@article{21264,
  abstract     = {Rodents' ability to encode the whisking phase has been extensively documented through neuronal recordings from ascending sensory pathways. Yet, while indicating that reafference originates from the mechanoreceptors, the mechanistic underpinnings of the whisking phase encoding within the follicle remain unclear. Here we present anatomical, histological, and biomechanical evidence for the presence of a distinctive elastic segment (ES) within the basal part of the whisker shaft inside the follicle. This ES, composed of immature keratin, is capable of both bending and twisting. Forces generated by whisker movement deform this segment, causing whisker shaft deflections that can stimulate specific mechanoreceptor subsets within the follicle at different phases of the whisking cycle. This mechanism appears to operate during both free‐air whisking and object contact. We propose that the ES enables torsion‐based mechanoreceptor activation, allowing encoding of the whisking phase.},
  author       = {Haidarliu, Sebastian and Nelinger, Guy and Gantar, Luka and Ahissar, Ehud and Saraf‐Sinik, Inbar},
  issn         = {1932-8494},
  journal      = {The Anatomical Record},
  publisher    = {Wiley},
  title        = {{An elastic segment of the whisker shaft enables coding of the whisking phase via whisker torsion in rats and mice}},
  doi          = {10.1002/ar.70051},
  year         = {2025},
}

@article{19076,
  abstract     = {For accurate perception and motor control, an animal must distinguish between sensory experiences elicited by external stimuli and those elicited by its own actions. The diversity of behaviors and their complex influences on the senses make this distinction challenging. Here, we uncover an action–cue hub that coordinates motor commands with visual processing in the brain’s first visual relay. We show that the ventral lateral geniculate nucleus (vLGN) acts as a corollary discharge center, integrating visual translational optic flow signals with motor copies from saccades, locomotion and pupil dynamics. The vLGN relays these signals to correct action-specific visual distortions and to refine perception, as shown for the superior colliculus and in a depth-estimation task. Simultaneously, brain-wide vLGN projections drive corrective actions necessary for accurate visuomotor control. Our results reveal an extended corollary discharge architecture that refines early visual transformations and coordinates actions via a distributed hub-and-spoke network to enable visual perception during action.},
  author       = {Vega Zuniga, Tomas A and Sumser, Anton L and Symonova, Olga and Koppensteiner, Peter and Schmidt, Florian and Jösch, Maximilian A},
  issn         = {1546-1726},
  journal      = {Nature Neuroscience},
  publisher    = {Springer Nature},
  title        = {{A thalamic hub-and-spoke network enables visual perception during action by coordinating visuomotor dynamics}},
  doi          = {10.1038/s41593-025-01874-w},
  volume       = {28},
  year         = {2025},
}

@misc{15385,
  abstract     = {Relevant information about the data can be found in the 'Readme_Data.txt' file. 
A previous version of the publication can be found on BioRxiv: https://www.biorxiv.org/content/10.1101/2022.10.11.511691v4
and published in Plos Biology (2024)},
  author       = {Burnett, Laura and Koppensteiner, Peter and Symonova, Olga and Masson, Tomas and Vega Zuniga, Tomas A and Contreras, Ximena and Rülicke, Thomas and Shigemoto, Ryuichi and Novarino, Gaia and Jösch, Maximilian A},
  keywords     = {ASD, periaqueductal gray, perception, behavior, potassium channels},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice}},
  doi          = {10.15479/AT:ISTA:15385},
  year         = {2024},
}

