Trail using ants follow idiosyncratic routes in complex landscapes.

A large volume of research on individually navigating ants has shown how path integration and visually guided navigation form a major part of the ant navigation toolkit for many species and are sufficient mechanisms for successful navigation. One of the behavioural markers of the interaction of these mechanisms is that experienced foragers develop idiosyncratic routes that require that individual ants have personal and unique visual memories that they use to guide habitual routes between the nest and feeding sites. The majority of ants, however, inhabit complex cluttered environments and social pheromone trails are often part of the collective recruitment, organisation and navigation of these foragers. We do not know how individual navigation interacts with collective behaviour along shared trails in complex natural environments. We thus asked here if wood ants that forage through densely cluttered woodlands where they travel along shared trails repeatedly follow the same routes or if they choose a spread of paths within the shared trail. We recorded three long homing trajectories of 20 individual wood ants in their natural woodland habitat. We found that wood ants follow idiosyncratic routes when navigating along shared trails through highly complex visual landscapes. This shows that ants rely on individual memories for habitual route guidance even in cluttered environments when chemical trail information is available. We argue that visual cues are likely to be the dominant sensory modality for the idiosyncratic routes. These experiments shed new light on how ants, or insects in general, navigate through complex multimodal environments.

The Drosophila NCAM homolog Fas2 signals independently of adhesion.

The development of tissues and organs requires close interaction of cells. To achieve this, cells express adhesion proteins such as the neural cell adhesion molecule (NCAM) or its Drosophila ortholog Fasciclin 2 (Fas2). Both are members of the Ig-domain superfamily of proteins that mediate homophilic adhesion. These proteins are expressed as isoforms differing in their membrane anchorage and their cytoplasmic domains. To study the function of single isoforms, we have conducted a comprehensive genetic analysis of Fas2 We reveal the expression pattern of all major Fas2 isoforms, two of which are GPI anchored. The remaining five isoforms carry transmembrane domains with variable cytoplasmic tails. We generated Fas2 mutants expressing only single isoforms. In contrast to the null mutation, which causes embryonic lethality, these mutants are viable, indicating redundancy among the different isoforms. Cell type-specific rescue experiments showed that glial-secreted Fas2 can rescue the Fas2 mutant phenotype to viability. This demonstrates that cytoplasmic Fas2 domains have no apparent essential functions and indicate that Fas2 has function(s) other than homophilic adhesion. In conclusion, our data suggest novel mechanistic aspects of a long-studied adhesion protein.

Inverse design of nanophotonic devices using dynamic binarization.

The complexity of applications addressed with photonic integrated circuits is steadily rising and poses increasingly challenging demands on individual component functionality, performance and footprint. Inverse design methods have recently shown great promise to address these demands using fully automated design procedures that enable access to non-intuitive device layouts beyond conventional nanophotonic design concepts. Here we present a dynamic binarization method for the objective-first algorithm that lies at the core of the currently most successful inverse design algorithms. Our results demonstrate significant performance advantages over previous implementations of objective first algorithms, which we show for a fundamental TE00 to TE20 waveguide mode converter both in simulation and in experiments with fabricated devices.

From skylight input to behavioural output: A computational model of the insect polarised light compass.

Many insects navigate by integrating the distances and directions travelled on an outward path, allowing direct return to the starting point. Fundamental to the reliability of this process is the use of a neural compass based on external celestial cues. Here we examine how such compass information could be reliably computed by the insect brain, given realistic constraints on the sky polarisation pattern and the insect eye sensor array. By processing the degree of polarisation in different directions for different parts of the sky, our model can directly estimate the solar azimuth and also infer the confidence of the estimate. We introduce a method to correct for tilting of the sensor array, as might be caused by travel over uneven terrain. We also show that the confidence can be used to approximate the change in sun position over time, allowing the compass to remain fixed with respect to 'true north' during long excursions. We demonstrate that the compass is robust to disturbances and can be effectively used as input to an existing neural model of insect path integration. We discuss the plausibility of our model to be mapped to known neural circuits, and to be implemented for robot navigation.

