bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro-generated inflammatory fibroblasts secrete extracellular matrix with biochemical and biophysical properties similar to tissue-remodelling fibroblasts
Authors: de la Jara Ortiz Fàtima , Cimmino Chiara , Grech Kurt , Huynen Martijn A. , Janssen Eline , Wagenaar Vera , van Zwam Maxime C. , van den Dries Koen , Ventre Maurizio , Cambi Alessandra
Published: September 2024

In solid cancers, inflammation and viral infections, two main fibroblast subtypes have been identified: myofibroblast-like fibroblasts and inflammatory fibroblasts. In the tumour microenvironment (TME), these cancer-associated fibroblast (CAF) subtypes are known as myCAFs, which generate a stiffened fibrotic extracellular matrix (ECM), and iCAFs, which secrete inflammatory cytokines to locally modulate the immune response. Yet, whether iCAFs contribute to shaping the ECM biochemical and biophysical properties remains unknown, mainly because robustin vitromodels to generate fibroblast subtypes are lacking. Here, we established anin vitrocell culture system based on murine NIH3T3 fibroblasts and stimulation by TGFβ and IL1α, alone or in combination, to induce fibroblast subtypes. Gene expression analysis of well-documented myCAF (Acta2/Tagln) and iCAF (Ccl2/Il6/Lif) markers revealed that TGFβ induced a myCAF-like phenotype, while a combination of TGFβ and IL1α induced an iCAF-like phenotype. We compared thesein vitrosubtypes to myCAFs and iCAFs from publicly available scRNAseq data of tumour tissues from cancer patients. We found that, similar to myCAFs, both tumour-associated andin vitroiCAFs expressActa2/Taglnas well as genes encoding for typical ECM proteins, which correlatedin vitrowith the ability to contract collagen. Furthermore, fluorescence microscopy and atomic force microscopy revealed thatin vitroboth subtypes generate thick, layered and stiff matrices with highly aligned ECM, demonstrating for the first time that iCAFs may also contribute to a pathological ECM. Finally, matrices generated from thesein vitrofibroblast subtypes, but not from uninduced or IL1α-only stimulated fibroblasts, enhanced the expression of the immune suppression marker Arg1 in co-cultured macrophages. Our study provides new insights in the contribution of inflammatory fibroblasts to ECM deposition and remodelling and puts forward a well-definedin vitromodel to generate different fibroblast subtypes for future in-depth mechanistic studies of their roles in cancer and other pathologies.
Sleep modulates neural timescales and spatiotemporal integration in the human cortex
Authors: Cusinato Riccardo , Seiler Andrea , Schindler Kaspar , Tzovara Athina
Published: September 2024

Spontaneous neural dynamics manifest across multiple timescales, which are intrinsic to brain areas and exhibit hierarchical organization across the cortex. In wake, a hierarchy of timescales is thought to naturally emerge from microstructural properties, gene expression, and recurrent connections. A fundamental question is timescales’ organization and changes in sleep, where physiological needs are different. Here, we describe two coexisting but distinct measures of neural timescales, obtained from broadband activity and gamma power, which display complementary properties. We leveraged intracranial electroencephalography (iEEG) data to characterize timescale changes from wake to sleep across the cortical hierarchy. We show that both broadband and gamma timescales are globally longer in sleep than in wake. While broadband timescales increase along the sensorimotor-association axis, gamma ones decrease. During sleep, slow waves can explain the increase of broadband and gamma timescales, but only broadband ones show a positive association with slow-wave density across the cortex. Finally, we characterize spatial correlations and their relationship with timescales as a proxy for spatiotemporal integration, finding high integration at long distances in wake for broadband and at short distances in sleep for gamma timescales. Our results suggest that mesoscopic neural populations possess different timescales that are shaped by anatomy and are modulated by the sleep/wake cycle.