@article{15404,
  abstract     = {We used diverse methods to characterize the role of avian lateral spiriform nucleus (SpL) in basal ganglia motor function. Connectivity analysis showed that SpL receives input from globus pallidus (GP), and the intrapeduncular nucleus (INP) located ventromedial to GP, whose neurons express numerous striatal markers. SpL-projecting GP neurons were large and aspiny, while SpL-projecting INP neurons were medium sized and spiny. Connectivity analysis further showed that SpL receives inputs from subthalamic nucleus (STN) and substantia nigra pars reticulata (SNr), and that the SNr also receives inputs from GP, INP, and STN. Neurochemical analysis showed that SpL neurons express ENK, GAD, and a variety of pallidal neuron markers, and receive GABAergic terminals, some of which also contain DARPP32, consistent with GP pallidal and INP striatal inputs. Connectivity and neurochemical analysis showed that the SpL input to tectum prominently ends on GABAA receptor-enriched tectobulbar neurons. Behavioral studies showed that lesions of SpL impair visuomotor behaviors involving tracking and pecking moving targets. Our results suggest that SpL modulates brainstem-projecting tectobulbar neurons in a manner comparable to the demonstrated influence of GP internus on motor thalamus and of SNr on tectobulbar neurons in mammals. Given published data in amphibians and reptiles, it seems likely the SpL circuit represents a major direct pathway-type circuit by which the basal ganglia exerts its motor influence in nonmammalian tetrapods. The present studies also show that avian striatum is divided into three spatially segregated territories with differing connectivity, a medial striato-nigral territory, a dorsolateral striato-GP territory, and the ventrolateral INP motor territory.},
  author       = {Reiner, Anton and Medina, Loreta and Abellan, Antonio and Deng, Yunping and Toledo, Claudio A.B. and Luksch, Harald and Vega Zuniga, Tomas A and Riley, Nell B. and Hodos, William and Karten, Harvey J.},
  issn         = {1096-9861},
  journal      = {Journal of Comparative Neurology},
  number       = {5},
  publisher    = {Wiley},
  title        = {{Neurochemistry and circuit organization of the lateral spiriform nucleus of birds: A uniquely nonmammalian direct pathway component of the basal ganglia}},
  doi          = {10.1002/cne.25620},
  volume       = {532},
  year         = {2024},
}

@article{17142,
  abstract     = {Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments—a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD.},
  author       = {Burnett, Laura and Koppensteiner, Peter and Symonova, Olga and Masson, Tomas and Vega Zuniga, Tomas A and Contreras, Ximena and Rülicke, Thomas and Shigemoto, Ryuichi and Novarino, Gaia and Jösch, Maximilian A},
  issn         = {1545-7885},
  journal      = {PLoS Biology},
  publisher    = {Public Library of Science},
  title        = {{Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice}},
  doi          = {10.1371/journal.pbio.3002668},
  volume       = {22},
  year         = {2024},
}

@article{18444,
  abstract     = {Animals rely on compensatory actions to maintain stability and navigate their environment efficiently. These actions depend on global visual motion cues known as optic-flow. While the optomotor response has been the traditional focus for studying optic-flow compensation in insects, its simplicity has been insufficient to determine the role of the intricate optic-flow processing network involved in visual course control. Here, we reveal a series of course control behaviours in Drosophila and link them to specific neural circuits. We show that bilateral electrical coupling of optic-flow-sensitive neurons in the fly’s lobula plate are required for a proper course control. This electrical interaction works alongside chemical synapses within the HS-H2 network to control the dynamics and direction of turning behaviours. Our findings reveal how insects use bilateral motion cues for navigation, assigning a new functional significance to the HS-H2 network and suggesting a previously unknown role for gap junctions in non-linear operations.},
  author       = {Pokusaeva, Victoria and Satapathy, Roshan K and Symonova, Olga and Jösch, Maximilian A},
  issn         = {2041-1723},
  journal      = {Nature Communications},
  publisher    = {Springer Nature},
  title        = {{Bilateral interactions of optic-flow sensitive neurons coordinate course control in flies}},
  doi          = {10.1038/s41467-024-53173-w},
  volume       = {15},
  year         = {2024},
}

