bluuebunny/crossref_metadata_2025 huggingface dataset:
Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2
Authors: Alves Chrystian Junqueira , Hannah Theodore , Sadia Sita , Kolsteeg Christy , Dixon Angela , Wiener Robert J. , Nguyen Ha , Tipping Murray J. , Ladeira Júlia Silva , Franklin Paula Fernandes da Costa , Dutra de Nigro Nathália de Paula , Dias Rodrigo Alves , Zabala Capriles Priscila V. , Rodrigues Furtado de Mendonça José P. , Slesinger Paul , Costa Kevin , Zou Hongyan , Friedel Roland H.
Published: January 2024

Glioblastoma (GBM) is a malignant brain tumor with uncontrolled invasive growth. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 to gain biomechanical plasticity for polarized migration through confined space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal active endocytosis at cell front and filamentous actin assembly at rear to propel GBM cells through constrictions. These two processes are interconnected and governed by Plexin-B2 that orchestrates cortical actin and membrane tension, shown by biomechanical assays. Molecular dynamics simulations predict that balanced membrane and actin tension are required for optimal migratory velocity and consistency. Furthermore, Plexin-B2 mechanosensitive function requires a bendable extracellular ring structure and affects membrane internalization, permeability, phospholipid composition, as well as inner membrane surface charge. Together, our studies unveil a key element of membrane tension and mechanoelectrical coupling via Plexin-B2 that enables GBM cells to adapt to physical constraints and achieve polarized confined migration.
Distinct profiles of tinnitus and hyperacusis in intensity deviant responses and auditory evoked potentials
Authors: Yukhnovich Ekaterina A , Alter Kai , Sedley William
Published: January 2024

ERPs in response to intensity deviant stimuli are assessed in four age and hearing matched groups of various combinations of tinnitus and hyperacusis (both conditions, one of the conditions, neither condition). Distinct profiles for tinnitus and hyperacusis are shown, as well as additional more nuanced interactions. This not only moves our understanding of each condition, but also speaks directly to possible mechanistic subtypes of tinnitus (and of hyperacusis) which might be disentangled through the cheap and available technique that is single-channel EEG. The current findings may also explain some discrepant findings in past literature.
Increased inflammatory signature in myeloid cells of non-small cell lung cancer patients with high clonal hematopoiesis burden
Authors: Sim Hyungtai , Park Hyun Jung , Park Geun-Ho , Kim Yeon Jeong , Park Woong-Yang , Lee Se-Hoon , Choi Murim
Published: January 2024

Clonal hematopoiesis of indeterminate potential (CHIP) allows estimation of clonal dynamics and documentation of somatic mutations in the hematopoietic system. Recent studies utilizing large cohorts of the general population and patients have revealed significant associations of CHIP burden with age and disease status, including in cancer and chronic diseases. An increasing number of cancer patients are treated with immune checkpoint inhibitors (ICI), but the association of ICI response in non-small cell lung cancer (NSCLC) patients with CHIP burden remains to be determined. We collected blood samples from 100 metastatic NSCLC patients before and after ICI for high-depth sequencing of the CHIP panel and 63 samples for blood single-cell RNA sequencing(scRNA-seq). Whole exome sequencing (WES) was performed in an independent replication cohort of 180 patients. The impact of CHIP status on the immunotherapy response was not significant. However, metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs 5/42 for controls;P= 0.01). In addition, lung squamous cell carcinoma patients showed increased burden of larger clones compared to lung adenocarcinoma patients (8/43 for LUSC vs 2/50 for LUAD;P= 0.04). Furthermore, single cell RNA-seq analysis of the matched patients showed significant enrichment of inflammatory pathways mediated by NF-ĸB in myeloid clusters of the severe CHIP group. Our findings suggest minimal involvement of CHIP mutation and clonal dynamics during immunotherapy but a possible role of CHIP as an indicator of immunologic response in NSCLC patients.
The Neuron as a Direct Data-Driven Controller
Authors: Moore Jason , Genkin Alexander , Tournoy Magnus , Pughe-Sanford Joshua , de Ruyter van Steveninck Rob R. , Chklovskii Dmitri B.
Published: January 2024

