Biology subjects

Neumann, J.

Publications and source records attributed to Neumann, J..

At least 19 recordsLinked to original sources

bioRxiv2026

On the evolution of emergence patterns driven by environmental cycles

Regular environmental cycles such as day and night or the lunar cycle are ubiquitous and drive many biological processes. Many organisms have evolved endogenous time-keeping mechanisms to anticipate these cycles to accurately time their behavior or synchronize physiological processes. The evolution of such synchronization to environmental cycles and their variability is not very well understood. As an example, we use the marine insect Clunio (Diptera, Chironomidae), which synchronize adult emergence and reproduction with the lunar cycle, and show different emergence patterns across populations. We use a model constructed with replicator-mutator dynamics to provide a novel outlook at the evolution of these emergence patterns. In particular, we investigate the effect of two traits of individual phenotypic variability of emergence, the spread and shape, on population-wide emergence patterns. We find that the semilunar and lunar emergence patterns are alternatively stable and occur when the phenotypic distribution has a narrow and is roughly flat. Arrhythmic emergence occurs when the phenotypic distribution is wide and nearly flat. The semi-lunar pattern can only be observed when the parameter of rhythmicity is changed. With our model, we introduce the concepts of frequency-dependent selection and individual phenotypic variability into the theory of chronobiology, which gives us insights into the evolution of rhythmicity in these organisms.

evolutionary biology↗

bioRxiv2026

Droplet single-cell CRISPR screens identify regulators of T cell-mediated target-cell killing

Cytotoxic CD8 T cells kill target cells through brief cell-cell encounters, but pooled genetic screens cannot readily link perturbations in individual T cells to the fate of the target cells they engage. We developed droplet single-cell CRISPR screening to pair individual primary human CD8 T cells with cancer cells, measure rapid target-cell death, and recover sgRNAs from phenotype-defined droplets. Applied across primary T cells from multiple donors, the platform recovered regulators of T cell receptor signaling, synapse formation, granule exocytosis and cytotoxic differentiation, and identified negative regulators of killing, including established inhibitory nodes such as PTEN, RASA2 and FOXO1, together with AFAP1L2 and components of the mTORC1 pathway. Validation across bispecific engager and TCR-engineered settings showed that selected hits modulate target-cell killing across recognition modalities and tumor models. Unexpectedly, perturbation of RPTOR or RHEB enhanced cytotoxic execution while reducing mTORC1 output, increasing AKT phosphorylation, and attenuating anabolic programs. Transient pharmacologic mTORC1 inhibition reproduced this rapid-killing state and improved antitumor activity after adoptive transfer. These results establish an interaction-resolved pooled genetic strategy for mapping cytotoxicity regulators and reveal that transient modulation of mTORC1 can shift T cells from anabolic growth toward rapid cytotoxic execution to enhance antitumor activity.

immunology↗

bioRxiv2026

Robot-based 3D-multispectral monitoring of soybean in a spatially heterogenous agrivoltaic environment

Agrophotovoltaic (APV) systems provide a unique opportunity for improving agricultural land-use efficiency by combining solar energy capture via photovoltaic panels with crop production. However, in-depth information on plant growth patterns within the spatially heterogenous microclimate created by the intermittent shading of APVs is largely missing. In the present study, we implement a customized robot-mounted 3D-multispectral imaging system to closely monitor the growth and spectral reflectance patterns of a conventional soybean cultivar "Eiko" (EK) and a chlorophyll-deficient mutant variety MinnGold (MG) under an APV system. Weekly trends in canopy morphometric features revealed significant variations in plant height, 3D leaf area, light penetration, and canopy volume across the APV field depending on the proximity with the overhead solar panels for both EK and MG, with plants receiving adequate rainfall and intermittent shade performing the best. Furthermore, although spectral indices exhibited variations between EK and MG due to intrinsic differences in pigmentation, symptoms of stress could be detected for both genotypes within rain-shaded areas of the APV plot. Hence, the present investigation depicts the potential for complementary usage of robotics and machine vision for high-precision high-throughput crop monitoring under APVs, which would enable better crop management within such non-homogenous cultivation systems.