@phdthesis{18568,
  abstract     = {Locomotion is ubiquitous in the animal kingdom because an animal's survival depends on its ability to navigate its environment to find food, avoid predators and locate potential mates. These behaviours require control mechanisms that can extract information from the environment, particularly visual cues. Selective evolutionary pressures have thus refined such visuomotor transformations in a species-specific manner to meet the specific ecological and ethological challenges of each organism. However, a common challenge across organisms as visual information processing
becomes increasingly detailed is the mechanisms required to synthesise disparate pieces of information into a coherent percept or unified picture of the world. In this thesis, I investigate how disparate visual information is combined in the brain of Drosophila melanogaster to effectively guide locomotion.
For this, I first designed and built a behavioural setup to record locomotion and present visual stimuli to freely-walking fruit flies in a closed-loop manner. This setup allowed the investigation of innate visually-guided behaviours, including the optomotor reflex and courtship.
Second, taking advantage of my system I investigated the optomotor response, a reflexive visual stabilisation behaviour in which flies turn in the direction of global motion to minimise retinal slip. This behaviour is thought to be mediated by Lobula plate tangential cells (LPTCs); a complex network of optic-flow-sensitive neurons essential for self-motion estimation. Using a novel genetic mutant, I demonstrate that electrical coupling between two LPTC subtypes, contralateral HS and H2 neurons, regulates the balance between smooth optomotor turning and saccadic anti-optomotor responses. These findings underscore the critical role of binocular motion cue integration in guiding course control. Finally, I developed a novel behavioural paradigm in which a sexually aroused male fruit fly is presented with an optomotor distractor. This setup creates competition between two visual behaviours, courtship tracking and the  optomotor response, enabling me to explore how the visual system resolves this conflict. In this setting, males
engaged in courtship selectively suppress their optomotor response based on the female's location. Furthermore, when this experiment is replicated with an “artificial female”, optogenetically aroused males alternate between tracking and optomotor responses. The probability and dynamics of this switching are determined by the relative strengths of the two competing stimuli. In summary, the results presented in this thesis explore two mechanisms – integration and competition - through which visual information is combined in the brain of the fruit fly to drive locomotion.},
  author       = {Satapathy, Roshan K},
  isbn         = {978-3-99078-047-3},
  issn         = {2663-337X},
  pages        = {114},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Mechanisms of visual integration and competition in innate behaviours in Drosophila melanogaster}},
  doi          = {10.15479/at:ista:18568},
  year         = {2024},
}

@misc{18579,
  abstract     = {Electrophysiological, calcium two-photon recordings and behavioral data for Vega-Zuniga et al.  Relevant information can be found in the 'README.txt' files. },
  author       = {Vega Zuniga, Tomas A and Sumser, Anton L and Symonova, Olga and Koppensteiner, Peter and Schmidt, Florian and Jösch, Maximilian A},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{A thalamic hub-and-spoke network enables visual perception during action by coordinating visuomotor dynamics}},
  doi          = {10.15479/AT:ISTA:18579},
  year         = {2024},
}

@misc{17488,
  abstract     = {Behavioural data for Pokusaeva, Satapathy et al. Relevant information can be found in the 'README.txt' file.},
  author       = {Satapathy, Roshan K and Jösch, Maximilian A and Symonova, Olga and Pokusaeva, Victoria},
  keywords     = {drosophila, behaviour, locomotion, gap junctions},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Bilateral interactions of optic-flow sensitive neurons coordinate course control in flies}},
  doi          = {10.15479/AT:ISTA:17488},
  year         = {2024},
}