FIMTrack: An open source tracking and locomotion analysis software for small animals.

Imaging and analyzing the locomotion behavior of small animals such as Drosophila larvae or C. elegans worms has become an integral subject of biological research. In the past we have introduced FIM, a novel imaging system feasible to extract high contrast images. This system in combination with the associated tracking software FIMTrack is already used by many groups all over the world. However, so far there has not been an in-depth discussion of the technical aspects. Here we elaborate on the implementation details of FIMTrack and give an in-depth explanation of the used algorithms. Among others, the software offers several tracking strategies to cover a wide range of different model organisms, locomotion types, and camera properties. Furthermore, the software facilitates stimuli-based analysis in combination with built-in manual tracking and correction functionalities. All features are integrated in an easy-to-use graphical user interface. To demonstrate the potential of FIMTrack we provide an evaluation of its accuracy using manually labeled data. The source code is available under the GNU GPLv3 at https://github.com/i-git/FIMTrack and pre-compiled binaries for Windows and Mac are available at http://fim.uni-muenster.de.

The Drosophila FHOD1-like formin Knittrig acts through Rok to promote stress fiber formation and directed macrophage migration during the cellular immune response.

A tight spatiotemporal control of actin polymerization is important for many cellular processes that shape cells into a multicellular organism. The formation of unbranched F-actin is induced by several members of the formin family. Drosophila encodes six formin genes, representing six of the seven known mammalian subclasses. Knittrig, the Drosophila homolog of mammalian FHOD1, is specifically expressed in the developing central nervous system midline glia, the trachea, the wing and in macrophages. knittrig mutants exhibit mild tracheal defects but survive until late pupal stages and mainly die as pharate adult flies. knittrig mutant macrophages are smaller and show reduced cell spreading and cell migration in in vivo wounding experiments. Rescue experiments further demonstrate a cell-autonomous function of Knittrig in regulating actin dynamics and cell migration. Knittrig localizes at the rear of migrating macrophages in vivo, suggesting a cellular requirement of Knittrig in the retraction of the trailing edge. Supporting this notion, we found that Knittrig is a target of the Rho-dependent kinase Rok. Co-expression with Rok or expression of an activated form of Knittrig induces actin stress fibers in macrophages and in epithelial tissues. Thus, we propose a model in which Rok-induced phosphorylation of residues within the basic region mediates the activation of Knittrig in controlling macrophage migration.

The Ol1mpiad: concordance of behavioural faculties of stage 1 and stage 3 Drosophila larvae.

Mapping brain function to brain structure is a fundamental task for neuroscience. For such an endeavour, the Drosophila larva is simple enough to be tractable, yet complex enough to be interesting. It features about 10,000 neurons and is capable of various taxes, kineses and Pavlovian conditioning. All its neurons are currently being mapped into a light-microscopical atlas, and Gal4 strains are being generated to experimentally access neurons one at a time. In addition, an electron microscopic reconstruction of its nervous system seems within reach. Notably, this electron microscope-based connectome is being drafted for a stage 1 larva - because stage 1 larvae are much smaller than stage 3 larvae. However, most behaviour analyses have been performed for stage 3 larvae because their larger size makes them easier to handle and observe. It is therefore warranted to either redo the electron microscopic reconstruction for a stage 3 larva or to survey the behavioural faculties of stage 1 larvae. We provide the latter. In a community-based approach we called the Ol1mpiad, we probed stage 1 Drosophila larvae for free locomotion, feeding, responsiveness to substrate vibration, gentle and nociceptive touch, burrowing, olfactory preference and thermotaxis, light avoidance, gustatory choice of various tastants plus odour-taste associative learning, as well as light/dark-electric shock associative learning. Quantitatively, stage 1 larvae show lower scores in most tasks, arguably because of their smaller size and lower speed. Qualitatively, however, stage 1 larvae perform strikingly similar to stage 3 larvae in almost all cases. These results bolster confidence in mapping brain structure and behaviour across developmental stages.

