bluuebunny/crossref_metadata_2025 huggingface dataset:
ComboPath: An ML system for predicting drug combination effects with superior model specification
Authors: Ranasinghe Duminda S. , Sanders Nathan , Tam Hok Hei , Liu Changchang , Spitz Dan
Published: January 2024

Drug combinations have been shown to be an effective strategy for cancer therapy, but identifying beneficial combinations through experiments is labor-intensive and expensive [Mokhtari et al., 2017]. Machine learning (ML) systems that can propose novel and effective drug combinations have the potential to dramatically improve the efficiency of combinatoric drug design. However, the biophysical parameters of drug combinations are degenerate, making it difficult to identify the ground truth of drug interactions even given experimental data of the highest quality available. Existing ML models are highly underspecified to meet this challenge, leaving them vulnerable to producing parameters that are not biophysically realistic and harming generalization. We have developed a new ML model, “ComboPath”, aimed at a novel ML task: to predict interpretable cellular dose response surface of a two-drug combination based on each drugs’ interactions with their known protein targets. ComboPath incorporates a biophysically-motivated intermediate parameterization with prior information used to improve model specification. This is the first ML model to nominate beneficial drug combinations while simultaneously reconstructing the dose response surface, providing insight on both the potential of a drug combination and its optimal dosing for therapeutic development. We show that our models were able to accurately reconstruct 2D dose response surfaces across held out combination samples from the largest available combinatoric screening dataset while substantially improving model specification for key biophysical parameters.
CPT1a regulates the delivery of extracellular fatty acids for cardiolipin turnover in prostate cancer cells
Authors: Santiappillai Nancy T , Hakeem-Sanni Mariam F , Withy Anabel , Butler Lisa M , Quek Lake-Ee , Hoy Andrew J
Published: January 2024

Mitochondrial fatty acid oxidation (FAO) has been proposed to be a major bioenergetic pathway in prostate cancer. However, this concept fails to consider FAO relative to other mitochondrial substrates. Here, we found extracellular long-chain fatty acids (LCFAs), including palmitate, stearate, oleate, linoleate, linolenate, are minor sources of carbon entering the TCA cycle compared to glucose and glutamine in prostate cancer cells, despite being assimilated in the mitochondria as acyl-carnitines. In contrast, cardiolipins were a prominent LCFAs sink, with some species achieving greater than 50%13C-labelling within 6 hours, suggesting high cardiolipin turnover using extracellular LCFAs. Knockdown of CPT1a, the rate-limiting enzyme of LCFA entry into mitochondria, reduced the incorporation of extracellular linoleate into cardiolipins. These results demonstrate that FAO is not a major input for the TCA cycle and provide evidence for an underappreciated role for CPT1a in regulating LCFAs entry into mitochondria for cardiolipin remodelling.
How cancer-associated fibroblasts promote T-cell exclusion in human lung tumors: a physical perspective
Authors: Ackermann Joseph , Bernard Chiara , Sirven Philemon , Salmon Hélène , Fraldi Massimiliano , Ben Amar Martine
Published: January 2024

The tumor stroma is a tissue composed primarily of extracellular matrix, fibroblasts, immune cells, and vasculature. Its structure and functions, such as nutrient support and waste removal, are altered during malignancy. Tumor cells transform fibroblasts into cancer-associated fibroblasts, which have important immunosuppressive activity on which growth, invasion, and metastasis depend. These activated fibroblasts prevent immune cell infiltration into the tumor nest, thereby promoting cancer progression and inhibiting T-cell-based immunotherapy. To understand these complex interactions, we measure the density of different cell types in the stroma using immunohistochemistry techniques on tumor samples from lung cancer patients. We incorporate these data, and also known information on cell proliferation rates and relevant biochemical interactions, into a minimal dynamical system with few parameters. A spatio-temporal approach to the inhomogeneous environment explains the cell distribution and fate of lung carcinomas. The model reproduces that cancer-associated fibroblasts act as a barrier to tumor growth, but also reduce the efficiency of the immune response. The final outcome depends on the parameter values for each patient and leads to either tumor invasion, persistence, or eradication as a result of the interplay between cancer cell growth, T-cell cytotoxic activity, and fibroblast attraction, activation, and spatial dynamics. Our conclusion is that a wide spectrum of scenarios exists as a result of the competition between the characteristic times of cancer cell growth and the activity rates of the other species. Nevertheless, distinct trajectories and patterns allow quantitative predictions that may help in the selection of new therapies and personalized protocols. We conclude with different options for further modeling.Graphical Abstract
Elucidating Resistance Mechanisms inStaphylococcus epidermidis: A High-Performing MALDI-TOF MS-Based Proteomic Approach for Predictive Modeling
Authors: Ren Michael , Chen Qiang , Zhang Jing
Published: January 2024