@phdthesis{18574,
  abstract     = {Biological vision is unlike a camera; rather than transmitting light information faithfully, early
visual circuits process the visual scene to convey only the relevant information in an efficient
manner. Consequentially, the nature of this visual processing then depends on what is the
relevant information in a scene and on the notion of efficiency. In this work, I study how visual
processing is modulated by two different variations in the visual scene. First, I discovered that
in the mouse (Mus musculus) retina, Retinal Ganglion Cells in the upper and lower visual
field have differences in the center surround structure of their receptive fields. Comparison
with models of efficient coding show that this adaptation likely evolved to cope with the
brightness gradient from the sky to the ground that is pervasive in natural scenes. In the
second project, I study how the downstream neurons in the Superior Colliculus dynamically
change their temporal selectivity depending on the ambient luminance and behavioral state.
As the scene gets darker or when the animal is is less aroused, the neuronal responses get
laggier, while still maintaining their relative timing with respect to the population. Overall, this
work emphasises the need to understand visual processing in the context of specific demands
of the animal in its the environment. The adaptive changes in the visual system, from the
retinal ganglion cells to the superior colliculus, highlight the intricate ways in which biological
vision optimizes the processing of visual information.
},
  author       = {Gupta, Divyansh},
  isbn         = {978-3-99078-050-3},
  issn         = {2663-337X},
  pages        = {86},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Visual adaptations to natural statistics}},
  doi          = {10.15479/at:ista:18574},
  year         = {2024},
}

@phdthesis{12716,
  abstract     = {The process of detecting and evaluating sensory information to guide behaviour is termed perceptual decision-making (PDM), and is critical for the ability of an organism to interact with its external world. Individuals with autism, a neurodevelopmental condition primarily characterised by social and communication difficulties, frequently exhibit altered sensory processing and PDM difficulties are widely reported. Recent technological advancements have pushed forward our understanding of the genetic changes accompanying this condition, however our understanding of how these mutations affect the function of specific neuronal circuits and bring about the corresponding behavioural changes remains limited. Here, we use an innate PDM task, the looming avoidance response (LAR) paradigm, to identify a convergent behavioural abnormality across three molecularly distinct genetic mouse models of autism (Cul3, Setd5 and Ptchd1). Although mutant mice can rapidly detect threatening visual stimuli, their responses are consistently delayed, requiring longer to initiate an appropriate response than their wild-type siblings. Mutant animals show abnormal adaptation in both their stimulus- evoked escape responses and exploratory dynamics following repeated stimulus presentations. Similarly delayed behavioural responses are observed in wild-type animals when faced with more ambiguous threats, suggesting the mutant phenotype could arise from a dysfunction in the flexible control of this PDM process.
Our knowledge of the core neuronal circuitry mediating the LAR facilitated a detailed dissection of the neuronal mechanisms underlying the behavioural impairment. In vivo extracellular recording revealed that visual responses were unaffected within a key brain region for the rapid processing of visual threats, the superior colliculus (SC), indicating that the behavioural delay was unlikely to originate from sensory impairments. Delayed behavioural responses were recapitulated in the Setd5 model following optogenetic stimulation of the excitatory output neurons of the SC, which are known to mediate escape initiation through the activation of cells in the underlying dorsal periaqueductal grey (dPAG). In vitro patch-clamp recordings of dPAG cells uncovered a stark hypoexcitability phenotype in two out of the three genetic models investigated (Setd5 and Ptchd1), that in Setd5, is mediated by the misregulation of voltage-gated potassium channels. Overall, our results show that the ability to use visual information to drive efficient escape responses is impaired in three diverse genetic mouse models of autism and that, in one of the models studied, this behavioural delay likely originates from differences in the intrinsic excitability of a key subcortical node, the dPAG. Furthermore, this work showcases the use of an innate behavioural paradigm to mechanistically dissect PDM processes in autism.},
  author       = {Burnett, Laura},
  issn         = {2663-337X},
  pages        = {178},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{To flee, or not to flee? Using innate defensive behaviours to investigate rapid perceptual decision-making through subcortical circuits in mouse models of autism}},
  doi          = {10.15479/at:ista:12716},
  year         = {2023},
}

