Biology subjects

Weber, D.

Publications and source records attributed to Weber, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Context makes the difference: Temporally Resolved Dopaminergic Teaching Signals Shape Associative Memory in Drosophila Larvae

Animals can adapt their behavioral responses to environmental cues by learning from experience. This ability relies on the formation and recall of memories that are shaped by beneficial or detrimental consequences and regulated by the dopaminergic system, which is highly conserved across insect species. In the Drosophila melanogaster larva, eight of total [~]120 dopaminergic neurons (DANs) innervate the mushroom body (MB), a key center for associative memory. This subset of DANs can be anatomically grouped into two clusters of four cells: the primary protocerebral anterior medial (pPAM) cluster, associated with reward signaling, and the dorsolateral 1 (DL1) cluster, associated with punishment. Such a functional dichotomy is observed in larval and adult Drosophila and reflects a fundamental organizational principle of reinforcement learning across invertebrate and even vertebrate species. Aversive reinforcement through high-salt exposure is encoded within the DL1 cluster in a combinatorial and heterogeneous manner, critically involving two neurons, DAN-f1 and DAN-g1. Using temporally precise optogenetic activation and inhibition during olfactory conditioning, we show that these neurons can modulate memory strength and valence. Their effects are most often consistent and predictable, enabling accurate computational modeling of DAN-driven teaching signals. By manipulating the intrinsic physiology of DAN-f1 and DAN-g1 and altering the valence of gustatory input, we are beginning to understand at the single-cell level how dopaminergic activity is systematically adjusted to control memory formation.

neuroscience↗

bioRxiv2026

Timed STING Inhibition Mitigates Gastrointestinal GvHD While Preserving Graft-versus-Leukemia Activity After Allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative for hematological malignancies but limited by graft-versus-host disease (GvHD), in which donor T cells damage host tissues. Current prophylaxis broadly suppresses donor immunity, often compromising the beneficial graft-versus-leukemia (GvL) response, highlighting the need for strategies that uncouple GvHD from GvL. The cGAS-STING pathway can be strongly activated during conditioning-induced tissue damage and represents a potential therapeutic target. However, its context-dependent roles in inflammation and homeostasis have constrained its clinical translation. Here, we show that "timed" administration of the covalent STING inhibitor H151 before conditioning reduced GvHD-associated mortality without impairing GvL in murine allo-BMT models. Donor T cell activation and effector function were preserved, indicating that the protective effect operates at the level of GvHD target tissues rather than through systemic immunosuppression. Timed STING inhibition protected the intestinal epithelium by limiting apoptosis, preserving intestinal stem cell function, and sustaining metabolic fitness during conditioning-induced injury, independently of type I interferon (IFN-I) signaling. In allo-HSCT patients, low intestinal STING expression is associated with reduced transplant-related mortality. Together, these findings identify timed STING inhibition as a tissue-protective prophylactic strategy that could be incorporated into existing conditioning regimens to enhance efficacy while minimizing toxicity.

immunology↗

bioRxiv2026

Computing tumor specificity of cancer antigen targets by k-mer indexing of healthy tissue transcriptomes

Individualized cancer immunotherapies rely on tumor-specific T-cell antigens, often predicted from somatic mutations as neoantigens. For tumors with low mutational burden, mRNA transcript variants, including gene fusions and novel splice junctions, can serve as important alternative targets. A main challenge in their identification from tumor RNA-seq is to confirm that their expression is tumor-restricted. Although large public collections of healthy-tissue RNA-seq exist, verifying tumor-specific expression requires computationally expensive re-analysis of these data for every novel candidate. To address this, we benchmarked nine k-mer indexing algorithms and developed k4neo, which leverages k-mer indexing of raw RNA-seq reads to compute the tumor specificity of any transcript variant. This mapping-free and transcript-class agnostic approach screens any candidate sequence against 18,960 samples across 51 healthy tissue types. We confirmed k4neos detection accuracy with qRT-PCR and showed that k4neo accurately classifies somatic and germline variants, gene fusions, and isoforms by tumor specificity. Applied to nine tumor cohorts, it nominated a median of 4-80 tumor-specific splice junctions per patient, including recurrent, long-read-confirmed novel antigen candidates. Together, k4neo enables efficient access to large-scale sequencing cohorts and accurately computes tumor specificity for any input transcript sequence, thereby expanding the repertoire of individual and shared cancer antigen targets.