The emergence ofStaphylococcus epidermidisas a significant nosocomial pathogen necessitates advancements in more efficient antimicrobial resistance (AMR) profiling. However, existing culture-based antimicrobial susceptibility testing (AST) methods can take up to 96 hours, while holistic PCR assays can cost thousands of dollars. This study combines machine learning with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to develop predictive models for various antibiotics using a comprehensive dataset containing thousands ofS. epidermidisisolates. Optimized machine learning models utilized feature selection and achieved high AUROC scores ranging from 0.80 to 0.95 while maintaining AUPRC scores up to 0.96 for balanced datasets. Shapley Additive exPlanations (SHAP) were employed to analyze relevant features and assess the significance of corresponding protein biomarkers while also verifying that predictive power was derived from the detection of proteins rather than noise. AMR prediction models were validated externally to evaluate model performance outside the original data collection site. The findings in this study demonstrate that combining machine learning with AMR profiling yields significant and relevant results, indicating that such an approach is a promising solution for rapid and cost-effective treatments for nosocomial infections. Models created to predict AMR can also aid in biomarker discovery. The workflow used in the present study is potentially applicable to other microbial pathogens in the future.
Structure, motion, and multiscale search of traveling networks
Authors: Cira Nate J. , Paull Morgan L. , Sinha Shayandev , Zanini Fabio , Ma Eric Yue , Riedel-Kruse Ingmar H.
Published: January 2024

Network models are widely applied to describe connectivity and flow in diverse systems. In contrast, the fact that many connected systems move through space as the result of dynamic restructuring has received little attention. Therefore, we introduce the concept of ‘traveling networks’, and we analyze a tree-based model where the leaves are stochastically manipulated to grow, branch, and retract. We derive how these restructuring rates determine key attributes of network structure and motion, enabling a compact understanding of higher-level network behaviors such as multiscale search. These networks self-organize to the critical point between exponential growth and decay, allowing them to detect and respond to environmental signals with high sensitivity. Finally, we demonstrate how the traveling network concept applies to real-world systems, such as slime molds, the actin cytoskeleton, and human organizations, exemplifying how restructuring rules and rates in general can select for versatile search strategies in real or abstract spaces.
The Calcitron: A Simple Neuron Model That Implements Many Learning Rules via the Calcium Control Hypothesis
Authors: Moldwin Toviah , Azran Li Shay , Segev Idan
Published: January 2024

Theoretical neuroscientists and machine learning researchers have proposed a variety of learning rules for linear neuron models to enable artificial neural networks to accomplish supervised and unsupervised learning tasks. It has not been clear, however, how these theoretically-derived rules relate to biological mechanisms of plasticity that exist in the brain, or how the brain might mechanistically implement different learning rules in different contexts and brain regions. Here, we show that the calcium control hypothesis, which relates plastic synaptic changes in the brain to calcium concentration [Ca2+] in dendritic spines, can reproduce a wide variety of learning rules, including some novel rules. We propose a simple, perceptron-like neuron model that has four sources of [Ca2+]: local (following the activation of an excitatory synapse and confined to that synapse), heterosynaptic (due to activity of adjacent synapses), postsynaptic spike-dependent, and supervisor-dependent. By specifying the plasticity thresholds and amount of calcium derived from each source, it is possible to implement Hebbian and anti-Hebbian rules, one-shot learning, perceptron learning, as well as a variety of novel learning rules.
MAIT Cells Modulate Innate Immune Cells and Inhibit Colon Cancer Growth
Authors: Cheng Olivia J. , Lebish Eric J. , Jensen Owen , Jacenik Damian , Trivedi Shubhanshi , Cacioppo Jackson , Aubé Jeffrey , Beswick Ellen J. , Leung Daniel T.
Published: January 2024

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we show that peritumoral injection ofin vivo-expanded MAIT cells into RAG1-/-mice with MC38-derived tumors inhibits tumor growth compared to control. Multiplex cytokine analyses show that tumors from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting an association between eosinophil recruitment and tumor inhibition. In a human peripheral leukocyte co-culture model, we show that leukocytes stimulated with MAIT ligand show an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we show that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.

Brief summary

In models of colon cancer, MAIT cells have anti-tumor activity, associated with increased production of proinflammatory and eosinophil-modulating cytokines.
It’s all in the timing: Delayed feedback in autism may weaken predictive mechanisms during contour integration
Authors: Knight Emily J. , Altschuler Ted S. , Molholm Sophie , Murphy Jeremy W. , Freedman Edward G. , Foxe John J.
Published: January 2024