In the quest to model neuronal function amidst gaps in physiological data, a promising strategy is to develop a normative theory that interprets neuronal physiology as optimizing a computational objective. This study extends the current normative models, which primarily optimize prediction, by conceptualizing neurons as optimal feedback controllers. We posit that neurons, especially those beyond early sensory areas, act as controllers, steering their environment towards a specific desired state through their output. This environment comprises both synaptically interlinked neurons and external motor sensory feedback loops, enabling neurons to evaluate the effectiveness of their control via synaptic feedback. Utilizing the novel Direct Data-Driven Control (DD-DC) framework, we model neurons as biologically feasible controllers which implicitly identify loop dynamics, infer latent states and optimize control. Our DD-DC neuron model explains various neurophysiological phenomena: the shift from potentiation to depression in Spike-Timing-Dependent Plasticity (STDP) with its asymmetry, the duration and adaptive nature of feedforward and feedback neuronal filters, the imprecision in spike generation under constant stimulation, and the characteristic operational variability and noise in the brain. Our model presents a significant departure from the traditional, feedforward, instant-response McCulloch-Pitts-Rosenblatt neuron, offering a novel and biologically-informed fundamental unit for constructing neural networks.
De novo multi-mechanism antimicrobial peptide design via multimodal deep learning
Authors: Wang Yue , Gong Haifan , Li Xiaojuan , Li Lixiang , Zhao Yinuo , Bao Peijing , Kong Qingzhou , Wan Boyao , Zhang Yumeng , Zhang Jinghui , Ni Jiekun , Han Zhongxue , Nan Xueping , Ju Kunping , Sun Longfei , Chang Huijun , Zheng Mengqi , Yu Yanbo , Yang Xiaoyun , Zuo Xiuli , Li Yanqing
Published: January 2024

Artificial intelligence (AI)-driven discovery of antimicrobial peptides (AMPs) is yet to fully utilise their three-dimensional (3D) structural characteristics, microbial specie-specific antimicrobial activities and mechanisms. Here, we constructed a QLAPD database comprising the sequence, structures and antimicrobial properties of 12,914 AMPs. QLAPD underlies a multimodal, multitask, multilabel, and conditionally controlled AMP discovery (M3-CAD) pipeline, which is proposed for thede novodesign of multi-mechanism AMPs to combat multidrug-resistant organisms (MDROs). This pipeline integrates the generation, regression, and classification modules, using a innovative 3D voxel coloring method to capture the nuanced physicochemical context of amino acids, significantly enhancing structural characterizations. QL-AMP-1, discovered by M3-CAD, which possesses four antimicrobial mechanisms, exhibited low toxicity and significant activity against MDROs. The skin wound infection model demonstrates its considerable antimicrobial effects and negligible toxicity. Altogether, integrating 3D features, specie-specific antimicrobial activities and mechanisms enhanced AI-driven AMP discovery, making the M3-CAD pipeline a viable tool forde novoAMP design.
BCI Toolbox: An Open-Source Python Package for the Bayesian Causal Inference Model
Authors: Zhu Haocheng , Beierholm Ulrik , Shams Ladan
Published: January 2024

Psychological and neuroscientific research over the past two decades has shown that the Bayesian causal inference (BCI) is a potential unifying theory that can account for a wide range of perceptual and sensorimotor processes in humans. Therefore, we introduce the BCI Toolbox, a statistical and analytical tool in Python, enabling researchers to conveniently perform quantitative modeling and analysis of behavioral data. Additionally, we describe the algorithm of the BCI model and test its stability and reliability via parameter recovery. The present BCI toolbox offers a robust platform for BCI model implementation as well as a hands-on tool for learning and understanding the model, facilitating its widespread use and enabling researchers to delve into the data to uncover underlying cognitive mechanisms.
Metabolome and transcriptome profiling of root chicory provide insights into laticifer development and specialized metabolism
Authors: Vahabi Khabat , Balcke Gerd U. , Hakkert Johanna C. , van der Meer Ingrid M. , Athmer Benedikt , Tissier Alain
Published: January 2024

Chicory roots produce inulin, a dietary fiber, as well as large quantities of bitter sesquiterpene lactones (STLs), which have valuable biological activities. In an effort to understand the compartmentalization of metabolism within chicory roots and the molecular basis of the development of laticifers that produce the chicory latex, we performed metabolomics and transcriptomics profiling. GC-MS and LC-MS identified a total of 22 580 features of which 135 were differentially abundant between cell types. Further analysis indicated that the major STLs accumulated primarily in the latex. Gene expression of known STL pathway genes indicates a compartmentalization of the biosynthesis across multiple tissues, with implications regarding the trafficking of pathway intermediates. Phytohormone measurements and gene expression analysis point to a major role for jasmonate signaling in the development and differentiation of laticifers. Furthermore, inulin accumulates mostly outside the laticifers but expression of inulin metabolic genes also point to a complex distribution and trafficking of inulin or inulin precursors across different root compartments. Altogether, the data presented here constitute a unique resource to investigate several biological processes in chicory roots, including laticifer development, STL biosynthesis and transport and inulin biosynthesis regulation.