bioinformatics↗

bioRxiv2026

Cervical spinal cord stimulation disrupts proprioception yet improves voluntary arm reaching

Whether proprioception is necessary for upper-limb motor control has been debated for decades. Classic studies in deafferented animals and humans suggested that proprioception may be dispensable for rapid, goal-directed movements. However, chronic sensory loss conflates the absence of proprioceptive input with years of compensatory adaptation. As a result, the field has lacked a strong causal test of proprioceptions contribution to motor control. Here, we leveraged a clinical trial of cervical spinal cord stimulation (SCS) in individuals with chronic post-stroke hemiparesis to study if electrical stimulation of sensory afferents causally perturbs proprioception and affects arm reaching. We found that turning SCS ON causally impaired proprioceptive perception and postural stabilization in response to force perturbations, and enhanced adaptation to visual errors during implicit learning. Yet visually and non-visually rapid, goal-directed reaching improved in smoothness, straightness and spatial accuracy. These findings provide strong causal evidence that proprioception is not required for rapid, goal-directed action, helping resolve a decades-long debate regarding its necessity for effective movement.

bioengineering↗

bioRxiv2026

Intracortical BCI Performance is Robust to Changes in Attentional Load During Dual-Tasking

High performance intracortical brain-computer interface (iBCI) control has been demonstrated in research settings, but performance can still vary within and between sessions. One potential source of this variability is the change in attentional load that comes from processing naturally occurring distractors such as thoughts, sounds, fatigue, or pain. To improve the consistency of iBCI performance in real-world environments where this sort of multi-tasking is inevitable, we must understand how shifts in attention can impact performance. Here we examined the effect of attentional load on iBCI performance and movement-related neural activity using a 2D cursor translation + click iBCI task paired with an N-Back working memory task to increase attentional load during dual-task performance. Two participants (P2 and P4) with tetraplegia completed the study while enrolled in a long-term clinical trial of an iBCI device (NCT1894802). Common neural correlates of attention (theta and alpha band power) were measured with simultaneously recorded scalp electroencephalography (EEG). While the EEG recordings and difficulty ratings suggested increased attentional load during dual tasking, iBCI performance was quite robust across the various dual tasking conditions. One participant, P2, experienced a small but significant increase in trial completion time and normalized path length during the mild attentional load condition. Signal quality differences between the two participants may have impacted the results, as P2 had lower signal quality and was therefore likely more vulnerable to attentional load. P4s higher signal quality likely allowed him to accommodate increased attentional load without a drop in performance. Overall, iBCI performance appears to be robust to attentional load, but the complex trends observed here reflect a need for continued investigation of BCI use under different cognitive states to elucidate potential challenges and compensatory mechanisms across participants.

bioengineering↗

bioRxiv2026

Early electrical stimulation promotes functional recovery after volumetric muscle loss

Volumetric muscle loss (VML) injuries overwhelm the inherent regenerative capacity of skeletal muscle, causing persistent functional deficits with no routinely effective therapies. Electrical stimulation (ES) has been shown to preserve muscle structure in other injury models, but technical barriers have prevented daily delivery during the acute post-injury window when critical regenerative programs are established. Here, we developed a fully implantable bioelectronic system with nanoporous platinum-modified electrodes enabling daily therapeutic stimulation and electromyographic recording without repeated anesthesia in a rat tibialis anterior VML model. Animals receiving ES during the acute post-injury period (10 sessions over days 0-14) showed sustained functional improvement, reaching 90% of baseline torque at 8 weeks compared to 71% in unstimulated controls. This recovery reflected enhanced remodeling of injured muscle rather than synergistic muscle compensation. Histological analysis revealed coordinated early increases in vascularization, pro-regenerative macrophages, and satellite cells. These findings establish early ES as a promising intervention for promoting muscle regeneration after catastrophic injury.