Humans rely on predictive mechanisms during visual processing to efficiently resolve incomplete or ambiguous sensory signals. While initial low-level sensory data are conveyed by feedforward connections, feedback connections are believed to shape sensory processing through conveyance of statistical predictions based on prior exposure to stimulus configurations. Individuals with autism spectrum disorder (ASD) show biases in stimulus processing toward parts rather than wholes, suggesting their sensory processing may be less shaped by statistical predictions acquired through prior exposure to global stimulus properties. Investigations of illusory contour (IC) processing in neurotypical (NT) adults have established a well-tested marker of contour integration characterized by a robust modulation of the visually evoked potential (VEP) – theIC-effect– that occurs over lateral occipital scalp during the timeframe of the N1 component. Converging evidence strongly supports the notion that thisIC-effectindexes a signal with significant feedback contributions. Using high-density VEPs, we compared theIC-effectin 6–17-year-old children with ASD (n=32) or NT development (n=53). Both groups of children generated anIC-effectthat was equivalent in amplitude. However, theIC-effectnotably onset 21ms later in ASD, even though timing of initial VEP afference was identical across groups. This suggests that feedforward information predominated during perceptual processing for 15% longer in ASD compared to NT children. This delay in the feedback dependentIC-effect, in the context of known developmental differences between feedforward and feedback fibers, suggests a potential pathophysiological mechanism of visual processing in ASD, whereby ongoing stimulus processing is less shaped by statistical prediction mechanisms.

SIGNIFICANCE STATEMENT

Children with autism often present with an atypical visual perceptual style that emphasizes parts or details over the whole. Using electroencephalography (EEG), this study identifies delays in the visual feedback from higher order sensory brain areas to primary sensory regions. Because this type of visual feedback is thought to carry information about prior sensory experiences, individuals with autism may have difficulty efficiently using prior experience and predictions to help make sense of incoming new visual information. This provides empirical neural evidence to support theories of disrupted sensory perception mechanisms in autism.
FateNet: an integration of dynamical systems and deep learning for cell fate prediction
Authors: Sadria Mehrshad , Bury Thomas M.
Published: January 2024

Understanding cellular decision-making, particularly its timing and impact on the biological system such as tissue health and function, is a fundamental challenge in biology and medicine. Existing methods for inferring fate decisions and cellular state dynamics from single-cell RNA sequencing data lack precision regarding decision points and broader tissue implications. Addressing this gap, we present FateNet, a computational approach integrating dynamical systems theory and deep learning to probe the cell decision-making process using scRNA-seq data. By leveraging information about normal forms and scaling behavior near tipping pointscommon to many dynamical systems, FateNet accurately predicts cell decision occurrence and offers qualitative insights into the new state of the biological system. Also, through in-silico perturbation experiments, FateNet identifies key genes and pathways governing the differentiation process in hematopoiesis. Validated using different scRNA-seq data, FateNet emerges as a user-friendly and valuable tool for predicting critical points in biological processes, providing insights into complex trajectories.
A Cell Model for the Detection of a Planar Surface Using Motion Stereo in Area MST of the Visual Cortex
Authors: Kawakami Susumu
Published: January 2024

I propose a series of modeled cells for detecting three plane parameters (i.e. a time-to-contact to a plane, its orientation, and its shortest distance) with motion stereo. This series is composed of lateral geniculate nucleus cells, nondirectionally selective simple cells, directionally selective (DS) simple cells, DS complex cells, motion-detection cells, and planar-surface-detection cells. These cell types perform the time delay, Hough transform, spatio-temporal correlation, accumulation, inverse Hough transform, and a combinations of the cross-ratio and polar transforms (or a small-circle transform) to detect these plane parameters, respectively. Each connection of the neural network connecting this series of cell types is modeled mathematically one by one using these transforms. The selective responses of SDCs to planar parameters are consistent with those of physiological experiments.
Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics
Authors: Liu Youxi , Yin Meimei , Mao Xiaoting , Wu Shuai , Wei Shuangping , Heng Shujun , Yang Yichun , Huang Jinwen , Guo Zhuolin , Li Chuan , Ji Chao , Hu Liu , Liu Wenjie , Zhang Ling-juan
Published: January 2024

Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+or CD8+lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion ofIfngr1in dermal fibroblasts in mice reducedCxcl9/10expression, dermal infiltration of CD8+T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+CD8+T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.
Beyond the Sin3/HDAC Complex: FAM60A emerges as a regulator of RNA Splicing
Authors: Huda Md Nazmul , Zimmermann Rosalyn , Nagar Preeti , Alam Jahangir , Islam Md Rafikul , Gerald Dayebgadoh , Miah Mojnu , Kempf Cassandra G , Thornton Janet L. , Zhang Ying , Wen Zhihui , Hatem Gaye , Gies Allen , Byrum Stephanie , Rahman Mohammad Alinoor , Florens Laurence , Washburn Michael P. , Miah Sayem
Published: January 2024