Significance statement

A combination of transcriptomics, targeted and untargeted metabolomics of different tissues of chicory roots was generated. These data constitute a resource basis for the investigation of various processes taking place in chicory taproots, including sesquiterpene lactone biosynthesis, laticifer development and inulin biosynthesis and trafficking.
Alzheimer’s disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy
Authors: Geut Hanne , van den Berg Emma , Boon Baayla D.C. , Hoozemans Jeroen J.M. , Tunold Jon-Anders , Pihlstrøm Lasse , Jonkman Laura E. , Rozemuller J.M. Annemieke , Lemstra A.W. Evelien , van de Berg Wilma D.J.
Published: January 2024

Background

In dementia with Lewy bodies (DLB), co-existence of Alzheimer’s disease (AD) pathology, i.e. amyloid-β plaques and tau tangles, has been associated with a more rapid disease progression. In post-mortem DLB brains, we examined the association between AD copathology and regional load and morphology of α-synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD.

Methods

We included 50 autopsy-confirmed DLB donors with a clinical DLB phenotype, categorized as having no/low levels of AD copathology (pure DLB,n= 15), or intermediate/high levels of AD copathology (mixed DLB+AD,n= 35), and autopsy-confirmed pure AD donors (n= 14) without α- synuclein pathology. We used percentage area of immunopositivity for quantitative assessment of pathology load, and visual scores for semi-quantitative assessment of different morphologies of α- synuclein, amyloid-β and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions.

Results

Mixed DLB+AD compared to pure DLB showed a shorter disease duration (6 ± 3 versus 8 ± 3 years,p= 0.021) and higher frequency ofAPOE-ε4 alleles. A-synuclein load was higher in neocortical regions (temporal, parietal and occipital), but not in brainstem and limbic regions, which was based upon an increase of Lewy bodies, α-synuclein-positive astrocytes and α-synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-β and p-tau load in temporal (r= 0.38 andr= 0.50 respectively) and occipital regions (r= 0.43 andr= 0.42 respectively). Compared to pure AD, mixed DLB+AD showed a lower amyloid-β load in temporal cortex, CA3 and CA4 region, and lower p-tau loads in frontal and parietal cortex, based both upon presence of fewer neuritic plaques as well as neurofibrillary tangles.

Conclusions

In DLB brains, AD copathology was associated with more neocortical α-synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial α-synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial α-synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline.
Effects of joint invasion: how co-invaders affect each other’s success in model food webs?
Authors: Móréh Ágnes , Jordán Ferenc , Scheuring István
Published: January 2024

While there is considerable research on interactions between invasive and native species, as well as on the impact of invasive species on the resident community, less focus has been placed on exploring the relationship and interactions among invasive species themselves. Nevertheless, it is widely acknowledged that invasive species can have either positive or negative effects on one another’s success, in addition to neutral outcomes. In the present theoretical study, we compared the success of two invasive non-native species in two scenarios: when they invaded the resident food web separately and simultaneously. We investigated the correlations between their direct and indirect ecological relationships and the topological positions of them in the food web, with the varying outcomes of joint invasion. Using the allometric bioenergetic model (ABM) for dynamical simulations, we detected the success of invasion (presence or absence of invaders) and the direction of their biomass change comparing separated and simultaneous invasion scenarios. We studied the relationships among these variables after detailed numerical simulations with variable key parameters of the model.

We found that direct and indirect ecological relationships between the two invaders are significantly modifies the invasion scenarios: the predator-prey relationship increases the probability of invasion success for both invaders, but the equilibrium biomass of at least one of them is more likely to be reduced than in separate invasions. The trophic cascade or competitive relationship between them during simultaneous invasion also affects their success rate, with the former having a positive effect and the latter a negative one. Further, we found that higher trophic level and lower betweenness centralities of the invaders reduces the likelihood of invasion success regardless of the presence or absence of another invasive species. The results of the study can be tested experimentally in micro- and mesocosms.