@phdthesis{12826,
  abstract     = {During navigation, animals can infer the structure of the environment by computing the optic flow cues elicited by their own movements, and subsequently use this information to instruct proper locomotor actions. These computations require a panoramic assessment of the visual environment in order to disambiguate similar sensory experiences that may require distinct behavioral responses. The estimation of the global motion patterns is therefore essential for successful navigation. Yet, our understanding of the algorithms and implementations that enable coherent panoramic visual perception remains scarce. Here I pursue this problem by dissecting the functional aspects of interneuronal communication in the lobula plate tangential cell network in Drosophila melanogaster. The results presented in the thesis demonstrate that the basis for effective interpretation of the optic flow in this circuit are stereotyped synaptic connections that mediate the formation of distinct subnetworks, each extracting a particular pattern of global motion. 
Firstly, I show that gap junctions are essential for a correct interpretation of binocular motion cues by horizontal motion-sensitive cells. HS cells form electrical synapses with contralateral H2 neurons that are involved in detecting yaw rotation and translation. I developed an FlpStop-mediated mutant of a gap junction protein ShakB that disrupts these electrical synapses. While the loss of electrical synapses does not affect the tuning of the direction selectivity in HS neurons, it severely alters their sensitivity to horizontal motion in the contralateral side. These physiological changes result in an inappropriate integration of binocular motion cues in walking animals. While wild-type flies form a binocular perception of visual motion by non-linear integration of monocular optic flow cues, the mutant flies sum the monocular inputs linearly. These results indicate that rather than averaging signals in neighboring neurons, gap-junctions operate in conjunction with chemical synapses to mediate complex non-linear optic flow computations.
Secondly, I show that stochastic manipulation of neuronal activity in the lobula plate tangential cell network is a powerful approach to study the neuronal implementation of optic flow-based navigation in flies. Tangential neurons form multiple subnetworks, each mediating course-stabilizing response to a particular global pattern of visual motion. Application of genetic mosaic techniques can provide sparse optogenetic activation of HS cells in numerous combinations. These distinct combinations of activated neurons drive an array of distinct behavioral responses, providing important insights into how visuomotor transformation is performed in the lobula plate tangential cell network. This approach can be complemented by stochastic silencing of tangential neurons, enabling direct assessment of the functional role of individual tangential neurons in the processing of specific visual motion patterns.
	Taken together, the findings presented in this thesis suggest that establishing specific activity patterns of tangential cells via stereotyped synaptic connectivity is a key to efficient optic flow-based navigation in Drosophila melanogaster.},
  author       = {Pokusaeva, Victoria},
  issn         = {2663-337X},
  pages        = {106},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Neural control of optic flow-based navigation in Drosophila melanogaster}},
  doi          = {10.15479/at:ista:12826},
  year         = {2023},
}

@article{13230,
  abstract     = {To interpret the sensory environment, the brain combines ambiguous sensory measurements with knowledge that reflects context-specific prior experience. But environmental contexts can change abruptly and unpredictably, resulting in uncertainty about the current context. Here we address two questions: how should context-specific prior knowledge optimally guide the interpretation of sensory stimuli in changing environments, and do human decision-making strategies resemble this optimum? We probe these questions with a task in which subjects report the orientation of ambiguous visual stimuli that were drawn from three dynamically switching distributions, representing different environmental contexts. We derive predictions for an ideal Bayesian observer that leverages knowledge about the statistical structure of the task to maximize decision accuracy, including knowledge about the dynamics of the environment. We show that its decisions are biased by the dynamically changing task context. The magnitude of this decision bias depends on the observer’s continually evolving belief about the current context. The model therefore not only predicts that decision bias will grow as the context is indicated more reliably, but also as the stability of the environment increases, and as the number of trials since the last context switch grows. Analysis of human choice data validates all three predictions, suggesting that the brain leverages knowledge of the statistical structure of environmental change when interpreting ambiguous sensory signals.},
  author       = {Charlton, Julie A. and Mlynarski, Wiktor F and Bai, Yoon H. and Hermundstad, Ann M. and Goris, Robbe L.T.},
  issn         = {1553-7358},
  journal      = {PLoS Computational Biology},
  number       = {6},
  publisher    = {Public Library of Science},
  title        = {{Environmental dynamics shape perceptual decision bias}},
  doi          = {10.1371/journal.pcbi.1011104},
  volume       = {19},
  year         = {2023},
}