FAM60A, traditionally linked to chromatin remodeling within the Sin3/HDAC complex, has emerged as a critical regulator in RNA splicing. Employing an integrative approach that combines immunological assays, CRISPR/Cas9 technology, comprehensive genomics, proteomics, and advanced cross-linking mass spectrometry, complemented by sophisticated 3D molecular modeling, our study challenges and extends the existing understanding of FAM60A’s functional dynamics. Contravening previous perceptions, our findings elucidate that FAM60A does not interact directly with SIN3A, rather establishes direct interactions with SAP30 and HDAC1, redefining its relationship with the Sin3/HDAC complex. These interactions, deciphered through detailed 3D structural analysis supported by cross-linking constraints, signify a complex architectural role of FAM60A within chromatin remodeling processes. Moreover, our research unveils FAM60A’s pivotal role in RNA processing, particularly in splicing regulation. Through extensive molecular interactions with a diverse array of mRNA-binding proteins and principal spliceosome components, FAM60A emerges as a key regulator of RNA splicing. This expanded role delineates its influence on gene expression regulation, spotlighting its capacity to modulate critical cellular processes. In sum, this study unveils FAM60A’s key role in gene regulation and RNA splicing, and suggests new paths for cellular and therapeutic research.
SHP2-triggered endothelium activation fuels estradiol-independent endometrial sterile inflammation
Authors: Pan Jie , Zhao Lixin , Fang Wen , Qu Jiao , Zhai Linhui , Tan Minjia , Xu Qiang , Du Qianming , Lv Wen , Sun Yang
Published: January 2024

Endometrial hyperplasia (EH) is a common gynecological disease primarily driven by excess estrogen. How endometrial sterile inflammation regulates EH remains unclear. First, we found the upregulation of SHP2 in endometrial endothelial cells from patients with EH by scRNA-Seq. SHP2 promoted inflammatory activation of endothelial cells, which promoted macrophage transendothelial migration. Subsequently, IL1β and TNFα from macrophages gave a feedforward loop to enhance endothelial cell activation and result in more IGF1 secretion, thereby sustaining sterile endometrial inflammation and facilitating endometrial epithelial cell proliferation even after estradiol withdrawal. Mechanistically, results of bulk RNA-Seq and phosphoproteomic analyses showed that endothelial SHP2 dephosphorylated RIPK1Y380after estradiol stimulation. This event promoted activator protein 1 (AP-1) activation, instigating inflammation and increased CXCL10, CXCL13, COX2 and IGF1 secretion. Furthermore, targeting SHP2 by SHP099 or endothelial-specific SHP2 deletion alleviated EH progression in mice. Collectively, our findings demonstrate that SHP2 mediates the transition of endothelial activation, from estradiol-driven short inflammation to macrophage-amplified continuous sterile inflammation. Targeting chronic sterile inflammation mediated by endothelial cell activation is a promising strategy for non-hormonal intervention in EH.
Discovery of Highly Active Kynureninases for Cancer Immunotherapy through Protein Language Model
Authors: Eom Hyunuk , Cho Kye Soo , Lee Jihyeon , Kim Stephanie , Park Sukhwan , Kim Hyunbin , Yang Jinsol , Han Young-Hyun , Lee Juyong , Seok Chaok , Lee Myeong Sup , Song Woon Ju , Steinegger Martin
Published: January 2024

Overcoming the immunosuppressive tumor microenvironment is a promising strategy in anticancer therapy. L-kynurenine, a strong immunosuppressive metabolite can be degraded through kynureninases. Through homology searches and protein language models, we identified and then experimentally determined the efficacy of four top-ranked kynureninases. The catalytically most active one nearly doubles turnover number over the prior best, reducing tumor weight by 3.42 times in mouse model comparisons, and thus, presenting substantial therapeutic potential.
Context-sensitive processing in a model neocortical pyramidal cell with two sites of input integration
Authors: Graham Bruce P. , Kay Jim W. , Phillips William A.
Published: January 2024

Neocortical layer 5 thick-tufted pyramidal cells are prone to exhibiting burst firing on receipt of coincident basal and apical dendritic inputs. These inputs carry different information, with basal inputs coming from feedforward sensory pathways and apical inputs coming from diverse sources that provide context in the cortical hierarchy. We explore the information processing possibilities of this burst firing using computer simulations of a noisy compartmental cell model. Simulated data on stochastic burst firing due to brief, simultaneously injected basal and apical currents allows estimation of burst firing probability for different stimulus current amplitudes. Information-theory-based partial information decomposition (PID) is used to quantify the contributions of the apical and basal input streams to the information in the cell output bursting probability. Four different operating regimes are apparent, depending on the relative strengths of the input streams, with output burst probability carrying more or less information that is uniquely contributed by either the basal or apical input, or shared and synergistic information due to the combined streams. We derive and fit transfer functions for these different regimes that describe burst probability over the different ranges of basal and apical input amplitudes. The operating regimes can be classified into distinct modes of information processing, depending on the contribution of apical input to out-put bursting:apical cooperation, in which both basal and apical inputs are required to generate a burst;apical amplification, in which basal input alone can generate a burst but the burst probability is modulated by apical input;apical drive, in which apical input alone can produce a burst; andapical integration, in which strong apical or basal inputs alone, as well as their combination, can generate bursting. In particular, PID and the transfer function clarify that the apical amplification mode has the features required for contextually-modulated information processing.
Endogenous retroelement activation is implicated in IFN-α production and anti-CCP autoantibody generation in early RA
Authors: Cooles Faye AH , Pedrola Gemma V , Naamane Najib , Pratt Arthur G , Barron-Millar Ben , Anderson Amy E , Hilkens Catharien MU , Casement John , Bondet Vincent , Duffy Darragh , Zhang Fan , Shukla Ruchi , Isaacs John D
Published: January 2024

Objectives

Endogenous retroelements (EREs) stimulate type 1 interferon (IFN-I) production but have not been explored as potential interferonogenic triggers in Rheumatoid Arthritis (RA). We investigated ERE expression in early RA (eRA), a period where IFN-I is increased.