plant biology↗

bioRxiv2025

A computational SOX10 network-based selection strategy to identify new drug targets in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), effective treatment options for metastatic UM are limited. The transcription factor SOX10 is crucial for CM initiation and survival, making it an interesting candidate for new targeted therapies, but its relevance in UM was unclear. We found that SOX10 was widely expressed in UM and essential for proliferation, cell cycle progression, and survival. The effects were partially mediated by SOX10-related genes including MITF, highlighting high addiction of UM to the SOX10-MITF axis. Additionally, SOX10 knockdown induced massive transcriptomic changes. Due to a lack of specific inhibitors of SOX10 and MITF, a computational approach was used to identify druggable targets by curating a UM-specific protein interaction network to search for candidates downregulated upon SOX10 inhibition. Thereby, the E2F transcription factor family was identified and their potential as druggable target candidates in UM was confirmed using the pan-E2F inhibitor HLM006474, resulting in cell cycle arrest and apoptosis. Taken together, SOX10 is crucial for UM survival and SOX10-associated proteins may serve as promising targets for developing new therapeutic strategies in UM.

cancer biology↗

bioRxiv2025

Functional immune profiling reveals CD4+ T cell dysregulation associated with celiac disease

T cells integrate signals from antigen and co-stimulatory receptors to calibrate the strength and quality of their responses. This signal integration is influenced by genetic background, which can modulate thresholds for immune tolerance and strength of responses to threat. Celiac disease (CeD) is an autoimmune disorder driven by well-defined genetic risk and characterised by immune dysregulation in response to dietary gluten. However, whether sensitivity or response differences in naive T cell programming contributes to disease susceptibility is not known. To investigate such variation, we developed a sensitive quantitative platform, the momentum assay, which combines standardised, T cell activation with subsequent stimulus withdrawal, enabling measurement of T cell proliferation and survival over time. This assay is integrated with the Cyton2 mathematical model to infer underlying cellular timer programs from population-level dynamics. We applied this method to assess whether naive T cells from individuals with celiac disease (CeD) exhibited altered responses compared to healthy donors (HDs). We found that CD4+ but not CD8+ T cells from CeD patients showed a hypo-proliferative response following stimulation, associated with impaired secretion of the proliferative and pro-survival cytokine IL-2. Moreover, surface expression of early activation marker, CD69 remained elevated for longer on CD4+ T cells from CeD donors after stimulus withdrawal, suggesting prolonged activation and subtle alterations in regulatory feedback mechanisms. These findings reveal previously unrecognised quantitative alterations in naive T cell programming in CeD and underscore the utility of model-based analytical frameworks for detecting subtle functional perturbations in complex immune-mediated diseases.

immunology↗

bioRxiv2025

AI.zymes - A modular platform for evolutionary enzyme design

The ability to create new-to-nature enzymes would substantially advance bioengineering, medicine, and the chemical industry. Despite recent breakthroughs in protein design and structure prediction, designing biocatalysts with activities rivaling those of natural enzymes remains challenging. Here, we present AI.zymes, a modular platform integrating cutting-edge protein engineering algorithms within an evolutionary framework. By combining programs such as Rosetta, ESMFold, ProteinMPNN, and FieldTools in iterative rounds of design and selection, AI.zymes optimizes a broad range of catalytically relevant properties, such as transition state affinity and protein stability. Notably, AI.zymes can also improve properties that are not targeted by the employed design algorithms. For instance, AI.zymes enhanced electrostatic catalysis by iteratively selecting variants with stronger catalytic electric fields. AI.zymes was benchmarked by improving the promiscuous Kemp eliminase activity of ketosteroid isomerase, yielding a 7.7-fold increase in activity after zero-shot experimental validation of only 7 variants. Due to its modularity, AI.zymes can readily incorporate emerging design algorithms, paving the way for a unifying framework for enzyme design. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/633707v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@f2ac2eorg.highwire.dtl.DTLVardef@61b2aorg.highwire.dtl.DTLVardef@e176edorg.highwire.dtl.DTLVardef@46d692_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Adults patients with autoinflammation of unknown origin partially phenocopy the immune presentation of Still's disease

Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAIDs), immunological disorders characterized by inappropriate activation of the innate immune response. Recent clinical research has identified multiple distinct disorders, although overlap in clinical characteristics and genetic drivers impede rapid and precise diagnosis, and the immunological underpinning of disease is poorly understood. Here we aimed to understand the immunological process behind patients with autoinflammation of unknown origin. In a multi-center European trial, we collected samples from 36 patients with recent disease activity, and used deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically-similar 92 SAID patients. Key immunological changes were upregulation of CD38 and HLA across T cell subsets and upregulation of acute phase plasma proteins in autoinflammation of unknown origin patients. These previously poorly characterised patients partially phenocopied the Stills disease presentation. Together this study identifies potential biomarkers and disease-mediators in autoinflammation of unknown origin.