HIGHLIGHTS

In a joint invasion, invaders can influence each other’s success

Predator-prey relationships between invaders increase the joint invasion success

Competition increases the failure of at least one invader

The trophic cascade between invaders increases the joint invasion success

Higher trophic levels or lower betweenness centralities of the invaders increase the probability of unsuccessful joint invasion

GRAPHICAL ABSTRACT
Thermogenetics for cardiac pacing
Authors: Balatskiy Alexander V. , Nesterenko Alexey M. , Lanin Aleksandr A. , Ovechkina Vera S. , Sabinin Semyon S. , Fetisova Elena S. , Moshchenko Alexander A. , Jappy David , Sokolov Rostislav A. , Biglova Diana Z. , Solius Georgy M. , Solyus Ekaterina M. , Korolev Sergei V. , Podgorny Oleg V. , Kelmanson Ilya V. , Rozov Andrei V. , Fedotov Andrei B. , Bruegmann Tobias , Zheltikov Alexei M. , Mozhaev Andrey A. , Belousov Vsevolod V.
Published: January 2024

Cardiac arrhythmias are common disorders that can be fatal. Modern methods of treating bradyarrhythmias include the implantation of pacemakers and cardioverters – defibrillators. However, the implantable devices can cause various complications including infectious ones, related to the electrodes installed inside the heart. Less invasive heart rhythm modulation could be beneficial for some cohorts of patients. We present an alternative approach to heart pacing based on thermogenetics. We used adeno-associated viruses to deliver genetic human transient receptor potential subfamily V member 1 (TRPV1), a heat-sensitive cation channel, into isolated cardiomyocytes and the mouse heart. This allowed us to induce action potentials and control contractility using short heat pulses delivered by infrared laser illumination. Using this approach, we demonstrated the thermogenetic pacing of isolated cardiomyocytesin vitroand in the mouse heartin vivo. Our results demonstrate the unique potential of thermogenetics for developing novel therapeutic strategies for heart rhythm modulation.
The opossum and other didelphids in the cultures of Costa Rican society and indigenous peoples: an approach to ecology and conservation
Authors: Romero Yara Azofeifa , Alvarado Francisco Durán
Published: January 2024

The opossumDidelphis marsupialis, commonly referred to as thezorro pelónin Costa Rica, is a marsupial that holds significant representation in both Costa Rican and indigenous cultures, such as the Talamanca natives. This species, along with the other ten opossums found in Costa Rica, constitute one of the groups of mammals with the least representation in scientific literature. This study aims to (1) document the knowledge, uses, perceptions, and human-zorro pelóninteractions through surveys conducted with individuals in three types of zones: rural, semi-urban, and urban; and (2) explore the presence of opossums in the 19th-century worldview of farmers and in the cosmovision of indigenous peoples. We performed an analysis on the text and Likert-scale data collected from 296 surveys conducted across seven provinces in Costa Rica. Nonparametric tests were conducted to assess whether the type of zone influenced the interactions and perceptions of individuals. Valuable information was obtained from key participants and informants regarding the behavior, observation sites, diet, and population trends of the species. The remarkable adaptability of thezorro pelónis evident in rural and semi-urban environments, but not in urban zones. The human-zorro pelóninteraction data between the rural and semi-urban zones are similar, but these differ significantly from the urban zone. Although people surveyed generally have a positive perception of the opossum, there has been a notable devaluation over time when compared to the imaginary of indigenous cultures. Parallels were observed in the beliefs and uses of marsupials between pre-Columbian societies and contemporary Costa Rican societies. As part of the educational strategies for the conservation of marsupials, it is important to promote their appreciation and refute negative stereotypes, such as by informing about their ecological role and their ability to resist pathogens and venom. In this context, the rich symbolism of the opossum can be utilized to adapt the message to the various regions of America.
Intensity mismatch asymmetry in tinnitus – in which direction should participants pay attention?
Authors: Yukhnovich Ekaterina A , Alter Kai , Sedley William
Published: January 2024

The effects attention has on intensity deviant Mismatch Negativity responses is an unknown factor in basic sensory neuroscience. It would be useful to understand how attention would affect responses to intensity deviants compared to each other (upward vs downward), and compared to other sensory dimensions such as frequency. Overall, previous research indicates that attention may modulate neuronal gain in healthy participants and change the amplitudes of evoked responses, and may mainly affect the responses to regularly repeating (standard) stimuli rather than deviants. Gain may respond differently in participants with tinnitus and/or hyperacusis under the same conditions compared to controls. Overall, results of the passive task condition were consistent with previous research. Auditory attention magnified MMN in response to upward deviants, while visual attention attenuated it in both control and tinnitus groups. However, auditory attention selectively enhanced downward deviant MMN in the tinnitus group (compared to passive attention). Using the auditory attention paradigm may be advantageous in MMN studies on tinnitus/hyperacusis because the observed differences would be particularly large.
Direct interrogation of context-dependent GPCR activity with a universal biosensor platform
Authors: Janicot Remi , Maziarz Marcin , Park Jong-Chan , Luebbers Alex , Green Elena , Zhao Jingyi , Philibert Clementine , Zhang Hao , Layne Mathew D. , Wu Joseph C. , Garcia-Marcos Mikel
Published: January 2024