Significance statement

Understanding the organization of intrinsic neural dynamics is crucial for investigating brain functions in health and disease. A key question is: how do neural dynamics change in the sleeping brain? Here we focus on neural timescales, which measure temporal autocorrelation and are organized hierarchically across the cortex, and spatial correlations. We show that two types of timescales exist in neural populations recorded with intracranial electroencephalography in humans, corresponding to broadband (0.5-80 Hz) and gamma (40-80 Hz) frequency ranges. Both timescales increase in sleep, where slow waves have an important role, but follow opposite hierarchies: broadband timescales increase from sensory to associative areas, while gamma timescales show the reverse pattern. Finally, timescales covary with spatial correlations, suggesting higher spatiotemporal integration over long distances in wake compared to sleep.
EMT Induction In Normal Breast Epithelial Cells ByCOX2-Expressing Fibroblasts
Authors: Kang Minwoo , Devarasou Somayadineshraj , Kwon Tae Yoon , Shin Jennifer H.
Published: September 2024

Background

The tumor microenvironment (TME) plays a pivotal role in cancer progression, with cancer-associated fibroblasts (CAFs) significantly influencing tumor behavior. Especially, elevatedCOX2expressing fibroblasts within the TME, notably in collagen-dense tumors like breast cancer, has been recently emphasized in the literature. However, the specific effect ofCOX2-expressing CAFs (COX2+CAFs) on neighboring cells and their consequent role in cancer progression is not fully elucidated.

Methods

We inducedCOX2+fibroblasts by forcing the fibroblasts forming aggregates to undergo Nemosis as a proxy forCOX2+CAFs. This approach enabled us to simulate the paracrine interactions betweenCOX2+CAFs and normal breast epithelial cells via conditioned media fromCOX2+fibroblasts. We developed an innovativein vitroplatform that combines cell mechanics-based analysis and biomolecular assays to study the interactions betweenCOX2+fibroblasts and normal breast epithelial cells. By focusing on the mechanical characteristics of the cells and the EMT marker expressions, we aimed to elucidate the paracrine mechanisms through whichCOX2+CAFs influence the tumor microenvironment.

Results

Ourin vitrofindings reveal thatCOX2+fibroblasts, through conditioned media, induce significant changes in the mechanical behavior of normal breast epithelial cells, facilitating their transition towards mesenchymal types. This transition was corroborated by increased expression of mesenchymal markers. By drawing parallels betweenCOX2+fibroblasts andCOX2+CAFs, we established a positive feedback loop involvingCOX2+CAFs, prostaglandin E2 (PGE2), and the EP4-SNAI1axes.

Conclusion

This study advances our understanding of the potential mechanisms by whichCOX2+CAFs influence tumor progression within the breast tumor microenvironment (TME) through controlledin vitroinvestigations. By integrating cell mechanics-based analysis, biomolecular assays, and innovativein vitrocell-based modeling ofCOX2+CAFs, we have delineated the contributory role of these cells in a controlled setting. These insights lay a groundwork for future studies that could explore the implications of these findingsin vivo, potentially guiding targeted therapeutic strategies.
Metagenomic co-assembly reveals mobile antibiotic resistance genes in airborne microbiomes in the Eastern Mediterranean
Authors: Erkorkmaz Burak Adnan , Zeevi David , Rudich Yinon
Published: September 2024