@phdthesis{12531,
  abstract     = {All visual experiences of the vertebrates begin with light being converted into electrical signals
by the eye retina. Retinal ganglion cells (RGCs) are the neurons of the innermost layer of the
mammal retina, and they transmit visual information to the rest of the brain.
It has been shown that RGCs vary in their morphology and genetic profiles, moreover they can
be unambiguously grouped into subtypes that share the same morphological and/or molecular
properties. However, in terms of RGCs function, it remains unclear how many distinct types
there are and what response properties their typology relies on. Even given the recent studies
that successfully classified RGCs in a patch of the retina [1] and in scotopic conditions [2], the
question remains whether the found subtypes persist across the entire retina.
In this work, using a novel imaging method, we show that, when sampled from a large portion
of the retina, RGCs can not be clearly divided into functional subtypes. We found that in
photopic conditions, which implies more prominent natural scene statistic differences across
the visual field, response properties can be exhibited by cells differently depending on their
location in the retina, which leads to formation of a gradient of features rather than distinct
classes.
This finding suggests that RGCs follow a global organization across the visual field of the
animal, adapting each RGC subtype to the requirements imposed by the natural scene statistics.},
  author       = {Kirillova, Kseniia},
  issn         = {2791-4585},
  pages        = {46},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Panoramic functional gradients across the mouse retina}},
  doi          = {10.15479/at:ista:12531},
  year         = {2023},
}

@article{12349,
  abstract     = {Statistics of natural scenes are not uniform - their structure varies dramatically from ground to sky. It remains unknown whether these non-uniformities are reflected in the large-scale organization of the early visual system and what benefits such adaptations would confer. Here, by relying on the efficient coding hypothesis, we predict that changes in the structure of receptive fields across visual space increase the efficiency of sensory coding. We show experimentally that, in agreement with our predictions, receptive fields of retinal ganglion cells change their shape along the dorsoventral retinal axis, with a marked surround asymmetry at the visual horizon. Our work demonstrates that, according to principles of efficient coding, the panoramic structure of natural scenes is exploited by the retina across space and cell-types.},
  author       = {Gupta, Divyansh and Mlynarski, Wiktor F and Sumser, Anton L and Symonova, Olga and Svaton, Jan and Jösch, Maximilian A},
  issn         = {1546-1726},
  journal      = {Nature Neuroscience},
  pages        = {606--614},
  publisher    = {Springer Nature},
  title        = {{Panoramic visual statistics shape retina-wide organization of receptive fields}},
  doi          = {10.1038/s41593-023-01280-0},
  volume       = {26},
  year         = {2023},
}

@misc{12370,
  abstract     = {Statistics of natural scenes are not uniform - their structure varies dramatically from ground to sky. It remains unknown whether these non-uniformities are reflected in the large-scale organization of the early visual system and what benefits such adaptations would confer. Here, by relying on the efficient coding hypothesis, we predict that changes in the structure of receptive fields across visual space increase the efficiency of sensory coding. We show experimentally that, in agreement with our predictions, receptive fields of retinal ganglion cells change their shape along the dorsoventral retinal axis, with a marked surround asymmetry at the visual horizon. Our work demonstrates that, according to principles of efficient coding, the panoramic structure of natural scenes is exploited by the retina across space and cell-types. },
  author       = {Gupta, Divyansh and Sumser, Anton L and Jösch, Maximilian A},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Research Data for: Panoramic visual statistics shape retina-wide organization of receptive fields}},
  doi          = {10.15479/AT:ISTA:12370},
  year         = {2023},
}

@article{12226,
  abstract     = {Background: Biases of DNA repair can shape the nucleotide landscape of genomes at evolutionary timescales. The molecular mechanisms of those biases are still poorly understood because it is difficult to isolate the contributions of DNA repair from those of DNA damage.