bioengineering↗

bioRxiv2026

Enabling Skilled Human-Computer Interaction After Paralysis via a Wearable sEMG Interface

Most individuals with tetraplegia retain some myoelectric function in their forearms, which offers the possibility of using surface electromyographic (sEMG) control for human-computer interaction (HCI). We demonstrate the potential of this approach by showing that people with motor-complete (n=5) and motor-incomplete (n=2) tetraplegia can accurately control myoelectric activity in their forearm to perform discrete button-click and continuous positioning tasks. These control inputs were mapped to the firing rate of motor units detected by a wireless wristband sensor designed for everyday use. Participants completed four testing sessions to assess their speed and accuracy. Motor units that displayed a wide dynamic range in their firing rate performed best during tasks requiring continuous, single-axis control. Interestingly, the level of impairment did not affect performance on the clicking and 1D cursor control tasks. However, those with motor-incomplete injuries showed greater independent control over two motor units than participants with motor-complete injuries, who exhibited stronger coupling between units. Participants also confirmed the practical utility of the device, successfully placing and removing the sEMG wristband on their own and consistently rating it as comfortable and easy to manage. These findings are significant because they offer the first demonstration of motor unit-based control in individuals with cervical spinal cord injury (SCI) using a fully wearable wristband interface, highlighting the feasibility of moving these systems out of the lab and into daily life. One-Sentence SummaryPeople with tetraplegia used a wristband sensor to detect forearm motor unit firing and perform human-computer interaction tasks.

bioengineering↗

bioRxiv2025

A microbial metabolite protects against graft-versus-host disease via mTORC1 and STING-dependent intestinal regeneration

Changes in the intestinal microbiome and microbiota-derived metabolites predict clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report that desaminotyrosine (DAT), a product of bacterial flavonoid metabolism, correlates with improved overall survival and reduced relapse rates in allo-HSCT patients. In preclinical mouse models, treatment with synthetic DAT prevents graft-versus-host disease by protecting the intestinal barrier and promoting intestinal regeneration and contributes to graft-vs.-leukemia responses. DATs beneficial effects on intestinal regeneration remain effective despite broad-spectrum antibiotics-induced dysbiosis, also when administered by fecal microbiota transfer with flavonoid-degrading F. plautii. Mechanistically, DAT promotes mTORC1-dependent activation and proliferation of intestinal stem cells, with concomitant engagement of the innate immune receptor STING required to mitigate metabolic stress and maintain an undifferentiated stem cell state independently of type-I interferon responses. Additionally, DAT can skew T cells towards an effector phenotype to modulate graft-versus-leukemia responses. Our data uncover DATs dual, tissue- and immune-modulating properties and underscore its potential in precision microbiome-based therapies to improve tissue regeneration and minimize immune-mediated side effects.