Methods

ERE expression in DMARD naïve eRA whole blood (LINE1; RT-PCR) and bulk synovial tissue (LTR5, LINE1, SINE; Nanostring) was examined alongside IFN-α activity. Circulating lymphocyte subsets, including B cell subsets, from eRA patients and early psoriatic arthritis (PsA), were flow cytometrically sorted and similarly examined. Existing established RA and osteoarthritis (OA) synovial single-cell sequencing data was re-interrogated to identify repeat elements, and associations explored.

Results

There was significant co-expression of all ERE classes andIFNAin eRA synovial tissue (n=22, p<0.0001) and significant positive associations between whole blood LINE1 expression (n=56) and circulating IFN-α protein (p=0.018) and anti-CCP titres (p<0.0001). ERE expression was highest in circulating eRA B cells, particularly naïve B cells compared with PsA, with ERE regulation by SAMDH1 implicated and associations withIFNAagain observed. Finally, in established RA synovium, LTRs, particularly ERVK, were most increased in RA compared with OA where, for all synovial subsets (monocytes, B cells, T cells and fibroblasts), ERE expression associated with increased IFN-I signalling (p<0.001).

Conclusions

Peripheral blood and synovial ERE expression is examined for the first time in eRA highlighting both a potential causal relationship between ERE and IFN-I production and an intriguing association with anti-CCP autoantibodies. This suggests EREs may contribute to RA pathophysiology with implications for future novel therapeutic strategies.
Protective Effects of Lipoxin A4and B4Signaling on the Inner Retina in a Mouse Model of Experimental Glaucoma
Authors: Liu Hsin-Hua , Cullen Paul F. , Sivak Jeremy M. , Gronert Karsten , Flanagan John G.
Published: January 2024

Glaucoma is a common neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and the retinal nerve fiber layer (RNFL), resulting in a gradual decline of vision. A recent study by our groups indicated that the levels of lipoxins A4(LXA4) and B4(LXB4) in the retina and optic nerve decrease following acute injury, and that restoring their function is neuroprotective. Lipoxins are members of the specialized pro-resolving mediator (SPM) family and play key roles to mitigate and resolve chronic inflammation and tissue damage. Yet, knowledge about lipoxin neuroprotective activity remains limited. Here we investigate thein vivoefficacy of exogenous LXA4and LXB4administration on the inner retina in a mouse model of chronic experimental glaucoma. To investigate the contribution of LXA4signaling we used transgenic knockout (KO) mice lacking the two mouse LXA4receptors (Fpr2/Fpr3-/-). Functional and structural changes of inner retinal neurons were assessed longitudinally using electroretinogram (ERG) and optical coherence tomography (OCT). At the end of the experiment, retinal samples were harvested for immunohistological assessment. While both lipoxins generated protective trends, only LXB4treatment was significant, and consistently more efficacious than LXA4in all endpoints. Both lipoxins also appeared to dramatically reduce Müller glial reactivity following injury. In comparison, Fpr2/Fpr3 deletion significantly worsened inner retinal injury and function, consistent with an essential protective role for endogenous LXA4. Together, these results support further exploration of lipoxin signaling as a treatment for glaucomatous neurodegeneration.
Comparative analysis of kidney transplantation modeled using precision-cut kidney slices and kidney transplantation in pigs
Authors: Moor Matthias B. , Nordström Johan , Burmakin Mikhail , Raki Melinda , Al-Saad Samer , Nowak Greg , Wennberg Lars , Patrakka Jaakko , Olauson Hannes
Published: January 2024

Kidney transplants are at risk for so far unavoidable ischemia-reperfusion injury. Several experimental kidney transplantation models are available to study this injury, but all have their own limitations. Here, we describe precision-cut kidney slices (PCKS) as a novel model of kidney ischemia-reperfusion injury in comparison with pig and human kidney transplantation.

Following bilateral nephrectomy in pigs, we applied warm ischemia (1h), cold ischemia (20h) and a reperfusion period (4h) to one whole kidney undergoing transplantation to a recipient pig and, in parallel, established PCKS undergoing ischemia and modeled reperfusion. Histopathological assessment revealed the presence of some but not all morphological features of tubular injury in PCKS as seen in pig kidney transplantation. RNAseq demonstrated that the majority of changes occurred after reperfusion only, with a partial overlap between PCKS and kidney transplantation, with some differences in transcriptional response attributable to systemic inflammatory responses and immune cell migration. Comparison of PCKS and pig kidney transplantation with RNAseq data from human kidney biopsies by gene set enrichment analysis revealed that both PCKS and pig kidney transplantation reproduced the post-reperfusion pattern of human kidney transplantation. In contrast, only post-cold ischemia PCKS and pig kidney partially resembled the gene set of human acute kidney injury.