immunology↗

bioRxiv2024

Generation of an inducible destabilized-domain Cre mouse line to target disease associated microglia

The function of microglia during progression of Alzheimers disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed a mouse strain that expresses destabilized-domain Cre recombinase (DD-Cre) from the Cst7 locus (Cst7DD-Cre) and tested this in 5xFAD amyloidogenic, Ai14 tdTomato cre-reporter line mice. Dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in disease associated microglia (DAM) without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. This model should allow inducible cre-loxP targeting of DAMs, without leakiness. HighlightsO_LIWe developed a new mouse strain which specifically enables recombination of loxP sites in disease associated microglia (DAMs) and can be used to manipulate DAM-gene expression. C_LIO_LIDAMs represent a subset of plaque associated microglia (PAMs), and DAM expression increases with disease progression. C_LIO_LISpatial transcriptomic analyses reveal that DAMs have higher expression of disease and inflammatory genes compared to other PAMs. C_LI

neuroscience↗

bioRxiv2024

Neural Representations of Extrasystoles: A Predictive Coding Perspective

The coordinated interplay between brain and body is essential for survival, with the heart-brain axis playing a fundamental role in perceptual, cognitive and motor processes. Central to this interaction, the heart-evoked potential (HEP) represents a neural correlate of the heart activity. Further, the HEP is thought to represent a neuronal prediction for each heartbeat, raising questions about its role in arrhythmia. Yet, previous studies have primarily focused on regular heart rhythms, with only a few investigations delving into arrhythmias and, notably, none into extrasystoles, a form of benign arrhythmias that disrupt the regular heart rhythm. Extrasystoles represent a unique possibility for investigating brain responses to unexpected pronounced alterations in heart rhythm. We took advantage of the largest dataset (103 subjects with 3000 extrasystoles), including both EEG and ECG recordings, and analysed the neural response to both types of extrasystoles (supraventricular and ventricular) using multiverse approaches and control analysis in time and source space. We found that the HEP was significantly reduced for ventricular extrasystoles with underlying sources in the left insular. For the postextrasystolic beat of both types of extrasystoles, we found a significantly earlier and increased HEP originating from sources in the left frontal orbital cortex and the anterior cingulate gyri. The reduced HEP response to the ventricular extrasystole might result from inactive interoceptive cardiac pathways. In contrast, increased HEP of the postextrasystolic beat along with the anatomical neural HEP generators may reflect an interoceptive prediction error arising from a naturally occurring discrepancy between the predicted and actual heart rhythm, with a main source in the anterior cingulate gyri, a primary location for prediction error processing.

neuroscience↗

bioRxiv2024

Evolution of the RNA alternative decay cis element into a high-affinity target for the immunomodulatory protein Roquin

RNA cis elements play pivotal roles in regulatory processes, e.g. in transcriptional and translational regulation. Two stem-looped cis elements, the constitutive and alternative decay elements (CDE and ADE, respectively) are shape-specifically recognized in mRNA 3 untranslated regions (UTRs) by the immune-regulatory protein Roquin. Roquin initiates mRNA decay and contributes to balanced transcript levels required for immune homeostasis. While the interaction of Roquin with several CDEs is described, our knowledge about ADE complex formation is limited to the mRNA of Ox40, a gene encoding for a T-cell co-receptor. The Ox40 3UTR comprises both a CDE and ADE, each sufficient for Roquin-mediated control. Opposed to highly conserved and abundant CDE structures, ADEs are rarer, but predicted to exhibit a greater structural heterogeneity. This raises the question how and when two structurally distinct cis elements evolved as equal target motifs for Roquin. Using an interdisciplinary approach we here monitor the evolution of sequence and structure features of the Ox40 ADE across species. We designed RNA variants to probe en-detail determinants steering Roquin-RNA complex formation. Specifically, those reveal the contribution of a second RNA-binding interface of Roquin for recognition of the ADE basal stem region. In sum, our study sheds light on how the conserved Roquin protein selected ADE-specific structural features to evolve a second high-affinity mRNA target cis-element relevant for adaptive immune regulation. As our findings also allow expanding the RNA target spectrum of Roquin, the approach can serve a paradigm for understanding RNA-protein specificity through back-tracing the evolution of the RNA element.