immunology↗

bioRxiv2024

Mitophagosomes induced during EV-D68 infection promote viral nonlytic release

Enterovirus-D68 (EV-D68) is a plus-strand RNA virus that primarily causes infant respiratory infections. In rare pediatric cases, infection with EV-D68 has been associated with acute flaccid myelitis, a polio-like paralytic disease. We have previously demonstrated that EV-D68 induces nonselective autophagy for its benefit. Here, we demonstrate that EV-D68 induces mitophagy, the specific autophagic degradation of mitochondria. EV-D68 infection induces mitophagosome formation and several hallmarks of mitophagy, including mitochondrial fragmentation, mitochondrial membrane potential loss, and Parkin translocation to the mitochondria were observed in EV-D68 infected cells. The 3C protease of EV-D68 cleaves the mitochondrial fusion protein, mitofusin-2, near the C-terminal HR2 domain to induce mitochondrial fragmentation, and these fragmented mitochondria colocalized with double-stranded RNA (dsRNA), which labels viral RNA replication sites after peak viral RNA replication. Depleting components of mitophagy signaling specifically reduced EV-D68 release without impacting viral intracellular titers. Our results suggest that whereas the machinery of macroautophagy supports various stages of enterovirus replication, including viral genomic RNA replication and capsid maturation, mitophagy is the specific form of autophagy that regulates the nonlytic release of enteroviruses from cells. SignificanceEV-D68 is a respiratory pathogen and a significant cause of acute respiratory illness in infants, against which no prophylactic vaccines or antivirals exist. We have previously shown that EV-D68, like other enteroviruses, triggers and benefits from nonselective autophagy. However, it was unclear whether the virus induces selective autophagy. Here, we demonstrate that EV-D68 infection induces mitophagy and uses mitophagosomes to traffic virions to the surface of cells for nonlytic release. Our findings suggest that mitophagy may constitute the specific form of autophagy that facilitates the autophagosome-mediated nonlytic release of enteroviruses from infected cells and that targeting mitophagy could be an effective strategy to impede EV-D68 nonlytic release.

microbiology↗

bioRxiv2024

Foxi1 regulates multiple steps of mucociliary development and ionocyte specification through transcriptional and epigenetic mechanisms

Foxi1 is a master regulator of ionocytes (ISCs / INCs) across species and organs. Two subtypes of ISCs exist, and both -and {beta}-ISCs regulate pH-and ion-homeostasis in epithelia. Gain and loss of FOXI1 function are associated with human diseases, including Pendred syndrome, male infertility, renal acidosis and cancers. Foxi1 was predominantly studied in the context of ISC specification, however, reports indicate additional functions in early and ectodermal development. Here, we re-investigated the functions of Foxi1 in Xenopus laevis embryonic mucociliary epidermis development and found a novel function for Foxi1 in the generation of Notch-ligand expressing mucociliary multipotent progenitors (MPPs). We demonstrate that Foxi1 has multiple concentration-dependent functions: At low levels, Foxi1 maintains ectodermal competence in MPPs through transcriptional and epigenetic mechanisms, while at high levels, Foxi1 induces a multi-step process of ISC specification and differentiation in cooperation with Ubp1 and Dmrt2. We further describe how foxi1 expression is affected through auto-and Notch-regulation, and how this developmental program affects mucociliary patterning. Together, we reveal novel functions for Foxi1 in Xenopus mucociliary epidermis formation, relevant to our understanding of vertebrate development and human disease.

developmental biology↗

bioRxiv2024

Epidural Spinal Cord Recordings (ESRs): Sources of Artifact in Stimulation Evoked Compound Action Potentials

IntroductionEvoked compound action potentials (ECAPs) measured using epidural spinal recordings (ESRs) during epidural spinal cord stimulation (SCS) can help elucidate fundamental mechanisms for the treatment of pain, as well as inform closed-loop control of SCS. Previous studies have used ECAPs to characterize the neural response to various neuromodulation therapies and have demonstrated that ECAPs are highly prone to multiple sources of artifact, including post-stimulus pulse capacitive artifact, electromyography (EMG) bleed-through, and motion artifact resulting from disturbance of the electrode/tissue interface during normal behavior. However, a thorough characterization has yet to be performed for how these sources of artifact may contaminate recordings within the temporal window commonly used to determine activation of A-beta fibers in a large animal model. MethodsWe characterized the sources of artifacts that can contaminate the recording of ECAPs in an epidural SCS swine model using the Abbott Octrode lead. Muscle paralytics were administered to block muscle activation preventing EMG from contaminating the recorded ECAPs. Concurrent EMG recordings of the longissimus, a long muscle of the back, were used to confirm a 2-4 millisecond (ms) latency source of EMG bleed-through that frequently contaminated the A-beta temporal window. Additionally, we obtained recordings approximately 5-10 minutes post-mortem after clear evoked A-beta and associated EMG responses ceased to characterize the representation of stimulation artifact across the array. ResultsSpinal ECAP recordings can be contaminated by capacitive artifact, short latency EMG from nearby long muscles of the back, and motion artifact from multiple sources. In many cases, the capacitive artifact can appear nearly identical in duration and waveshape to evoked A-beta responses. These sources of EMG can have phase shifts across the electrode array, very similar to the phase shift anticipated by propagation of an evoked A-beta fiber response across the array. This short latency EMG is often evident at currents similar to those needed to activate A-beta fibers associated with the treatment of pain. Changes in cerebrospinal fluid between the cord and dura, and motion induced during breathing created a cyclic oscillation in all evoked components of the recorded ECAP signal. ConclusionCareful controls must be implemented to accurately separate neural signal from the sources of artifact in spinal cord ECAPs. To address this, we suggest experimental procedures and associated reporting requirements necessary to disambiguate the underlying neural response from these confounds. These data are important to better understand the conceptual framework for recorded ESRs, with components such as ECAPs, EMG responses and artifacts, and have important implications for closed-loop control algorithms to account for transient motion such as postural changes and cough.

