

bioRxiv2023

The cytoplasmic phosphate level has a central regulatory role in the phosphate starvation response of Caulobacter crescentus

In bacteria, the availability of environmental inorganic phosphate is typically sensed by the conserved PhoR-PhoB two-component signal transduction pathway, which is thought to use the flux through the PstSCAB phosphate transporter as a readout of the extracellular phosphate level to control phosphate-responsive genes. While the sensing of environmental phosphate is well-investigated, the regulatory effects of cytoplasmic phosphate are unclear. Here, we disentangle the physiological and transcriptional responses of Caulobacter crescentus to changes in the environmental and cytoplasmic phosphate levels by uncoupling phosphate uptake from the activity of the PstSCAB system, using an additional, heterologously produced phosphate transporter. This approach reveals a two-pronged response of C. crescentus to phosphate limitation, in which PhoR-PhoB signaling mostly facilitates the utilization of alternative phosphate sources, whereas the cytoplasmic phosphate level controls the morphological and physiological adaptation of cells to growth under global phosphate limitation. These findings open the door to a comprehensive understanding of phosphate signaling in bacteria.

microbiology↗

bioRxiv2023

FLN-2 functions in parallel to LINC complexes and Cdc42/actin pathways during P-cell nuclear migration through constricted spaces in Caenorhabditis elegans

Nuclear migration through narrow constrictions is important for development, metastasis, and pro-inflammatory responses. Studies performed in tissue culture cells have implicated LINC (linker of nucleoskeleton and cytoskeleton) complexes, microtubule motors, the actin cytoskeleton, and nuclear envelope repair machinery as important mediators of nuclear movements through constricted spaces. However, little is understood about how these mechanisms operate to move nuclei in vivo. In C. elegans larvae, 6 pairs of hypodermal P cells migrate from lateral to ventral positions through a constricted space between the body wall muscles and the cuticle. P-cell nuclear migration is mediated in part by LINC complexes using a microtubule-based pathway and by an independent CDC-42/actin-based pathway. However, when both LINC complex and actin-based pathways are knocked out, many nuclei still migrate, suggesting the existence of additional pathways. Here we show that FLN-2 functions in a third pathway to mediate P-cell nuclear migration. The predicted N-terminal actin binding domain in FLN-2 that is found in canonical filamins is dispensable for FLN-2 function, this and structural predictions suggest that FLN-2 is not a divergent filamin. The immunoglobulin (Ig)-like repeats 4-8 of FLN-2 were necessary for P-cell nuclear migration. Furthermore, in the absence of the LINC complex component unc-84, fln-2 mutants had an increase in P-cell nuclear rupture. We conclude that FLN-2 functions to maintain the integrity of the nuclear envelope in parallel with the LINC complex and CDC-42/actin-based pathways to move P-cell nuclei through constricted spaces.

genetics↗

bioRxiv2022

Genomic accordions may hold the key to Monkeypox Clade IIb's increased transmissibility

The currently expanding monkeypox epidemic is caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. In contrast to monkeypox cases caused by clade I and subclade IIa MPXV, the prognosis of current cases is generally favorable, but person-to-person transmission is much more efficient. MPXV evolution is driven by selective pressure from hosts and loss of virus-host interacting genes. However, there is no satisfactory genetic explanation using single-nucleotide polymorphisms (SNPs) for the observed increased MPXV transmissibility. We hypothesized that key genomic changes may occur in the genomes low-complexity regions (LCRs), which are highly challenging to sequence and have been dismissed as uninformative. Using a combination of highly sensitive techniques, we determined a first high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This effort revealed significant variation in short-tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of SNPs and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs) 153, 204, and 208 could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. Consequently, we posit that genomic studies focusing on phenotypic MPXV clade-/subclade-/lineage-/strain differences should change their focus to the study of LCR variability instead of SNP variability.

genomics↗

bioRxiv2021

A functional network target for tic reduction during thalamic stimulation for Tourette Syndrome

BackgroundDeep brain stimulation (DBS) of the medial thalamus is an evolving therapy for severe, treatment-refractory Tourette syndrome (TS). It remains unanswered which functionally connected networks need to be modulated to obtain optimal treatment results. MethodsWe assessed treatment response of 15 patients with TS untergoing thalamic DBS six and twelve months postoperatively using the Yale Global Tic Severity Scale (YGTSS) tic score. For each time point, functional connectivity maps seeding from stimulation sites were calculated based on a normative functional connectome derived from 1000 healthy subjects. Resulting maps were analyzed in a voxel-wise mixed model for repeated measurements to identify patterns of connectivity associated with tic reduction. ResultsConnectivity of stimulation to the medial frontal cortex, bilateral insulae and sensorimotor cortex was associated with tic reduction. Connectivity with the temporal lobe, cerebellum, ventral striatum and orbitofrontal cortex was negatively associated. The overall connectivity pattern was robust to leave-one-out cross-validation, explaining 25 % of outcome variance (R = 0.500; p = 0.005). ConclusionsWe delineated a functional connectivity profile seeding from stimulation sites associated with TS-DBS outcome. This pattern comprised areas linked to the processing of premonitory urges and tic execution, thereby extending our current understanding of effective neuromodulation for TS.

neuroscience↗

bioRxiv2020

Chronic deep brain stimulation of the human nucleus accumbens region disrupts the stability of inter-temporal preferences.