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically-relevant contexts. Here, we developed a collection of compactONEvectorG-proteinOptical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed new insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally-occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states. In summary, this open-source platform makes the direct interrogation of context-dependent GPCR activity broadly accessible.
Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood
Authors: Bulgarelli Chiara , Blasi Anna , McCann Samantha , Milosavljevic Bosiljka , Ghillia Giulia , Mbye Ebrima , Touray Ebou , Fadera Tijan , Acolatse Lena , Moore Sophie E. , Lloyd-Fox Sarah , Elwell Clare E. , Eggebrecht Adam T. ,   the BRIGHT Study Team
Published: January 2024

Functional brain network organization, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, e.g. undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onward. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5 to 24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3-5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.
Editing of endogenous tubulins reveals varying effects of tubulin posttranslational modifications on axonal growth and regeneration
Authors: Lu Yu-Ming , Yan Shan , Ti Shih-Chieh , Zheng Chaogu
Published: January 2024

Tubulin posttranslational modifications (PTMs) modulate the dynamic properties of microtubules and their interactions with other proteins. However, the effects of tubulin PTMs were often revealed indirectly through the deletion of modifying enzymes or the overexpression of tubulin mutants. In this study, we directly edited the endogenous tubulin loci to install PTM-mimicking or -disabling mutations and studied their effects on microtubule stability, neurite outgrowth, axonal regeneration, cargo transport, and sensory functions in the touch receptor neurons ofCaenorhabditis elegans. We found that the status of β-tubulin S172 phosphorylation and K252 acetylation strongly affected microtubule dynamics, neurite growth, and regeneration, whereas α-tubulin K40 acetylation had little influence. Polyglutamylation and detyrosination in the tubulin C-terminal tail had more subtle effects on microtubule stability likely by modulating the interaction with kinesin-13. Overall, our study systematically assessed and compared several tubulin PTMs for their impacts on neuronal differentiation and regeneration and established anin vivoplatform to test the function of tubulin PTMs in neurons.
Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis
Authors: Pei Xintong , Wang Zhe , He Wenting , Li Shunqin , Lan Yongguang , Yuan Lin , Xu Pingyong
Published: January 2024

As a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3’-UTRs ofNox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake onNox4mRNA translation, and thus, the uncontrolled translation ofNox4leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to theIns2gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restoredMafAtranslation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specificEi24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2and normal biological functions under physiological conditions.
Dominant negative mutations in yeast Hsp90 reveal triage decision mechanism targeting client proteins for degradation
Authors: Flynn Julia M. , Joyce Margot E. , Bolon Daniel N. A.
Published: January 2024

Most of the fundamental processes of cells are mediated by proteins. However, the biologically-relevant mechanism of most proteins are poorly understood. Dominant negative mutations have provided a valuable tool for investigating protein mechanisms but can be difficult to isolate because of their toxic effects. We used a mutational scanning approach to identify dominant negative mutations in yeast Hsp90. Hsp90 is a chaperone that forms dynamic complexes with many co-chaperones and client proteins. In vitro analyses have elucidated some key biochemical states and structures of Hsp90, co-chaperones, and clients; however, the biological mechanism of Hsp90 remains unclear. For example, high throughput studies have found that many E3 ubiquitin ligases bind to Hsp90, but it is unclear if these are primarily clients or acting to tag other clients for degradation. We introduced a library of all point mutations in the ATPase domain of Hsp90 into yeast and noticed that 176 were more than 10-fold depleted at the earliest point that we could analyze. There were two hot spot regions of the depleted mutations that were located at the hinges of a loop that closes over ATP. We quantified the dominant negative growth effects of mutations in the hinge regions using a library of mutations driven by an inducible promoter. We analyzed individual dominant negative mutations in detail and found that addition of the E33A mutation that prevents ATP hydrolysis by Hsp90 abrogated the dominant negative phenotype. Pull-down experiments did not reveal any stable binding partners, indicating that the dominant effects were mediated by dynamic complexes. DN Hsp90 decreased the expression level of two model Hsp90 clients, glucocorticoid receptor (GR) and v-src kinase. Using MG132, we found that GR was rapidly destabilized in a proteasome-dependent fashion. These findings provide evidence that the binding of E3 ligases to Hsp90 may serve a quality control function fundamental to eukaryotes.
Long range projections of oxytocin neurons in the marmoset brain
Authors: Lefevre Arthur , Meza Jazlynn , Miller Cory T.
Published: January 2024