neuroscience↗

bioRxiv2023

Evolutionary origin of morphologically cryptic species imprints co-occurrence and sympatry patterns

AimMorphologically cryptic species are an important part of global biodiversity, yet it remains unclear how these species contribute to and integrate into communities at different geographic scales. It is especially unclear at which scales they co-occur, and if and how their ranges overlap. To adequately protect biodiversity, an accurate understanding of the underlying processes and adequate level of protection is needed, in particularly for often overlooked cryptic species. QuestionWe analyzed patterns of syntopies (local co-occurrences) and sympatries (range overlap) to test how the evolutionary origin of cryptic species shapes biodiversity patterns at different geographic scales. We hypothesized i) that syntopies are more common among phylogenetically deeply divergent cryptic species than among close relatives, and ii) that sympatries are an outcome of phylogenetic relatedness and dispersal, with range size as a proxy of dispersal ability. LocationWestern Europe. TaxonSubterranean amphipod crustaceans of the polyphyletic Niphargus rhenorhodanensis species complex. MethodsUnilocus species delimitations (PTP, ASAP), calibrated multilocus phylogenetic analyses, co-occurrence analyses using a probabilistic model, generalized linear models (GLM). ResultsThe studied species complex comprises 37-48 molecular operational taxonomic units (MOTUs) from nine different clades. Syntopies are random or less frequent than expected, implying an insufficient between-MOTU differentiation allowing stable coexistence. GLM suggested that age of divergence does not predict species sympatries, although they emerge more frequently among MOTUs from different clades. By contrast, sympatries emerge when at least one MOTU disperses over a large geographic range. Biodiversity rich regions were found at the foothills of the Alps, the Jura and the Central Massif, regardless the inference method. Main conclusionsBiodiversity patterns of the herein studied species complex are driven mainly by dispersal and reflect geographic circumstances of speciation. While species richness on a local scale may be the outcome of competition and dispersal, regional biodiversity patterns emerged through biogeographic history on a clade-level.

ecology↗

bioRxiv2023

Water diviners multiplied: cryptic diversity in the Niphargus aquilex species complex in Northern Europe

As for many other groups, patterns of biodiversity for subter-ranean crustaceans in Europe indicate larger morphospecies ranges at higher latitudes (the so-called Rapoport effect). However, this observed correlation may be artefactual if many of those high-latitude, widely distributed morphospecies are actually species complexes. To test this hypothesis, we looked for previously undetected species boundaries within Niphargus aquilex and Niphargus schellenbergi, two closely related morphospecies of groundwater amphipods widely distributed in northern Europe, by sequencing fragments of the mitochondrial cytochrome c oxidase subunit I gene (COI) and of the nuclear 28S ribosomal RNA gene of 198 individuals collected across their area of distribution. Distance-based and allele sharing-based species delimitation approaches were congruent in revealing the existence of at least eight species within N. aquilex and at least two species with N. schellenbergi. Our data demonstrate that these two common morphospecies with large ranges are actually complexes of species with narrower distributions, suggesting that the Rapoport effect might be the result of increased morphological stasis at high latitudes rather than actual differences in sizes of distribution ranges.