Therapy-induced modulation of tumor vasculature and oxygenation in a murine glioblastoma model quantified by deep learning-based feature extraction.

Glioblastoma presents characteristically with an exuberant, poorly functional vasculature that causes malperfusion, hypoxia and necrosis. Despite limited clinical efficacy, anti-angiogenesis resulting in vascular normalization remains a promising therapeutic approach. Yet, fundamental questions concerning anti-angiogenic therapy remain unanswered, partly due to the scale and resolution gap between microscopy and clinical imaging and a lack of quantitative data readouts. To what extend does treatment lead to vessel regression or vessel normalization and does it ameliorate or aggravate hypoxia? Clearly, a better understanding of the underlying mechanisms would greatly benefit the development of desperately needed improved treatment regimens. Here, using orthotopic transplantation of Gli36 cells, a widely used murine glioma model, we present a mesoscopic approach based on light sheet fluorescence microscopic imaging of wholemount stained tumors. Deep learning-based segmentation followed by automated feature extraction allowed quantitative analyses of the entire tumor vasculature and oxygenation statuses. Unexpectedly in this model, the response to both cytotoxic and anti-angiogenic therapy was dominated by vessel normalization with little evidence for vessel regression. Equally surprising, only cytotoxic therapy resulted in a significant alleviation of hypoxia. Taken together, we provide and evaluate a quantitative workflow that addresses some of the most urgent mechanistic questions in anti-angiogenic therapy.

Deep learning predicts therapy-relevant genetics in acute myeloid leukemia from Pappenheim-stained bone marrow smears.

ABSTRACT: The detection of genetic aberrations is crucial for early therapy decisions in acute myeloid leukemia (AML) and recommended for all patients. Because genetic testing is expensive and time consuming, a need remains for cost-effective, fast, and broadly accessible tests to predict these aberrations in this aggressive malignancy. Here, we developed a novel fully automated end-to-end deep learning pipeline to predict genetic aberrations directly from single-cell images from scans of conventionally stained bone marrow smears already on the day of diagnosis. We used this pipeline to compile a multiterabyte data set of >2 000 000 single-cell images from diagnostic samples of 408 patients with AML. These images were then used to train convolutional neural networks for the prediction of various therapy-relevant genetic alterations. Moreover, we created a temporal test cohort data set of >444 000 single-cell images from further 71 patients with AML. We show that the models from our pipeline can significantly predict these subgroups with high areas under the curve of the receiver operating characteristic. Potential genotype-phenotype links were visualized with 2 different strategies. Our pipeline holds the potential to be used as a fast and inexpensive automated tool to screen patients with AML for therapy-relevant genetic aberrations directly from routine, conventionally stained bone marrow smears already on the day of diagnosis. It also creates a foundation to develop similar approaches for other bone marrow disorders in the future.

Human fertilization in vivo and in vitro requires the CatSper channel to initiate sperm hyperactivation.

The infertility of many couples rests on an enigmatic dysfunction of the man's sperm. To gain insight into the underlying pathomechanisms, we assessed the function of the sperm-specific multisubunit CatSper-channel complex in the sperm of almost 2,300 men undergoing a fertility workup, using a simple motility-based test. We identified a group of men with normal semen parameters but defective CatSper function. These men or couples failed to conceive naturally and upon medically assisted reproduction via intrauterine insemination and in vitro fertilization. Intracytoplasmic sperm injection (ICSI) was, ultimately, required to conceive a child. We revealed that the defective CatSper function was caused by variations in CATSPER genes. Moreover, we unveiled that CatSper-deficient human sperm were unable to undergo hyperactive motility and, therefore, failed to penetrate the egg coat. Thus, our study provides the experimental evidence that sperm hyperactivation is required for human fertilization, explaining the infertility of CatSper-deficient men and the need of ICSI for medically assisted reproduction. Finally, our study also revealed that defective CatSper function and ensuing failure to hyperactivate represents the most common cause of unexplained male infertility known thus far and that this sperm channelopathy can readily be diagnosed, enabling future evidence-based treatment of affected couples.