Antibiotic resistance is a significant threat to global ecological health. Mobile resistance genes are of particular concern due to their ability to transfer between organisms. In environmental settings and within the microbiota of humans and animals, these genes can sometime move into pathogens, promoting the spread of resistance. While various dispersal mechanisms have been studied, the role of air masses and dust storms in spreading antibiotic resistance genes globally remains largely unexplored. We analyzed air samples from non-dusty conditions and Middle Eastern dust storms using a metagenomic co-assembly approach to identify mobile antibiotic resistance genes dispersed by these air masses. Our analysis shows that co-assembling low-biomass air samples of similar origin produces longer genome fragments, allowing for a more detailed bioinformatic analysis that links functional features to specific taxa. Through this method, we identified genes associated with resistance to antibiotics such as aminoglycosides, beta-lactams, bleomycin, fosfomycin, chloramphenicol, daunorubicin, fluoroquinolones, glycopeptides, quinolones, streptomycin, and tetracyclines. Approximately 10% of these genes were linked to mobile genetic elements. These findings demonstrate the potential for global spread of resistance genes across ecosystems via air masses, particularly dust storms, and underscore the need for continuous atmospheric monitoring and further research to develop strategies that mitigate their impact on public health, the environment, and agriculture.
Executive dysfunction is associated with altered hippocampal-prefrontal functional connectivity in male 3xTg Alzheimer’s model mice
Authors: Cunliffe Grace , Tan Li Yang , Sangyong Jung , Turner Jonathan , Gigg John
Published: September 2024

Executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC). How abnormalities in this pathway lead to cognitive dysfunction in Alzheimer’s disease (AD) have yet to be elucidated. Here, male 3xTg AD mice at 6-months displayed maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex at this age showed layer-specific reductions in response amplitude and paired-pulse ratio following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. Bulk RNA sequencing of the mPFC in 6-month-old mice identified differential gene expression changes associated with calcium ion transport, glutamatergic, GABAergic, and dopaminergic neurotransmission. Seven of these genes (Gpm6b, Slc38a5, Ccr5, Kcnj10, Ddah1, Gad1, Slc17a8) were also differentially expressed in 3-month mice. These results reveal a pre-clinical deficit in executive function correlating with synaptic plasticity and gene expression changes in the mPFC of male 3xTg mice.
A persistent bacterialRegiellatransinfection in the bird cherry-oat aphidRhopalosiphum padiincreasing host fitness and decreasing plant virus transmission
Authors: Yu Wenjuan , Yang Qiong , Gill Alex , Chirgwin Evatt , Gu Xinyue , Joglekar Chinmayee , Umina Paul A. , Hoffmann Ary A.
Published: September 2024

The bird cherry-oat aphid,Rhopalosiphum padi, is a major pest of agriculture due to its ability to directly damage crops and transmit plant viruses. As industries move away from chemical pest control, there is interest in exploring new options to suppress the impact of this pest. Here we describe the production of a transinfected line ofR. padicarrying the bacterial endosymbiont,Regiella insecticola, originating from the green peach aphid,Myzus persicae. We show thatRegiellaincreases the fitness of its novel host despite decreasing fitness in its native host.Regiellaalso shows a low level of horizontal transmission. Importantly the infection suppresses the ability ofR. padito transmit the barley yellow dwarf virus which damages wheat plants. This transinfection could be released to suppress virus transmission by aphids with its ability to persist and spread, making it potentially suitable for wide area release.
Spatiotemporal variation in size-dependent growth rates in small isolated populations of Arctic charr (Salvelinus alpinus)
Authors: Mittell Elizabeth A. , Leblanc Camille A. , Kristjánsson Bjarni K. , Ferguson Moira M. , Räsänen Katja , Morrissey Michael B.
Published: September 2024

As a key life-history trait, growth rates are often used to measure individual performance and to inform parameters in demographic models. Furthermore, intra-specific trait variation generates diversity in nature. Therefore, partitioning out and understanding drivers of spatiotemporal variation in growth rate is of fundamental interest in ecology and evolution. However, this has rarely been attempted due to the amount of individual-level data required through both time and space, and issues with missing data in important covariates. Here we implemented a Bayesian state-space model using individual-level data from 20 populations of Arctic charr (Salvelinus alpinus) across 15 capture occasions, which allowed us to: (1) integrate over the uncertainty of missing recapture records; (2) robustly estimate size-dependence; and (3) include a covariate (water temperature) that contained missing data. Interestingly, although there was substantial spatial, temporal, and spatiotemporal variation in growth rate, this was only weakly associated with variation in water temperature and almost entirely independent of size, suggesting that spatiotemporal variation in other environmental conditions affected individuals across sizes similarly. This fine-scale spatiotemporal variation emphasises the importance of local conditions and highlights the potential for spatiotemporal variation in a size-dependent life-history trait, even when environmental conditions are apparently very similar.
The ‘sexual selection hypothesis’ for the origin of aposematism
Authors: Maisonneuve Ludovic , Aubier Thomas G.
Published: September 2024