Overall, the present study established that a PCKS protocol can model kidney transplantation and its reperfusion-related damage on a histological and a transcriptomic level. PCKS may thus expand the toolbox for developing novel therapeutic strategies against ischemia-reperfusion injury.
Mitochondrially targeted deferasirox kills cancer cellsviasimultaneous iron deprivation and ferroptosis induction
Authors: Jadhav Sukanya B , Sandoval-Acuña Cristian , Pacior Yaiza , Klanicova Kristyna , Blazkova Kristyna , Sedlacek Radislav , Stursa Jan , Werner Lukas , Truksa Jaroslav
Published: January 2024

Iron chelation has been proposed as an anti-cancer approach; however, iron chelators are generally non-specific for cancer cells and rely on the higher sensitivity of malignant cells to iron deprivation and accumulation of the drug in tumor tissueviathe enhanced permeability and retention effect. Here, we present mitochondrially targeted deferasirox (mitoDFX), a redox-active iron chelator that deprives cells of biologically active iron, as evidenced by a decrease in [Fe-S] cluster and heme-containing proteins. Notably, mitoDFX also depletes the major cellular antioxidant glutathione and induces lipid peroxidation, both of which are hallmarks of ferroptosis, resulting in selective induction of cell death in cancer cells. In summary, targeting deferasirox into the mitochondria results in an agent that has a unique ability to elicit iron deprivation and produce toxic lipid peroxidesviaits redox activity, thus harnessing the dual nature of iron in a single molecule to combat cancer.
Energy Optimization Induces Predictive-coding Properties in a Multicompartment Spiking Neural Network Model
Authors: Zhang Mingfang(Lucy) , Bohte Sander M.
Published: January 2024

Abstract

Predictive coding is a prominent theoretical framework for understanding the hierarchical sensory processing in the brain, yet how it could be implemented in networks of cortical neurons is still unclear. While most existing works have taken a hand-wiring approach to creating microcircuits that match experimental results, recent work in applying an optimisation approach to rate-based artificial neural networks revealed that cortical connectivity might result from self-organisation given some fundamental computational principle, such as energy efficiency. As no corresponding approach has studied this in more plausible networks of spiking neurons, we here investigate whether predictive coding properties in a multi-compartment spiking neural network can emerge from energy optimisation. We find that a model trained with an energy objective in addition to a task-relevant objective is able to reconstruct internal representations given top-down expectation signals alone. Additionally, neurons in the energy-optimised model also show differential responses to expected versus unexpected stimuli, qualitatively similar to experimental evidence for predictive coding. These findings indicate that predictive-coding-like behaviour might be an emergent property of energy optimisation, providing a new perspective on how predictive coding could be achieved in the cortex.
Dorsal horn dendrite polarization during Spinal Cord Stimulation (SCS) predicted using the quasi-uniform-mirror assumption
Authors: Zannou Adantchede Louis , Koochesfahani Mojtaba Belali , Russo Marc , Bikson Marom
Published: January 2024

While the mechanisms of Spinal Cord Stimulation are traditionally assumed to follow pacing of dorsal columns axons, the development of sub-paresthesia SCS and new waveforms has encouraged consideration of different cellular targets. Given their relative proximity to the stimulation electrodes and role in pain processing (e.g., synaptic processing and gate control theory), spinal cord dorsal horn interneurons may be direct targets of stimulation. We developed a novel computational modeling pipeline termed ‘quasi-uniform-mirror assumption’ and apply it to predict polarization of dorsal horn inter-neuron cell types (Islet type, Central type, Stellate/Radial, Vertical-like) to SCS. The quasi-uniform-mirror assumption allows prediction, for each cell type and location in the dorsal horn, the peak and axis of dendritic polarization as well as the impact of stimulation pulse width. For long pulse (dc), the peak polarization per mA of SCS with a bipolar montage were: Islet type 3.5 mV, Central type 2 mV, Stellate/Radial 1.4 mV, Vertical-like 2.5 mV. For Stellate/Radial the peak dendritic polarization was dorsal-ventral, and for Islet type Central peak dendrite polarization was in the rostral-caudal axis. For Islet type and Central type cells peak dendrite polarization was between stimulation electrodes, while for Stellate/Radial and Vertical-like peak dendrite polarization was under stimulation electrodes. The impact of pulse width depended on cell membrane time constants, which in the quasi-uniform-mirror assumption are uniform first-order. Assuming 1 ms time constant, for a 1 ms or 100 us pulse width, the peak dendrite polarization decreases (from the dc values) by ∼33% and ∼88%. These results suggest, for the conditions modeled, maximum polarization is of islet-cells in the superficial dorsal horn at locations between electrodes; applying 2 mA 1 ms pulse SCS, the peak islet-cell dendrite polarization is ∼4.7 mV. Polarizations of a few mV have been shown to modulate synaptic processing through sub-threshold mechanisms.
Apical cell expansion maintained by Dusky-like establishes a scaffold for corneal lens morphogenesis
Authors: Ghosh Neha , Treisman Jessica E.
Published: January 2024