The neurohormone oxytocin (OT) has become a major target for the development of novel therapeutic strategies to treat psychiatric disorders such as autism spectrum disorder because of its integral role in governing many facets of mammalian social behavior. Whereas extensive work in rodents has produced much of our knowledge of OT, we lack basic information about its neurobiology in primates making it difficult to interpret the limited effects that OT manipulations have had in human patients. In fact, previous studies have revealed only limited OT fibers in primate brains. Here, we investigated the OT connectome in marmoset using immunohistochemistry, and mapped OT fibers throughout the brains of adult male and female marmoset monkeys. We found extensive OT projections reaching limbic and cortical areas that are involved in the regulation of social behaviors, such as the amygdala, the medial prefrontal cortex and the basal ganglia. The pattern of OT fibers observed in marmosets is notably similar to the OT connectomes described in rodents. Our findings here contrast with previous results by demonstrating a broad distribution of OT throughout the marmoset brain. Given the prevalence of this neurohormone in the primate brain, methods developed in rodents to manipulate endogenous OT are likely to be applicable in marmosets.
An opponent striatal circuit for distributional reinforcement learning
Authors: Lowet Adam S. , Zheng Qiao , Meng Melissa , Matias Sara , Drugowitsch Jan , Uchida Naoshige
Published: January 2024

Machine learning research has achieved large performance gains on a wide range of tasks by expanding the learning target from mean rewards to entire probability distributions of rewards — an approach known as distributional reinforcement learning (RL)1. The mesolimbic dopamine system is thought to underlie RL in the mammalian brain by updating a representation of mean value in the striatum2,3, but little is known about whether, where, and how neurons in this circuit encode information about higher-order moments of reward distributions4. To fill this gap, we used high-density probes (Neuropixels) to acutely record striatal activity from well-trained, water-restricted mice performing a classical conditioning task in which reward mean, reward variance, and stimulus identity were independently manipulated. In contrast to traditional RL accounts, we found robust evidence for abstract encoding of variance in the striatum. Remarkably, chronic ablation of dopamine inputs disorganized these distributional representations in the striatum without interfering with mean value coding. Two-photon calcium imaging and optogenetics revealed that the two major classes of striatal medium spiny neurons — D1 and D2 MSNs — contributed to this code by preferentially encoding the right and left tails of the reward distribution, respectively. We synthesize these findings into a new model of the striatum and mesolimbic dopamine that harnesses the opponency between D1 and D2 MSNs5–15to reap the computational benefits of distributional RL.
Single-cell RNA-seq analysis profiling characterizes differences in cell composition and physiology between normal tissue, treatment naive, and cisplatin-treated ovarian cancer
Authors: Guo Fang , Yang Zhi , Sehouli Jalid , Kaufmann Andreas M.
Published: January 2024

Background

Intense efforts have focused on identifying heterogeneity of the cellular composition in ovarian cancer. However, tissue composition and physiological conditions of cancer cells in cisplatin-sensitive ovarian cancer remains largely unknown. Moreover, comparisons of different cellular states in normal tissue, in treatment naive ovarian cancer, and in cisplatin-treated tissue after adjuvant therapy of cisplatin-sensitive ovarian cancer at the single-cell level might offer clues for ovarian cancer treatment and prevention of cisplatin-resistance formation.

Methods

Single-cell transcriptome sequencing of a cisplatin-treated ovarian cancer was performed. Data sets of non-tumorous ovarian tissues and treatment-naive ovarian cancer were downloaded from the European Genome-phenome Archive (accession number EGAS00001004987). Quality control, batch effect correction, integration, and clustering analysis of the integrated single-cell transcriptome data was done. Cell subsets were annotated based on surface marker phenotypes. Finally, the proportions of subclusters, the immune cell population, and the potential biological processes among different cellular states were compared.

Results

Sixteen distinct cell subsets were identified from the integrated single-cell transcriptome sequencing data of a pool of all tissues. The composition of the three different tissue types was characterized. The proportion of fibroblasts in cisplatin-treated ovarian tumor was remarkably lower than in treatment-naive ovarian tumor (1.33% vs. 13.53%, p < 0.05). Moreover, each subject’s sample had differing relative proportions of the identified cell types. In primary untreated ovarian cancer, the prevalent immune cells were B cells and myeloid-related immunosuppressive M2 macrophages. However, there were less B cells and myeloid-related immunosuppressive M2 macrophages after cisplatin-treatment, while significantly more T cells were found. The physiological cellular state in primary untreated ovarian tumors was associated with dysfunctional gene expression and modulation of cellular homeostasis, while cells from cisplatin-treated tumor showed more activation of immune and inflammatory genes as compared to healthy ovarian tissue.