The evolution of aposematism, in which prey exhibit conspicuous signals indicating the presence of anti-predator defenses, is puzzling. Before predators learn to associate the signal with defense, increased visibility makes the conspicuous prey highly vulnerable to predation. Although several hypotheses have been proposed to explain the evolution of aposematism, they often assume that these signals can only be recognized by predators. Yet, many studies show that aposematic signals can also be involved in mate choice. Here, we demonstrate that some aposematic signals may have originally evolved as mating signals driven by sexual selection. In this study, we analyze a mathematical model to explore how sexual selection can drive the evolution of aposematism. We thereby identify key features of this ‘sexual selection hypothesis’ for the origin of aposematism to be tested with empirical data. Our results show that the evolution of conspicuous signals through sexual selection increases the visibility of prey to predators and thus predation pressure. This, in turn, promotes the evolution of defense mechanisms, ultimately leading to aposematism when predators learn to associate the signal with defense. Additionally, we show that when sexual selection drives the evolution of aposematism, it often results in sexual dimorphism in both signaling and defense traits.
The Simultaneous Measurement of Reversed Phase-Encoding EPI in a Single fMRI Session at 7T: Quantitative and Qualitative Evaluation of Geometric Distortion Correction in Submillimetre fMRI
Authors: Yun Seong Dae , Genc Erhan , Shah N. Jon
Published: September 2024

Motivation

Currently, geometric distortions in EPI are generally corrected using a method that employs the reversed phase-encoding direction. This approach is usually implemented by applying an extra run of the same protocol, only with the phase-encoding direction changed, leading to a substantial increase in redundant acquisition time and specific absorption ratio. Furthermore, while the distortion correction method has been widely employed in numerous fMRI studies, its impact on submillimetre fMRI analysis has remained largely unexplored.

Methods

This work presents an EPI scheme that acquires both the original and reversed phase-encoding data in a single fMRI session. The feasibility of using the method for submillimetre EPI (0.73 × 0.73 mm2) was verified with visual fMRI at 7T. EPI distortions were corrected using the ANTs software, and its performance was evaluated using various criteria, including spatial resolution, functional mapping accuracy, and histogram distribution.

Results

The presented scheme effectively reduced redundant acquisition time and therefore total radio-frequency energy. The distortion-corrected fMRI data demonstrated significant improvements in co-registration with anatomical scans and functional mapping accuracy. As a result, the ratio of grey-matter-activated voxels was substantially enhanced (on average, 88.58%). These improvements were achieved without significant degradation of spatial resolution or alternation of the functional activation distribution; a high degree of similarity between the original and distortion-corrected cases (ρ > 0.99) was observed in the t-value histograms.

Conclusions

This work presents a simultaneous acquisition scheme for reversed phase-encoding EPI, demonstrating its effectiveness and the benefits achieved through distortion correction in submillimetre fMRI at 7T.
Immortalization of human valve interstitial cells: anin vitrotool for studying fibro-calcific aortic valve degeneration
Authors: Moschetta Donato , Massaiu Ilaria , Bertolini Francesca , Valerio Vincenza , Rusconi Valentina , De Giorgi Donato , Myasoedova Veronika A. , Poggio Paolo
Published: September 2024