When choosing between rewards that differ in temporal proximity (inter-temporal choice), human preferences are typically stable, constituting a clinically-relevant transdiagnostic trait. Here we show in patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessivecompulsive disorder (OCD), that long-term chronic (but not phasic) DBS disrupts inter-temporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of inter-temporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not due to range restriction, the presence of OCD symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human nucleus accumbens region to inter-temporal preference stability over time. Significance StatementChoosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation (DBS) of the human anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessive compulsive disorder disrupts the stability of inter-temporal preferences. These findings show that chronic stimulation of one of the brains central motivational hubs can disrupt preferences thought to depend on this circuit.

neuroscience↗

bioRxiv2020

Dorsal horn CGRP-expressing interneurons contribute to nerve injury-induced mechanical hypersensitivity

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CGRPCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally-directed, dendrites and ventrally-directed axons. Neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive A{beta} primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. In contrast, chemogenetic activation produced a significant mechanical hypersensitivity. Importantly, the CGRP interneurons could be activated after peripheral nerve injury, but only with concurrent innocuous, brush stimulation. These findings suggest that hyperexcitability of dorsal horn CGRP interneurons is an important contributor to the circuits that render touch painful after peripheral nerve damage.

neuroscience↗

bioRxiv2020

Discovery of a novel simian pegivirus in common marmosets (Callithrix jacchus) with lymphocytic enteritis

From 2010 to 2015, 73 common marmosets (Callithrix jacchus) housed at the Wisconsin National Primate Research Center (WNPRC) were diagnosed postmortem with lymphocytic enterocolitis. We used unbiased deep-sequencing to screen the blood of deceased enterocolitis-positive marmosets for the presence of RNA viruses. In five out of eight marmosets with lymphocytic enterocolitis, we discovered a novel pegivirus that was not present in ten subsequently deep-sequenced matched, clinically-normal common marmosets with no evidence of lymphocytic enterocolitis. The novel virus, which we have named Southwest bike trail virus (SOBV), is most closely related (68% nucleotide identity) to a strain of simian pegivirus A that was previously isolated from a three-striped night monkey (Aotus trivirgatus). To determine the prevalence of this novel virus within the WNPRC marmoset colony, we screened 146 living animals and found an overall prevalence of 34% (50/146). Over the next four years, 85 of the 146 screened marmosets died or were euthanized and were examined histologically for lymphocytic enterocolitis. Out of these 85 animals, 27 SOBV-positive common marmosets had developed lymphocytic enterocolitis, compared to 42 SOBV-negative common marmosets, indicating no evidence of an association between this virus and development of enterocolitis in this cohort (p=0.0798). The novel pegivirus was also found in two of 32 (6%) clinically-normal common marmosets screened while in quarantine during the transfer from the New England Primate Research Center to the WNPRC, suggesting SOBV has different prevalence at different centers and could exert confounding influences on the comparison of marmoset studies from multiple centers. ImportanceCommon marmosets (Callithrix jacchus) are a valuable model species. We discovered two variants of a novel simian pegivirus, which we named the Southwest bike trail virus (SOBV), in common marmosets which had postmortem histologic diagnosis of lymphocytic enterocolitis. The virus was not present in ten matched, clinically-normal controls. We screened 146 live healthy common marmosets in the Wisconsin National Primate Research Center colony and found 34% (50/146) of the animals were SOBV-positive. SOBV was also present in two of 32 (6%) clinically-normal common marmosets from the New England Primate Research Center. These findings could have confounding effects in animal studies, especially those in which infection-free animals are desired, and they demonstrate the need for further investigations into SOBV transmission, the length of time of SOBV persistence, and SOBV prevalence at other primate centers, in order to increase understanding of the effects of SOBV and of this viral genus.

microbiology↗

bioRxiv2020

Molecular Detection of SARS-CoV-2 in Formalin Fixed Paraffin Embedded Specimens

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of human coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019. The virus rapidly spread globally, resulting in a public-health crisis including more than one million cases and tens of thousands of deaths. Here, we describe the identification and evaluation of commercially available reagents and assays for the molecular detection of SARS-CoV-2 in infected formalin fixed paraffin embedded (FFPE) cell pellets. We identified a suitable rabbit polyclonal anti-SARS-CoV spike protein antibody and a mouse monoclonal anti-SARS-CoV nucleocapsid protein (NP) antibody for cross detection of the respective SARS-CoV-2 proteins by immunohistochemistry (IHC) and immunofluorescence assay (IFA). Next, we established RNAscope in situ hybridization (ISH) to detect SARS-CoV-2 RNA. Furthermore, we established a multiplex fluorescence ISH (mFISH) to detect positive-sense SARS-CoV-2 RNA and negative-sense SARS-CoV-2 RNA (a replicative intermediate indicating viral replication). Finally, we developed a dual staining assay using IHC and ISH to detect SARS-CoV-2 antigen and RNA in the same FFPE section. These reagents and assays will accelerate COVID-19 pathogenesis studies in humans and in COVID-19 animal models.