biochemistry↗

bioRxiv2024

APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology

BackgroundApolipoprotein E {varepsilon}4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease (LOAD). A recent case report identified a rare variant in APOE, APOE3-R136S (Christchurch), proposed to confer resistance to autosomal dominant Alzheimers Disease (AD). However, it remains unclear whether and how this variant exerts its protective effects. MethodsWe introduced the R136S variant into mouse Apoe (ApoeCh) and investigated its effect on the development of AD-related pathology using the 5xFAD model of amyloidosis and the PS19 model of tauopathy. We used immunohistochemical and biochemical analysis along with single-cell spatial transcriptomics and proteomics to explore the impact of the ApoeCh variant on AD pathological development and the brains response to plaques and tau. ResultsIn 5xFAD mice, ApoeCh enhances a Disease-Associated Microglia (DAM) phenotype in microglia surrounding plaques, and reduces plaque load, dystrophic neurites, and plasma neurofilament light chain. By contrast, in PS19 mice, ApoeCh suppresses the microglial and astrocytic responses to tau-laden neurons and does not reduce tau accumulation or phosphorylation, but partially rescues tau-induced synaptic and myelin loss. We compared how microglia responses differ between the two mouse models to elucidate the distinct DAM signatures induced by ApoeCh. We identified upregulation of antigen presentation-related genes in the DAM response in a PS19 compared to a 5xFAD background, suggesting a differential response to amyloid versus tau pathology that is modulated by the presence of ApoeCh. ConclusionsThese findings highlight the ability of the ApoeCh variant to modulate microglial responses based on the type of pathology, enhancing DAM reactivity in amyloid models and dampening neuroinflammation to promote protection in tau models. This suggests that the Christchurch variants protective effects likely involve multiple mechanisms, including changes in receptor binding and microglial programming.

neuroscience↗

bioRxiv2023

Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability

Neural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formation in vitro and in vivo and show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.

neuroscience↗

bioRxiv2022

CRISPR-Mediated Generation and Characterization of a Gaa Homozygous c.1935C>A (p.D645E) Pompe Disease Knock-in Mouse Model Recapitulates Human Infantile Onset-Pompe Disease

Pompe disease (PD) is an autosomal recessive disorder caused by deficient lysosomal acid -glucosidase (GAA), leading to reduced degradation and subsequent accumulation of intra-lysosomal glycogen in tissues, especially skeletal and oftentimes cardiac muscle. The c.1935C>A (p.Asp645Glu) variant is the most frequent GAA pathogenic mutation in people of Taiwanese and Southern Chinese ethnicity, causing infantile-onset PD (IOPD), which presents neonatally with severe hypertrophic cardiomyopathy, profound muscle hypotonia, and respiratory failure leading to premature death if untreated. To further investigate the pathogenic mechanism and facilitate development of therapies pertaining to this variant, we applied CRISPR-Cas9 homology-directed repair (HDR) using a novel dual sgRNA approach flanking the target site to generate a GaaEm1935C>A knock-in mouse model as well as a myoblast cell line carrying the Gaa c.1935C>A mutation. Herein we describe the molecular, biochemical, physiological, histological, and behavioral characterization of 3-month-old homozygous GaaEm1935C>A mice. Homozygous GaaEm1935C>A knock-in mice exhibited normal Gaa mRNA expression levels relative to wild-type mice, but GAA enzymatic activity was almost completely abolished, leading to a substantial increase in tissue glycogen storage, and significant concomitant impairment of autophagy. Echocardiography of 3-month-old knock-in mice revealed significant cardiac hypertrophy. The mice also demonstrated skeletal muscle weakness but, paradoxically, not early mortality. Longitudinal studies of this model, including assessment of its immune response to exogenously supplied GAA enzyme, are currently underway. In summary, the GaaEm1935C>A knock-in mouse model recapitulates the molecular, biochemical, histopathologic, and phenotypic aspects of human IOPD caused by the GAA c.1935C>A pathogenic variant. It is an ideal model to assess innovative therapies to treat IOPD, including personalized therapeutic strategies that correct pathogenic variants, restore GAA activity and produce functional phenotypes.

genetics↗

bioRxiv2022

True-to-scale DNA-density maps correlate with major accessibility differences between active and inactive chromatin

Chromatin compaction differences may have a strong impact on accessibility of individual macromolecules and macromolecular assemblies to their DNA target sites. Estimates based on fluorescence microscopy with conventional resolution, however, suggested only modest compaction differences ([~]2-10x) between active and inactive nuclear compartments (ANC and INC). Here, we present maps of nuclear landscapes with true-to-scale DNA-densities, ranging from <5 Mbp/{micro}m3 to >300 Mbp/{micro}m3. Maps were generated from individual human and mouse cell nuclei with single-molecule localization microscopy at [~]20 nm lateral and [~]100 nm axial resolution and supplemented by electron spectroscopic imaging. Microinjection of fluorescent nanobeads with sizes corresponding to macromolecular assemblies for transcription and replication into nuclei of living cells, demonstrated their localization and movements within the ANC and exclusion from the INC.