A Systematic Evaluation of Machine Learning-Based Biomarkers for Major Depressive Disorder.

Importance: Biological psychiatry aims to understand mental disorders in terms of altered neurobiological pathways. However, for one of the most prevalent and disabling mental disorders, major depressive disorder (MDD), no informative biomarkers have been identified. Objective: To evaluate whether machine learning (ML) can identify a multivariate biomarker for MDD. Design, Setting, and Participants: This study used data from the Marburg-Münster Affective Disorders Cohort Study, a case-control clinical neuroimaging study. Patients with acute or lifetime MDD and healthy controls aged 18 to 65 years were recruited from primary care and the general population in Münster and Marburg, Germany, from September 11, 2014, to September 26, 2018. The Münster Neuroimaging Cohort (MNC) was used as an independent partial replication sample. Data were analyzed from April 2022 to June 2023. Exposure: Patients with MDD and healthy controls. Main Outcome and Measure: Diagnostic classification accuracy was quantified on an individual level using an extensive ML-based multivariate approach across a comprehensive range of neuroimaging modalities, including structural and functional magnetic resonance imaging and diffusion tensor imaging as well as a polygenic risk score for depression. Results: Of 1801 included participants, 1162 (64.5%) were female, and the mean (SD) age was 36.1 (13.1) years. There were a total of 856 patients with MDD (47.5%) and 945 healthy controls (52.5%). The MNC replication sample included 1198 individuals (362 with MDD [30.1%] and 836 healthy controls [69.9%]). Training and testing a total of 4 million ML models, mean (SD) accuracies for diagnostic classification ranged between 48.1% (3.6%) and 62.0% (4.8%). Integrating neuroimaging modalities and stratifying individuals based on age, sex, treatment, or remission status does not enhance model performance. Findings were replicated within study sites and also observed in structural magnetic resonance imaging within MNC. Under simulated conditions of perfect reliability, performance did not significantly improve. Analyzing model errors suggests that symptom severity could be a potential focus for identifying MDD subgroups. Conclusion and Relevance: Despite the improved predictive capability of multivariate compared with univariate neuroimaging markers, no informative individual-level MDD biomarker-even under extensive ML optimization in a large sample of diagnosed patients-could be identified.

Kinesin heavy chain function in Drosophila glial cells controls neuronal activity.

Kinesin heavy chain (Khc) is crucially required for axonal transport and khc mutants show axonal swellings and paralysis. Here, we demonstrate that in Drosophila khc is equally important in glial cells. Glial-specific downregulation of khc by RNA interference suppresses neuronal excitability and results in spastic flies. The specificity of the phenotype was verified by interspecies rescue experiments and further mutant analyses. Khc is mostly required in the subperineurial glia forming the blood-brain barrier. Following glial-specific knockdown, peripheral nerves are swollen with maldistributed mitochondria. To better understand khc function, we determined Khc-dependent Rab proteins in glia and present evidence that Neurexin IV, a well known blood-brain barrier constituent, is one of the relevant cargo proteins. Our work shows that the role of Khc for neuronal excitability must be considered in the light of its necessity for directed transport in glia.

Immersive training of clinical decision making with AI driven virtual patients - a new VR platform called medical tr.AI.ning.

Background: Medical students need to be prepared for various situations in clinical decision-making that cannot be systematically trained with real patients without risking their health or integrity. To target system-related limitations of actor-based training, digital learning methods are increasingly used in medical education, with virtual reality (VR)- training seeming to have high potential. Virtually generated training scenarios allow repetitive training of highly relevant clinical skills within a protected, realistic learning environment. Thanks to Artificial Intelligence (AI), face-to-face interaction with virtual agents is feasible. Combining this technology with VR-simulations offers a new way of situated context-based, first-person training for medical students. Project goal and method: The authors' aim is to develop a modular digital training platform for medical education with virtual, interactable agents and to integrate this platform into the medical curriculum. The medical tr.AI.ning platform will provide veridical simulation of clinical scenarios with virtual patients, augmented with highly realistic medical pathologies within a customizable, realistic situational context. Medical tr.AI.ning is scaled to four complementary developmental steps with different scenarios that can be used separately and so each outcome can successively be integrated early within the project. Every step has its own focus (visual, movement, communication, combination) and extends an author toolbox through its modularity. The modules of each step will be specified and designed together with medical didactics experts. Perspective: To ensure constant improvement of user experience, realism, and medical validity, the authors will perform regular iterative evaluation rounds.Furthermore, integration of medical tr.AI.ning into the medical curriculum will enable long-term and large-scale detection of benefits and limitations of this approach, providing enhanced alternative teaching paradigms for VR technology.