microbiology↗

bioRxiv2020

Temporal discounting in adolescents and adults with Tourette syndrome

BackgroundTourette syndrome is a neurodevelopmental disorder with the clinical hallmarks of motor and phonic tics which are associated with hyperactivity in dopaminergic networks. Dopaminergic hyperactivity in the basal ganglia has previously been linked to increased sensitivity to positive reinforcement and increases in choice impulsivity. ObjectiveWe address whether this extends to changes in temporal discounting, where impulsivity is operationalized as an increased preference to choose smaller-but-sooner over larger-but-later rewards. Results are discussed with respect to neural models of temporal discounting, dopaminergic alterations in Tourette syndrome and the developmental trajectory of temporal discounting. MethodsIn the first study we included nineteen adolescent patients with Tourette syndrome and nineteen age- and education matched controls. In the second study, we compared twenty-five adult patients with Tourette syndrome and twenty-five age- and education-matched controls. ResultsIn the light of the dopaminergic hyperactivity model, we predicted differences in temporal discounting in patients with Tourette syndrome. However, computational modeling of choice behavior using hierarchical Bayesian parameter estimation revealed reduced impulsive choice in adolescent patients, and no group differences in adults. ConclusionWe speculate that adolescents might show reduced discounting due to improved inhibitory functions that also affect choice impulsivity and/or the developmental trajectory of executive control functions. The absence of an effect in adults might be due to differences in the clinical population (e.g. patients who acquired successful tic inhibition during adolescence might have gone into remission). Future studies would benefit from adopting longitudinal approaches to further elucidate the developmental trajectory of these effects.

neuroscience↗

bioRxiv2019

Toward a unified connectomic target for deep brain stimulation in obsessive-compulsive disorder

Multiple surgical targets have been proposed for treating obsessive-compulsive disorder (OCD) with deep brain stimulation (DBS). However, different targets may modulate the same neural network responsible for clinical improvement. Here we analyzed data from four cohorts of OCD patients (N = 50) that underwent DBS to the anterior limb of the internal capsule (ALIC), the nucleus accumbens (NAcc) or the subthalamic nucleus (STN). Fiber tracts that were predominantly connected to electrodes in good or poor DBS responders were isolated from a normative structural connectome and assigned a predictive value. Strikingly, the same fiber bundle was related to treatment response when independently analyzing two large training cohorts that targeted either ALIC or STN. This discriminative tract is a subsection of the ALIC and connects frontal regions (such as the dorsal anterior cingulate, dACC, and ventral prefrontal, vlPFC, cortices to the STN). When informing the tract solely based on one cohort (e.g. ALIC), clinical improvements in the other (e.g. STN) could be significantly predicted, and vice versa. Finally, clinical improvements of eight patients from a third center with electrodes in the NAcc and six patients from a fourth center in which electrodes had been implanted in both STN and ALIC were significantly predicted based on this novel tract-based DBS target. Results suggest a functional role of a limbic hyperdirect pathway that projects from dACC and vlPFC to anteriomedial STN. Obsessive-compulsive symptoms seem to be tractable by modulating the specific bundle isolated here. Our results show that connectivity-derived improvement models can inform clinical improvement across DBS targets, surgeons and centers. The identified tract is now three-dimensionally defined in stereotactic standard space and will be made openly available.

neuroscience↗

bioRxiv2019

Gene sharing networks to automate genome-based prokaryotic viral taxonomy

Viruses of bacteria and archaea are likely to be critical to all natural, engineered and human ecosystems, and yet their study is hampered by the lack of a universal or scalable taxonomic framework. Here, we introduce vConTACT 2.0, a network-based application to establish prokaryotic virus taxonomy that scales to thousands of uncultivated virus genomes, and integrates confidence scores for all taxonomic predictions. Performance tests using vConTACT 2.0 demonstrate near-identical correspondence to the current official viral taxonomy (>85% genus-rank assignments at 96% accuracy) through an integrated distance-based hierarchical clustering approach. Beyond "known viruses", we used vConTACT 2.0 to automatically assign 1,364 previously unclassified reference viruses to tentative taxa, and scaled it to modern metagenomic datasets for which the reference network was robust to adding 16,000 viral contigs. Together these efforts provide a systematic reference network and an accurate, scalable taxonomic analysis tool that is critically needed for the research community.

bioinformatics↗