Results: Here, we develop a genome-wide assay whereby the same DNA lesion is repaired in different genomic contexts. We insert thousands of barcoded transposons carrying a reporter of DNA mismatch repair in the genome of mouse embryonic stem cells. Upon inducing a double-strand break between tandem repeats, a mismatch is generated if the break is repaired through single-strand annealing. The resolution of the mismatch showed a 60–80% bias in favor of the strand with the longest 3′ flap. The location of the lesion in the genome and the type of mismatch had little influence on the bias. Instead, we observe a complete reversal of the bias when the longest 3′ flap is moved to the opposite strand by changing the position of the double-strand break in the reporter.

Conclusions: These results suggest that the processing of the double-strand break has a major influence on the repair of mismatches during single-strand annealing.},
  author       = {Pokusaeva, Victoria and Diez, Aránzazu Rosado and Espinar, Lorena and Pérez, Albert Torelló and Filion, Guillaume J.},
  issn         = {1474-760X},
  journal      = {Genome Biology},
  publisher    = {Springer Nature},
  title        = {{Strand asymmetry influences mismatch resolution during single-strand annealing}},
  doi          = {10.1186/s13059-022-02665-3},
  volume       = {23},
  year         = {2022},
}

@article{12288,
  abstract     = {To understand the function of neuronal circuits, it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low throughput, low selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotropic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of ‘starter’ AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the mouse hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.},
  author       = {Sumser, Anton L and Jösch, Maximilian A and Jonas, Peter M and Ben Simon, Yoav},
  issn         = {2050-084X},
  journal      = {eLife},
  keywords     = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Medicine, General Neuroscience},
  publisher    = {eLife Sciences Publications},
  title        = {{Fast, high-throughput production of improved rabies viral vectors for specific, efficient and versatile transsynaptic retrograde labeling}},
  doi          = {10.7554/elife.79848},
  volume       = {11},
  year         = {2022},
}

@article{15268,
  abstract     = {Apolipoprotein A‐I (apoA‐I) has a key function in the reverse cholesterol transport. However, aggregation of apoA‐I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural consequences introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA‐I. We combined evolutionary studies, in silico mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation‐prone regions (APRs) present in apoA‐I. Sequence analysis demonstrated that among the four amyloidogenic regions described for human apoA‐I, only two (APR1 and APR4) are evolutionary conserved across different species of Sarcopterygii. Moreover, stability analysis carried out with the FoldX engine showed that APR1 contributes to the marginal stability of apoA‐I. Structural properties of full‐length apoA‐I models suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its native fold. Compared to silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of amyloid mutations showed evidence of a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the alpha‐helix bundle with the concomitant exposure of APR1 to the solvent, suggesting an insight into the early steps involved in its aggregation. Our findings highlight APR1 as a relevant component for apoA‐I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of this region.},
  author       = {Gisonno, Romina A. and Masson, Tomas and Ramella, Nahuel A. and Barrera, Exequiel E. and Romanowski, Víctor and Tricerri, M. Alejandra},
  issn         = {1097-0134},
  journal      = {Proteins: Structure, Function, and Bioinformatics},
  keywords     = {Molecular Biology, Biochemistry, Structural Biology},
  number       = {1},
  pages        = {258--269},
  publisher    = {Wiley},
  title        = {{Evolutionary and structural constraints influencing apolipoprotein A‐I amyloid behavior}},
  doi          = {10.1002/prot.26217},
  volume       = {90},
  year         = {2022},
}