The biconvex shape of theDrosophilacorneal lens, which enables it to focus light onto the retina, arises by organized assembly of chitin and other apical extracellular matrix components. We show here that the Zona Pellucida domain-containing protein Dusky-like is essential for normal corneal lens morphogenesis. Dusky-like transiently localizes to the expanded apical surfaces of the corneal lens-secreting cells, and in its absence, these cells undergo apical constriction and apicobasal contraction. Dusky-like also controls the arrangement of two other Zona Pellucida-domain proteins, Dumpy and Piopio, external to the developing corneal lens. Loss of eitherdusky-likeordumpydelays chitin accumulation and disrupts the outer surface of the corneal lens. Artificially inducing apical constriction with constitutively active Myosin light chain kinase is sufficient to similarly alter chitin deposition and corneal lens morphology. These results demonstrate the importance of cell shape for the morphogenesis of overlying apical extracellular matrix structures.
Stronger effect of temperature on body growth in cool than in warm populations suggests lack of local adaptation
Authors: Lindmark Max , Ohlberger Jan , Gårdmark Anna
Published: January 2024

Body size is a key functional trait that has declined in many biological communities, partly due to changes in individual growth rates in response to climate warming. However, our understanding of growth responses in natural ecosystems is limited by relatively short time series without large temperature contrasts and unknown levels of adaptation to local temperatures across populations. In this study, we collated back-calculated length-at-age data for the fish Eurasian perch (Perca fluviatilis) from 10 populations along the Baltic Sea coast between 1953–2015 (142023 length-at-age measurements). We fitted individual-level growth trajectories using the von Bertalanffy growth equation, and reconstructed local temperature time series using generalized additive models fitted to three data sources. Leveraging a uniquely large temperature contrast due to climate change and artificial heating, we then estimated population-specific and global growth-temperature relationships using Bayesian mixed models, and evaluated if they conformed to local adaption or not. We found little evidence for local adaptation in the temperature-dependence of individual growth curves. Instead, population-specific curves mapped onto a global curve, resulting in body growth increasing with warming in cold populations but decreasing in warm populations. Understanding to which degree the effects of warming on growth and size are population-specific is critical for generalizing predictions of climate impacts on growth, which is a key biological trait affecting multiple levels of biological organisation from individuals to ecosystem functioning.
Estimation of Uncertainty and Location-specific Variation in Regional Food Web Interactions
Authors: Brothers Aaron , Santillán Vinicio , Quitián Marta , Neuschulz Eike Lena , Schleuning Matthias , Böhning-Gaese Katrin , Alvarez Orlando , Thron Christopher
Published: January 2024

We demonstrate a methodology for estimating uncertainties and intra-regional variations in bird-plant food web interactions, based on transect observations at multiple locations with the region. We model species-species interaction measurements at each location as Poisson random variables whose mean is proportional to the interaction strength at that location. We also model the location-dependent interaction strength as having uniform probability on an interval. A Bayesian approach is used to estimate this interaction strength interval based on measurements at specific locations. We present and discuss the implications of graphical representations to show how the estimated means and ranges of regional interaction strength (and the variances of these estimates) depend on measurements, in the case where measurements are taken at 3 locations. Among other properties, we show that taking the mean of three measured interaction frequencies will tend to underestimate the actual mean interaction strength, assuming a uniform interval model.

The methodology is applied to a specific case of transect survey data for avian frugivore species’ interactions with fruit-bearing plants from three locations within each of six regions in Ecuador. We hypothesize that species within the same genus tend to substitute for each other out in different locations within the same region. We test this hypothesis by comparing the estimated location-dependent variances of species-species and genus-genus interactions. Results contraindicate the hypothesis: different species from the same genus tend to have higher interaction strengths in similar locations, i.e. “species in the same genus flock together.”

We also find some evidence that fragmentation of the environment due to human activity, even if it does not reduce species diversity, may have a uniformizing effect so that the site-to-site variability in bird-fruit interactions is reduced.
Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced aberrant calcium transient
Authors: Tatekoshi Yuki , Chen Chunlei , Shapiro Jason , Chang Hsiang-Chun , Blancard Malorie , Lyra-Leite Davi , Burridge Paul W. , Feinstein Matthew , D’Aquila Richard , Hsue Priscilla , Ardehali Hossein
Published: January 2024