zoology↗

bioRxiv2023

Four Individually Identified Paired Dopamine Neurons Signal Taste Punishment in Larval Drosophila

Dopaminergic neurons (DANs) carry out multiple tasks in the brain, including the transmission of information related to rewards and punishments across various animal species. They are responsible for evaluating sensory input, storing resulting associations as memory, and continuously updating them based on their relevance and reliability. Accurate comprehension of the dopaminergic systems operation necessitates an understanding of the specific functions mediated by individual DANs. To this end, our research employs Drosophila larvae, which possess approximately 12,000 neurons in their brains, of which only around 1% (approximately 120) are DANs. The presynaptic projections to the mushroom body (MB) - a brain region pivotal for associative olfactory learning in insects - are limited to only eight larval dopaminergic neurons. These DANs are further subdivided into two clusters: the primary protocerebral anterior medial cluster (pPAM) comprises four cells, and the dorsolateral 1 cluster (DL1) comprises the remaining four cells. Our findings confirm previous research that demonstrates that the pPAM DANs innervating the MBs medial lobe encode for a gustatory sugar reward signal. Furthermore, we have identified four DANs in the DL1 cluster - DAN-c1, DAN-d1, DAN-f1, and DAN-g1 - each of which innervates distinct compartments of the MB peduncle, lateral appendix, and vertical lobe. Optogenetic activation of DAN-f1 and DAN-g1 alone suffices to substitute for punishment. Furthermore, optogenetic inhibition, calcium imaging results and electron microscopy-based reconstruction of all sensory input circuits to the four DL1 DANs demonstrate that each DAN encodes a different aspect of punishment, with DAN-g1 being of central importance for the salt dependent teaching signal. To summarize, our investigation has revealed the existence of a cellular division of labor among larval DANs concerning the transmission of dopaminergic reward (pPAM cluster) and punishment signals (DL1 cluster). Individual DANs in each cluster encode for distinct but partially overlapping aspects of the teaching signal. The striking resemblance in the organizing principle of larval DANs with that of its adult counterpart and the mammalian basal ganglion suggests that there may be a limited number of efficient neural circuit solutions available to address more complex cognitive challenges in nature.

animal behavior and cognition↗

bioRxiv2023

Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates

Splicing is dysregulated in many tumors and may result in tumor-specific transcripts that can encode neoantigens, which are promising targets for cancer immunotherapy. Detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumor transcriptomes also appear in healthy tissues. Here, we developed splice2neo to integrate the predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq for individual cancer patients. Splice2neo excludes splice junctions from healthy tissue samples, annotates resulting transcript and peptide sequences, and provides targeted re-quantification of supporting RNA-seq reads. We developed a stringent detection rule to predict splice junctions as mutation-derived targets and identified 1.7 target splice junctions per tumor with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted MHC-I or MHC-II binding. Compared to neoepitope candidates derived from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had a lower self-similarity to corresponding wild-type peptides. In conclusion, we demonstrate that identifying mutation-derived and tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies. Key PointsO_LIsplice2neo is a versatile tool for identifying and analyzing of splice junctions as a source of neoantigen candidates C_LIO_LIWe identified mutation-retrieved splice junctions supported by RNA-seq in melanoma samples C_LIO_LIThe predicted target splice junctions exhibited a strong tumor-specificity as they were absent in healthy tissues. C_LIO_LITarget splice junctions often lead to frame-shift peptides and encode promising neoantigen candidates C_LI

bioinformatics↗

bioRxiv2022

Rewarding capacity of optogenetically activating a giant GABAergic central-brain interneuron in larval Drosophila