Human primary valve interstitial cells (VIC) are essential for studying the detrimental fibrocalcification processes typical of aortic valve degeneration. However, their limited lifespan poses a significant challenge. To address this, we immortalized VICs to extend their lifespan and facilitate genetic manipulation, enabling the study of dysregulated molecular and cellular pathways in this pathology and the test of potential drugsin vitro. We achieved immortalization by transducing primary VICs with simian virus 40 gene and human telomerase large T gene. Post-immortalization, we conducted RNA sequencing on both primary and immortalized VICs to identify pathways regulation following infection. Additionally, we assessed whether immortalized VICs retained their mesenchymal markers and responded to the pro-osteogenic and pro-calcific stimuli similarly to primary VICs. Given the comparable data obtained from both cell types, we propose using immortalized VICs as a reliable tool forin vitrostudy of fibro-calcific aortic valve degeneration.
Cerebellar control of targeted tongue movements
Authors: Bina Lorenzo , Ciapponi Camilla , Yu Si-yang , Wang Xiang , Bosman Laurens W.J. , De Zeeuw Chris I.
Published: September 2024

The cerebellum is critical for coordinating movements related to eating, drinking and swallowing. Cerebellar Purkinje cell activity has been shown to encode ongoing tongue movements, but it is unclear how this activity can alter the trajectory of the tongue. To elucidate the impact of Purkinje cells on goal-directed tongue movements, we recorded their activity in the vermis and hemispheres during spontaneous licking from a stationary or moving water spout. Some Purkinje cells encode rhythmic tongue movements with their complex spikes, others with their simple spikes or a combination of both. Complex spikes predominantly marked the start and end of a licking bout, and thus encoded behavioural state changes, while simple spike firing was more related to individual licks. In addition, complex spikes reported unexpected changes in the position of the water spout and subsequent modulation of simple spike firing caused bending of the tongue, reaching out for the new target position. Using machine learning, we demonstrated that it is possible to predict licking activity based on the spiking patterns of individual Purkinje cells. Using optogenetic stimulation of Purkinje cells, we could experimentally replicate the impact of modulated simple spike firing, suggesting that increased simple spike activity indeed causes ipsilateral bending of the tongue during goal-directed movements. Our data highlight that directional control of movements is paramount in cerebellar function and that complex spike and simple spike modulation complement each other during sensorimotor coordination. These results bring us closer to understanding clinical implications of cerebellar disorders during eating, drinking and swallowing.

Key points

When drinking, mice make rhythmic tongue movements directed towards the water source.

Cerebellar Purkinje cells can fire rhythmically in tune with the tongue movements.

Purkinje cells encode changes in the position of the water source with complex spikes.

Purkinje cell simple spike firing affects the direction of tongue movements.

Purkinje cells that report changes in the position of the target can also adjust movements in the right direction.
Brain-derived neurotrophic factor and adenosine A2A receptor interaction modulates oligodendrogenesis derived from postnatal SVZ neural stem cells
Authors: Mateus J.M. , Barateiro A. , Santos B. , Moreira J.B. , Plachtij N. , Sebastião A.M. , Fernandes A. , Xapelli S.
Published: September 2024

Oligodendrocytes (OLs) are vital for myelin formation in the Central Nervous System. OLs can be produced by the maturation of oligodendrocyte precursor cells (OPCs) present throughout the brain parenchyma or from the differentiation of subventricular zone-derived neural stem cells (SVZ-NSCs). Importantly, efficient differentiation from SVZ-NSCs remains a significant area of research due to its potential for remyelination in demyelinating disorders. In this work, we studied the role of brain-derived neurotrophic factor (BDNF) and adenosine A2A receptors (A2ARs), as well as the putative crosstalk between these two modulatory mechanisms, in regulating oligodendrogenesis from SVZ-NSCs. Using a neurosphere culture system, we observed that BDNF significantly increased the mRNA expression levels of OPC cell markers after 2 days in vitro (DIV), an effect blocked by the A2AR antagonist ZM 241385. This early transcriptional regulation by BDNF was followed by changes in the percentage of both OPCs and mature OLs in culture at DIV 7 and 14. Interestingly, blocking A2ARs prevented the potentiating effect of BDNF on the percentage of OLs at DIV 14. Concerning the morphology of mature OLs, BDNF influenced their maturation by reducing branching near the soma at DIV 7, an effect that was not observed at 14 DIV, when all treatments resulted in similar OL morphology. Overall, our results establish BDNF as a regulator of OL formation from SVZ-NSCs, with A2AR-BDNF interaction modulating the differentiation process.
Comparative transcriptomic rhythms in the mouse and human prefrontal cortex
Authors: Burns Jennifer N. , Jenkins Aaron K. , Xue Xiangning , Petersen Kaitlyn A. , Ketchesin Kyle D. , Perez Megan S. , Vadnie Chelsea A. , Scott Madeline R. , Seney Marianne L. , Tseng George C. , McClung Colleen A.
Published: September 2024