CATER: Combined Animal Tracking & Environment Reconstruction.

Quantifying the behavior of small animals traversing long distances in complex environments is one of the most difficult tracking scenarios for computer vision. Tiny and low-contrast foreground objects have to be localized in cluttered and dynamic scenes as well as trajectories compensated for camera motion and drift in multiple lengthy recordings. We introduce CATER, a novel methodology combining an unsupervised probabilistic detection mechanism with a globally optimized environment reconstruction pipeline enabling precision behavioral quantification in natural environments. Implemented as an easy to use and highly parallelized tool, we show its application to recover fine-scale motion trajectories, registered to a high-resolution image mosaic reconstruction, of naturally foraging desert ants from unconstrained field recordings. By bridging the gap between laboratory and field experiments, we gain previously unknown insights into ant navigation with respect to motivational states, previous experience, and current environments and provide an appearance-agnostic method applicable to study the behavior of a wide range of terrestrial species under realistic conditions.

Event-driven adaptive optical neural network.

We present an adaptive optical neural network based on a large-scale event-driven architecture. In addition to changing the synaptic weights (synaptic plasticity), the optical neural network's structure can also be reconfigured enabling various functionalities (structural plasticity). Key building blocks are wavelength-addressable artificial neurons with embedded phase-change materials that implement nonlinear activation functions and nonvolatile memory. Using multimode focusing, the activation function features both excitatory and inhibitory responses and shows a reversible switching contrast of 3.2 decibels. We train the neural network to distinguish between English and German text samples via an evolutionary algorithm. We investigate both the synaptic and structural plasticity during the training process. On the basis of this concept, we realize a large-scale network consisting of 736 subnetworks with 16 phase-change material neurons each. Overall, 8398 neurons are functional, highlighting the scalability of the photonic architecture.

An overview and a roadmap for artificial intelligence in hematology and oncology.

BACKGROUND: Artificial intelligence (AI) is influencing our society on many levels and has broad implications for the future practice of hematology and oncology. However, for many medical professionals and researchers, it often remains unclear what AI can and cannot do, and what are promising areas for a sensible application of AI in hematology and oncology. Finally, the limits and perils of using AI in oncology are not obvious to many healthcare professionals. METHODS: In this article, we provide an expert-based consensus statement by the joint Working Group on "Artificial Intelligence in Hematology and Oncology" by the German Society of Hematology and Oncology (DGHO), the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), and the Special Interest Group Digital Health of the German Informatics Society (GI). We provide a conceptual framework for AI in hematology and oncology. RESULTS: First, we propose a technological definition, which we deliberately set in a narrow frame to mainly include the technical developments of the last ten years. Second, we present a taxonomy of clinically relevant AI systems, structured according to the type of clinical data they are used to analyze. Third, we show an overview of potential applications, including clinical, research, and educational environments with a focus on hematology and oncology. CONCLUSION: Thus, this article provides a point of reference for hematologists and oncologists, and at the same time sets forth a framework for the further development and clinical deployment of AI in hematology and oncology in the future.

Volumetric imaging reveals VEGF-C-dependent formation of hepatic lymph vessels in mice.