cell biology↗

bioRxiv2022

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Genome-Wide Association Studies revealed the TREM2 R47H variant as one of the strongest genetic risk factors for late-onset Alzheimers Disease (AD). Unfortunately, many current TREM2*R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. We have developed the Trem2R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele, without evidence of cryptic splicing products, and appropriate inflammatory responses to cuprizone challenge. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in response to pathology. At an early disease stage (4 mo), homozygous Trem2R47H NSS; hemizygous 5xFAD (Trem2R47H NSS ; 5xFAD) mice have reduced size and number of microglia plus impaired interaction with plaques, that is associated with increased dystrophic neurites and axonal damage detected through plasma neurofilament light chain (NfL) level and suppressed inflammation. However, homozygosity for Trem2R47H NSS suppressed LTP deficits and presynaptic puncta loss caused by the 5xFAD transgene array. At a more advanced disease stage (12 mo,) Trem2R47H NSS ; 5xFAD mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Furthermore, Trem2R47H NSS ; 5xFAD mice also display robust LTP deficits and exacerbated presynaptic loss. Collectively, we provide a Trem2R47H variant mouse without cryptic splicing, and demonstrate it has disease stage dependent effects when combined with a plaque bearing model, with an initial loss of function that ultimately resolves, giving rise to a unique interferon signature and associated tissue damage.

neuroscience↗

bioRxiv2021

Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimers disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in behavior, cognition, and long-term potentiation followed by quantification of amyloid beta (A{beta}) plaque burden and neurofibrillary tau tangles, biochemical levels of A{beta} and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline. The results from these analyses are freely available via the AD Knowledge Portal (https://admodelexplorer.synapse.org). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD. Contribution to the Field StatementAlzheimers Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory impairments and affects more than 30 million individuals worldwide. Using animal models of AD, researchers have elucidated disease progression and hallmark pathologies that may underpin the memory impairments seen in patients. However, therapeutic targets have failed to translate successfully from animal studies to human clinical trials, prompting a reassessment of the development, use, and interpretation of data acquired using the innumerous AD animal models available to researchers. To address these shortcomings, we have developed a robust and reproducible modern characterization of pathologies within current and future animal models of AD to better assess distinct pathologies that arise at specific brain regions and ages of different models. Using the popular 3xTg-AD mouse, we demonstrate the utility of these deep-phenotyping analyses and highlight the drift that affected development of pathologies in this line over the past two decades. Utilizing this same systematic characterization, we also perform a direct comparison with 5xFAD mice, another popular animal model of AD. The robust and standardized data generated from these systematic deep-phenotyping analyses are available for broad use by the AD research community to assess, compare, and determine appropriate animal models of AD.

neuroscience↗

bioRxiv2021

Artificial Intelligence Resolves Kinetic Pathways of Magnesium Binding to RNA

Magnesium is an indispensable cofactor in countless vital processes. In order to understand its functional role, the characterization of the binding pathways to biomolecules such as RNA is crucial. Despite the importance, a molecular description is still lacking since the transition from the water-mediated outer-sphere to the direct inner-sphere conformation is on the millisecond timescale and therefore out of reach for conventional simulation techniques. To fill this gap, we use transition path sampling to resolve the binding pathways and to elucidate the role of the solvent in the reaction. The results reveal that the molecular void provoked by the leaving phosphate oxygen of the RNA is immediately filled by an entering water molecule. In addition, water molecules from the first and second hydration shell couple to the concerted exchange. To capture the intimate solute-solvent coupling, we perform a committor analysis as basis for a machine learning algorithm that derives the optimal deep learning model from thousands of scanned architectures using hyperparameter tuning. The results reveal that the properly optimized deep network architecture recognizes the important solvent structures, extracts the relevant information and predicts the commitment probability with high accuracy. Our results provide a quantitative description of solute-solvent coupling which is ubiquitous for kosmotropic ions and governs a large variety of biochemical reactions in aqueous solutions.

bioinformatics↗

bioRxiv2021

Systematic Phenotyping and Characterization of the 5xFAD mouse model of Alzheimer's Disease

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimers disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6J strain background, across its lifespan - including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, A{beta} biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the UCI Mouse Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.

neuroscience↗