Larvae of the fruit fly Drosophila melanogaster are a powerful study case for understanding the neural circuits underlying behavior. Indeed, the numerical simplicity of the larval brain has permitted the reconstruction of its synaptic connectome, and genetic tools for manipulating single, identified neurons allow neural circuit function to be investigated with relative ease and precision. We focus on one of the most complex neurons in the brain of the larva (of either sex), the GABAergic anterior paired lateral neuron (APL). Using behavioral and connectomic analyses, optogenetics, Ca2+ imaging and pharmacology, we study how APL affects associative olfactory memory. We first provide a detailed account of the structure, regional polarity, connectivity, and metamorphic development of APL, and further confirm that optogenetic activation of APL has an inhibiting effect on its main targets, the mushroom body Kenyon cells. All these findings are consistent with the previously identified function of APL in the sparsening of sensory representations. To our surprise, however, we found that optogenetically activating APL can also have a strong rewarding effect. Specifically, APL activation together with odor presentation establishes an odor-specific, appetitive, associative short-term memory, whereas naive olfactory behavior remains unaffected. An acute, systemic inhibition of dopamine synthesis as well as an ablation of the dopaminergic pPAM neurons impair reward learning through APL activation. Our findings provide a study case of complex circuit function in a numerically simple brain, and suggest a previously unrecognized capacity of central-brain GABAergic neurons to engage in dopaminergic reinforcement. Significance statementThe single, identified giant anterior paired lateral (APL) neuron is one of the most complex neurons in the insect brain. It is GABAergic and contributes to the sparsening of neuronal activity in the mushroom body, the memory center of insects. We provide the most detailed account yet of the structure of APL in larval Drosophila as a neurogenetically accessible study case. We further reveal that, contrary to expectations, the experimental activation of APL can exert a rewarding effect, likely via dopaminergic reward pathways. The present study both provides an example of unexpected circuit complexity in a numerically simple brain, and reports an unexpected effect of activity in central-brain GABAergic circuits.

neuroscience↗

bioRxiv2022

Multiple instance learning to predict immune checkpoint blockade efficacy using neoantigen candidates

A successful response to immune checkpoint blockade treatment (ICB) depends on the functional re-invigoration of neoantigen-specific T cells and their anti-tumoral activity. Previous studies showed that the patients neoantigen candidate load is an imperfect predictor of the response to ICB. Further studies provided evidence that the overall response to ICB is also affected by the qualitative properties of a few or even single candidates, limiting the predictive power based on candidate quantity alone. To our knowledge, this is the first study to predict the response to ICB therapy based on qualitative neoantigen candidate profiles in the context of the mutation type, using a multiple instance learning approach. Multiple instance learning is a special branch of machine learning which classifies labelled bags that are formed by a set of unlabeled instances. The multiple instance learning approach performed systematically better than random guessing and was independent of the neoantigen candidate load. Qualitative modeling performed better in comparison to the quantitative approach, in particular for modelling low-abundant fusion genes. Our findings suggest that multiple instance learning is an appropriate method to predict immunotherapy efficacy based on qualitative neoantigen candidate profiles without relying on direct T-cell response information and provide a foundation for future developments in the field.

bioinformatics↗

bioRxiv2020

Two Parallel Pathways Mediate Olfactory-Driven Backward Locomotion

Although animals switch to backward walking upon sensing an obstacle or danger in their path, the initiation and execution of backward locomotion is poorly understood. The discovery of Moonwalker Descending Neurons (MDNs), made Drosophila useful to study neural circuits underlying backward locomotion. MDNs were demonstrated to receive visual and mechanosensory inputs. However, whether other modalities converge onto MDNs and what are the neural circuits activating MDNs are unknown. We show that aversive but not appetitive olfactory input triggers MDN-mediated backward locomotion. We identify in each hemisphere, a single Moonwalker Subesophageal Zone neuron (MooSEZ), which triggers backward locomotion. MooSEZs act both upstream and in parallel to MDNs. Surprisingly, MooSEZs also respond mostly to aversive odor. Contrary to MDNs, blocking MooSEZs activity has little effect on odor-evoked backward locomotion. Thus, this work reveals another important modality input to MDNs in addition to a novel olfactory pathway and MDN-independent backward locomotion pathway.

neuroscience↗