Heart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy (ART) suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this paper, we studied calcium transient in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in culture to simulate the cardiomyocyte relaxation defect noted in of PLWH and HFpEF and to assess whether various drugs have an effect. We show that treatment of hiPSC-CMs with inflammatory cytokines (such as interferon-γ or TNF-α) impair their Ca2+uptake into sarcoplasmic reticulum and that SGLT2 inhibitors, clinically proven as effective for HFpEF, reverse this effect. Additionally, treatment with mitochondrial antioxidants (like mito-Tempo) and certain antiretrovirals resulted in the reversal of the effects of these cytokines on calcium transient. Finally, incubation of hiPSC-CMs with serum from HIV patients with and without diastolic dysfunction did not alter their Ca2+-decay time, indicating that the exposure to the serum of these patients is not sufficient to induce the decrease in Ca2+uptakein vitro. Together, our results indicate that hiPSC-CMs can be used as a model to study molecular mechanisms of inflammation-mediated abnormal cardiomyocyte relaxation and screen for potential new interventions.
Therapeutic targeting of KRAS mutation-driven tumorigenesis by extracellular vesicles loaded with small interfering RNA
Authors: Zhai Yanhua , Niu Shuiqin , Qiu Tao , Yi Yuan , Yan Yu , Hu Rui , He Xinjun , Xu Ke
Published: January 2024

RASis a well-known oncogene contributing to significant proportion of cancer incidences, yet it remains as an undruggable target to majority of therapeutic modalities. Here, we explored the potential of extracellular vesicles (EVs) for therapeutic targeting ofKRASmutation-driven tumorigenesis. EVs loaded with small interfering RNA (siRNA) againstKRASsuccessfully inhibited tumor xenograft growth when injected intratumorally in mice models. Intriguingly, when injected intravenously, EVs were still able to accumulate in tumors and deliverKRAStargeting siRNA payload in sufficient amount to show tumor growth inhibition. Therefore, EV-siRNA platform show great promises for therapeutic targeting ofKRASmutations and other undruggable targets.
Cell-autonomous and non-cell-autonomous effects of arginase-II on cardiac aging
Authors: Potenza Duilio M. , Cheng Xin , Ajalbert Guillaume , Brenna Andrea , Giraud Marie-Noelle , Frobert Aurelien , Cook Stephane , Mertz Kirsten D. , Yang Zhihong , Ming Xiu-Fen
Published: January 2024

Aging is a predominant risk factor for heart disease. Aging heart reveals low-grade chronic inflammation, cell apoptosis, cardiac fibrosis, and increased vulnerability to ischemic injury. The underlying molecular mechanisms responsible for the cardiac aging phenotype and its susceptibility to injury are far from being fully understood. Although previous literature reports a role of the mitochondrial enzyme arginase-II (Arg-II) in development of heart failure, contradictory results are reported and no systematic analysis of cellular expression and localization of Arg-II in the heart has been performed. Whether and how Arg-II participates in cardiac aging are still unknown. In this study, we demonstrate, to our surprise, that Arg-II is not expressed in cardiomyocytes from aged mice and human patients, but upregulated in non-myocytes of the aging heart, including macrophages, fibroblasts, endothelial cells. Mice with genetic deficiency ofarg-ii(arg-ii-/-) are protected from age-associated cardiac inflammation, myocyte apoptosis, interstitial and perivascular fibrosis, endothelial-mesenchymal transition (EndMT), and susceptibility to ischemic injury. Further experiments show that Arg-II mediates IL-1β release from macrophages of old mice, contributing to the above-described cardiac aging phenotype. In addition, Arg-II enhances mitochondrial reactive oxygen species (mtROS) and activates cardiac fibroblasts that is inhibited by inhibition of mtROS. Thus, our study demonstrates a non-cell-autonomous effect of Arg-II on cardiomyocytes, fibroblasts, and endothelial cells mediated by IL-1β from aging macrophages as well as a cell-autonomous effect of Arg-II through mtROS in fibroblasts contributing to cardiac aging phenotype.
Comprehensive characterization of the viscoelastic properties of Bovine Submaxillary Mucin (BSM) hydrogels and the effect of additives
Authors: Rulff Hanna , Schmidt Robert F. , Wei Ling-Fang , Fentker Kerstin , Kerkhoff Yannic , Mertins Philipp , Mall Marcus A. , Lauster Daniel , Gradzielski Michael
Published: January 2024

This study presents a comprehensive characterization of the viscoelastic and structural properties of Bovine Submaxillary Mucin (BSM), which is widely used as a commercial source to conduct mucus-related research. We conducted concentration studies of BSM and examined the effects of various additives - NaCl, CaCl2, lysozyme, and DNA - on its rheological behavior. A notable connection between BSM concentration and viscoelastic properties was observed, particularly under varying ionic conditions. The rheological spectra could be well-described by a fractional Kelvin-Voigt Model with a minimum of model parameters. A detailed proteomics analysis provided insight into the molecular interactions within BSM, showing MUC19 as main component. Cryo-scanning electron microscopy allowed to visualize the network structure in relation to the rheological data. By elucidating the complex interplay between mucin concentration, environmental conditions, and viscoelastic properties, this research significantly contributes to the field of mucus research and lays an important basis for its further advancement.