@article{17071,
  abstract     = {The eukaryotic nucleus pro­tects the genome and is enclosed by the two membranes of the nuclear envelope. Nuclear pore complexes (NPCs) perforate the nuclear envelope to facilitate nucleocytoplasmic transport. With a molecular weight of ∼120 MDa, the human NPC is one of the larg­est protein complexes. Its ~1000 proteins are taken in multiple copies from a set of about 30 distinct nucleoporins (NUPs). They can be roughly categorized into two classes. Scaf­fold NUPs contain folded domains and form a cylindrical scaffold architecture around a central channel. Intrinsically disordered NUPs line the scaffold and extend into the central channel, where they interact with cargo complexes. The NPC architecture is highly dynamic. It responds to changes in nuclear envelope tension with conforma­tional breathing that manifests in dilation and constriction movements. Elucidating the scaffold architecture, ultimately at atomic resolution, will be important for gaining a more precise understanding of NPC function and dynamics but imposes a substantial chal­lenge for structural biologists.
Considerable progress has been made toward this goal by a joint effort in the field. A synergistic combination of complementary approaches has turned out to be critical. In situ structural biology techniques were used to reveal the overall layout of the NPC scaffold that defines the spatial reference for molecular modeling. High-resolution structures of many NUPs were determined in vitro. Proteomic analysis and extensive biochemical work unraveled the interaction network of NUPs. Integra­tive modeling has been used to combine the different types of data, resulting in a rough outline of the NPC scaffold. Previous struc­tural models of the human NPC, however, were patchy and limited in accuracy owing to several challenges: (i) Many of the high-resolution structures of individual NUPs have been solved from distantly related species and, consequently, do not comprehensively cover their human counterparts. (ii) The scaf­fold is interconnected by a set of intrinsically disordered linker NUPs that are not straight­forwardly accessible to common structural biology techniques. (iii) The NPC scaffold intimately embraces the fused inner and outer nuclear membranes in a distinctive topol­ogy and cannot be studied in isolation. (iv) The conformational dynamics of scaffold NUPs limits the resolution achievable in structure determination.
In this study, we used artificial intelligence (AI)–based prediction to generate an exten­sive repertoire of structural models of human NUPs and their subcomplexes. The resulting models cover various domains and interfaces that so far remained structurally uncharac­terized. Benchmarking against previous and unpublished x-ray and cryo–electron micros­copy structures revealed unprecedented accu­racy. We obtained well-resolved cryo–electron tomographic maps of both the constricted and dilated conformational states of the hu­man NPC. Using integrative modeling, we fit­ted the structural models of individual NUPs into the cryo–electron microscopy maps. We explicitly included several linker NUPs and traced their trajectory through the NPC scaf­fold. We elucidated in great detail how mem­brane-associated and transmembrane NUPs are distributed across the fusion topology of both nuclear membranes. The resulting architectural model increases the structural coverage of the human NPC scaffold by about twofold. We extensively validated our model against both earlier and new experimental data. The completeness of our model has enabled microsecond-long coarse-grained molecular dynamics simulations of the NPC scaffold within an explicit membrane en­vironment and solvent. These simulations reveal that the NPC scaffold prevents the constriction of the otherwise stable double-membrane fusion pore to small diameters in the absence of membrane tension
Our 70-MDa atomically re­solved model covers >90% of the human NPC scaffold. It captures conforma­tional changes that occur during dilation and constriction. It also reveals the precise anchoring sites for intrinsically disordered NUPs, the identification of which is a prerequisite for a complete and dy­namic model of the NPC. Our study exempli­fies how AI-based structure prediction may accelerate the elucidation of subcellular ar­chitecture at atomic resolution.},
  author       = {Mosalaganti, Shyamal and Obarska-Kosinska, Agnieszka and Siggel, Marc and Taniguchi, Reiya and Turoňová, Beata and Zimmerli, Christian E. and Buczak, Katarzyna and Schmidt, Florian and Margiotta, Erica and Mackmull, Marie-Therese and Hagen, Wim J. H. and Hummer, Gerhard and Kosinski, Jan and Beck, Martin},
  issn         = {1095-9203},
  journal      = {Science},
  number       = {6598},
  publisher    = {American Association for the Advancement of Science},
  title        = {{AI-based structure prediction empowers integrative structural analysis of human nuclear pores}},
  doi          = {10.1126/science.abm9506},
  volume       = {376},
  year         = {2022},
}