Conclusion

Our molecular gene expression analysis allowed for the separation and identification of differences in normal ovarian tissues, treatment-naive, and cisplatin-sensitive ovarian cancer cell populations at single-cell resolution. We identified different cell type composition and discriminative marker expression concerning specific cell subsets and identified differences among their physiological cell states. This knowledge may open new possibilities for elucidating important pathogenetic features and therapeutic strategies for treating ovarian cancer.
Inhibiting YAP1 reduced abdominal aortic aneurysm formation by suppressing adventitial fibroblast phenotype transformation and migration
Authors: Xie Cuiping , Hu Yanting , Yin Zhehui , Xie Cuiping
Published: January 2024

BACKGROUND

The adventitial fibroblast (AF) is the most abundant cell in the vascular adventitia, a few studies had confirmed that AF contributed to abdominal aortic aneurysm (AAA) development; YAP1 involved in several vascular diseases by promoting AF transformed to myofibroblast, the role of YAP1 in AAA is not clear yet. This study aims to determine whether YAP1 play a role in AAA process by regulating AF function.

METHODS

Elastase-induced and Cacl2-induced mice AAA model were used in this study, we applied YAP1 inhibitor-Verteporfinin vivoto explore the role of YAP1 in AAA information;in vitro, Verteporfin and YAP1-siRNA were used to intervened TGF-β1 induced fibroblasts phenotype transformation and migration model.

RESULTS

At first, we use immunohistochemistry (IHC) and western blotting (WB) to compare the expression of YAP1 in aneurysm tissues of AAA patients with normal adjacent vascular tissues, we found that the expression of YAP1 in AAA tissues was significantly increased, and YAP1 mainly increased in adventitia. YAP1 also upregulated in elastase-induced and Cacl2-induced mice AAA model. Then, we diminished YAP1 function with YAP1 inhibitor-Verteporfin in above mice AAA model, AAA incident rate was remarkably declined, and the collagen deposition in the adventitia was alleviated obviously. Afterwards, we studied the effect of YAP1 on the function of AF, we found that the process of AF transforming to myofibroblast and migration were almost completely eliminated after inhibiting YAP1 expression.

CONCLUSIONS

This study demonstrated that YAP1 may play a key role in AAA development, inhibiting YAP1 significantly reduced AAA formation through suppressed the process of AF transformed to myofibroblast and migration.
SYNTERUPTOR: mining genomic islands for non-classical specialised metabolite gene clusters
Authors: Haas Drago , Barba Matthieu , Vicente Cláudia M. , Nezbedová Šarká , Garénaux Amélie , Bury-Moné Stéphanie , Lorenzi Jean-Noël , Hôtel Laurence , Laureti Luisa , Thibessard Annabelle , Goff Géraldine Le , Ouazzani Jamal , Leblond Pierre , Aigle Bertrand , Pernodet Jean-Luc , Lespinet Olivier , Lautru Sylvie
Published: January 2024

Microbial specialised metabolite biosynthetic gene clusters (SMBGCs) are a formidable source of natural products of pharmaceutical interest. With the multiplication of genomic data available, very efficient bioinformatic tools for automatic SMBGC detection have been developed. Nevertheless, most of these tools identify SMBGCs based on sequence similarity with enzymes typically involved in specialised metabolism and thus may miss SMBGCs coding for under characterised enzymes. Here we present SYNTERUPTOR (https://bioi2.i2bc.paris-saclay.fr/synteruptor), a program that identifies genomic islands, known to be enriched in SMBGCs, in the genomes of closely related species. With this tool, we identified a SMBGC in the genome ofStreptomyces ambofaciensATCC23877, undetected by earlier versions of antiSMASH, and experimentally demonstrated that it directs the biosynthesis of two metabolites, one of which was identified as sphydrofuran. SYNTERUPTOR is also a valuable resource for the delineation of individual SMBGCs within antiSMASH regions that may encompass multiple clusters, and for refining the boundaries of these SMBGCs.
Local delivery of cell surface-targeted immunocytokines programs systemic anti-tumor immunity
Authors: Santollani Luciano , Zhang Yiming J. , Maiorino Laura , Palmeri Joseph R. , Stinson Jordan A. , Duhamel Lauren R. , Qureshi Kashif , Suggs Jack R. , Porth Owen T. , Pinney William , Msari Riyam Al , Dane Wittrup K. , Irvine Darrell J.
Published: January 2024