The liver is a major biosynthetic and detoxifying organ in vertebrates, but also generates 25%-50% of the lymph passing through the thoracic duct and is thereby the organ with the highest contribution to lymph flow. In contrast to its metabolic function, the role of the liver for lymph generation and composition is presently severely understudied. We took a rigorous, volume imaging-based approach to describe the microarchitecture and spatial composition of the hepatic lymphatic vasculature with cellular resolution in whole mount immune stained specimen ranging from thick sections up to entire mouse liver lobes. Here, we describe that in healthy adult livers, lymphatic vessels were exclusively located within the portal tracts, where they formed a unique, highly ramified tree. Ragged, spiky initials enmeshed the portal veins along their entire length and communicated with long lymphatic vessels that followed the path of the portal vein in close association with bile ducts. Together these lymphatic vessels formed a uniquely shaped vascular bed with a delicate architecture highly adapted to the histological structure of the liver. Unexpectedly, with the exception of short collector stretches at the porta hepatis, which we identified as exit point of the liver lymph vessels, the entire hepatic lymph vessel system was comprised of capillary lymphatic endothelial cells only. Functional experiments confirmed the space of Disse as the origin of the hepatic lymph and flow via the space of Mall to the portal lymph capillaries. After entry into the lymphatic initials, the lymph drained retrograde to the portal blood flow towards the exit at the liver hilum. Perinatally, the liver undergoes complex changes transforming from the main hematopoietic to the largest metabolic organ. We investigated the time course of lymphatic vessel development and identified the hepatic lymphatics to emerge postnatally in a process that relies on input from the VEGF-C/VERGFR-3 growth factor-receptor pair for formation of the fully articulate hepatic lymph vessel bed.

Perspectives in machine learning for wildlife conservation.

Inexpensive and accessible sensors are accelerating data acquisition in animal ecology. These technologies hold great potential for large-scale ecological understanding, but are limited by current processing approaches which inefficiently distill data into relevant information. We argue that animal ecologists can capitalize on large datasets generated by modern sensors by combining machine learning approaches with domain knowledge. Incorporating machine learning into ecological workflows could improve inputs for ecological models and lead to integrated hybrid modeling tools. This approach will require close interdisciplinary collaboration to ensure the quality of novel approaches and train a new generation of data scientists in ecology and conservation.

An uncertainty-aware, shareable, and transparent neural network architecture for brain-age modeling.

The deviation between chronological age and age predicted from neuroimaging data has been identified as a sensitive risk marker of cross-disorder brain changes, growing into a cornerstone of biological age research. However, machine learning models underlying the field do not consider uncertainty, thereby confounding results with training data density and variability. Also, existing models are commonly based on homogeneous training sets, often not independently validated, and cannot be shared because of data protection issues. Here, we introduce an uncertainty-aware, shareable, and transparent Monte Carlo dropout composite quantile regression (MCCQR) Neural Network trained on N = 10,691 datasets from the German National Cohort. The MCCQR model provides robust, distribution-free uncertainty quantification in high-dimensional neuroimaging data, achieving lower error rates compared with existing models. In two examples, we demonstrate that it prevents spurious associations and increases power to detect deviant brain aging. We make the pretrained model and code publicly available.

Resolving Colliding Larvae by Fitting ASM to Random Walker-Based Pre-Segmentations.

Drosophila melanogaster is an important model organism for research in neuro- and behavioral biology. Automated studies of their locomotion are crucial to link sensory input and neural processing to motor output which has led to numerous vision-based tracking systems. However, most of these approaches share the inability to segment the contours of colliding animals causing identity losses, appearing and disappearing animals, and the absence of posture and motion related measurements during the time of the collision. We present a novel collision resolution algorithm enabling an accurate contour segmentation of multiple touching Drosophila larvae. Our algorithm utilizes an adapted active shape model (ASM) to learn a low dimensional posture space which is fitted to random-walker generated pre-segmentations. We evaluate our collision resolution algorithm using three publicly available datasets and compare it with the current state-of-the-art methods. In addition, we introduce a refined dataset enabling a segmentation evaluation on the level of pixel accuracy. The results demonstrate that our approach outperforms the state-of-the-art approaches in both accuracy and computational time. We will incorporate this algorithm into our widely used tracking program to improve the statistical strength of the behavioral quantification and allow marker-free studies of interacting Drosophila larvae.