Cytokine therapies are potent immunotherapy agents but exhibit severe dose-limiting toxicities. One strategy to overcome this involves engineering cytokines for intratumoral retention following local delivery. Here, we develop a localized cytokine therapy that elicits profound anti-tumor immunity by engineered targeting to the ubiquitous leukocyte receptor CD45. We designed CD45-targeted immunocytokines (αCD45-Cyt) that, upon injection, decorated the surface of leukocytes in the tumor and tumor-draining lymph node (TDLN) without systemic exposure. αCD45-Cyt therapy eradicated both directly treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models. Mechanistically, αCD45-Cyt triggered prolonged pSTAT signaling and reprogrammed tumor-specific CD8+T cells in the TDLN to exhibit an anti-viral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
Environmental biofilms versus POCIS: efficiency to highlight environmental presence of pharmaceuticals and their effect on biofilm microbiome
Authors: Chonova Teofana , Bouchez Agnès , Mondamert Leslie , Aubertheau Elodie , Labanowski Jérôme
Published: January 2024

Pharmaceutical compounds (PhC) are an important environmental issue, because of their high variety, potentially toxic byproducts and bioactivity at low concentrations. PhC concentrations in WWTP effluents often exhibit large and rapid variations that are difficult to record. Passive samplers are helpful to incorporate spot pollution events and register PhC occurrence at low concentrations.

In this work, we aim at (i) studying PhC accumulation in polar organic chemical integrative samplers (POCIS) and environmental biofilms exposed to urban (U) and hospital (H) treated effluents and (ii) evaluating the capacity of POCIS to predict changes in biofilm microbiome over a defined time period. Moreover, we (iii) determine the enrichment of PhC in the recipient river to evaluate levels of environmental contamination and potential effects on microbial biofilms. Biofilms and POCIS were installed in treated effluents and in the recipient river to measure the accumulation of PhC. In parallel, microbial biofilm communities were studied using DNA metabarcoding. The duration of each deployment was one month and the experiment was repeated six times. The performance of POCIS and biofilms to quantify PhC was depending on the compound. POCIS appeared well adapted to reveal contamination trends similar to these in the water column and to identify key PhC drivers of microbial changes. POCIS have the potential to predict pharmaceutical effects on biofilm community structure.
Combinatorial prediction of therapeutic perturbations using causally-inspired neural networks
Authors: Gonzalez Guadalupe , Lin Xiang , Herath Isuru , Veselkov Kirill , Bronstein Michael , Zitnik Marinka
Published: January 2024

Phenotype-driven approaches identify disease-counteracting compounds by analyzing the phenotypic signatures that distinguish diseased from healthy states. These approaches can guide the discovery of targeted perturbations, including small-molecule drugs and genetic interventions, that modulate disease phenotypes toward healthier states. Here, we introduce PDGrapher, a causally inspired graph neural network (GNN) designed to predict combinatorial perturbagens (sets of therapeutic targets) capable of reversing disease phenotypes. Unlike methods that learn how perturbations alter phenotypes, PDGrapher solves the inverse problem of directly predicting the perturbagens needed to achieve a desired response. PDGrapher is a GNN that embeds disease cell states into gene regulatory or protein-protein interaction networks, learns a latent representation of these states, and identifies the optimal combinatorial perturbations that most effectively shift the diseased state toward the desired treated state within that latent space. In experiments in nine cell lines with chemical perturbations, PDGrapher identified effective perturbagens in up to 13.33% more test samples than competing methods and achieved a normalized discounted cumulative gain of up to 0.12 higher to classify therapeutic targets. It also demonstrated competitive performance on ten genetic perturbation datasets. A key advantage of PDGrapher is its direct prediction paradigm, in contrast to the indirect and computationally intensive models traditionally employed in phenotype-driven research. This approach accelerates training by up to 25 times compared to existing methods. PDGrapher provides a fast approach for identifying therapeutic perturbations and advancing phenotype-driven drug discovery.
Enzymatic modulation of the pulmonary glycocalyx alters susceptibility toStreptococcus pneumoniae
Authors: Goekeri Cengiz , Linke Kerstin A.K. , Hoffmann Karen , Lopez-Rodriguez Elena , Gluhovic Vladimir , Voß Anne , Kunder Sandra , Zappe Andreas , Timm Sara , Nettesheim Alina , Schickinger Sebastian M.K. , Zobel Christian M. , Pagel Kevin , Gruber Achim D. , Ochs Matthias , Witzenrath Martin , Nouailles Geraldine
Published: January 2024

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the precise role of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice withStreptococcus pneumoniaein the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma levels of pro-inflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage and pulmonary inflammation in mice infected withStreptococcus pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier. Notably, enzymatic pre-treatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococcal-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in controlling pneumococcal virulence, pulmonary inflammation, and epithelial barrier function.