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents. Here, we use RNA sequencing to lay the groundwork for translational studies of molecular rhythms through a sex-specific, cross species comparison of transcriptomic rhythms between the mouse medial PFC (mPFC) and two subregions of the human PFC, the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). We find that while circadian rhythm signaling is conserved across species and subregions, there is a phase shift in the expression of core clock genes between the mouse mPFC and human PFC subregions that differs by sex. Furthermore, we find that the identity of rhythmic transcripts is largely unique between the mouse mPFC and human PFC subregions, with the most overlap (20%, 236 transcripts) between the mouse mPFC and the human ACC in females. Nevertheless, we find that basic biological processes are enriched for rhythmic transcripts across species, with key differences between regions and sexes. Together, this work highlights both the evolutionary conservation of transcriptomic rhythms and the advancement of the human PFC, underscoring the importance of considering cross-species differences when using animal models.
Weak, specific chemical interactions dictate barnase stability in diverse cellular environments
Authors: Tahir Ume , Davis Caitlin M.
Published: September 2024

It is well-established that in vitro measurements do not reflect protein behaviors in-cell, where macromolecular crowding and chemical interactions modulate protein stability and kinetics. Recent work suggests that peptides and small proteins experience the cellular environment differently from larger proteins, as their small sizes leave them primarily susceptible to chemical interactions. Here, we investigate this principle in diverse cellular environments, different intracellular compartments and host organisms. Our small protein folding model is barnase, a bacterial ribonuclease that has been extensively characterized in vitro. Using fast relaxation imaging, we find that FRET-labeled barnase is stabilized in the cytoplasm and destabilized in the nucleus of U2-OS cells. These trends could not be reproduced in vitro by Ficoll and M-PERTM, which mimic macromolecular crowding and non-specific chemical interactions, respectively. Instead, in-cell trends were best replicated by cytoplasmic and nuclear lysates, indicating that weak specific interactions with proteins in either compartment are responsible for the in-cell observations. Interestingly, in the cytoplasm barnase’s unfolded state is unstable and prone to aggregation, while in the nucleus a stable unfolded state exists prior to aggregation. In the more biologically relevant environment of bacterial cells, barnase folding resembled that in the nucleus, but with no aggregation at higher temperatures. These findings show that protein interactions are evolved for their native environment, which highlights the importance of studying and designing proteins in situ.
TRiC/CCT Chaperonin Governs RNA Polymerase II Activity in the Nucleus to Support RNA Homeostasis
Authors: Gvozdenov Zlata , Peng Audrey Yi Tyan , Biswas Anusmita , Barcutean Zeno , Gestaut Daniel , Frydman Judith , Struhl Kevin , Freeman Brian C.
Published: September 2024

The chaperonin TRiC/CCT is a large hetero-oligomeric ringed-structure that is essential in eukaryotes. While present in the nucleus, TRiC/CCT is typically considered to function in the cytosol where it mediates nascent polypeptide folding and the assembly/disassembly of protein complexes. Here, we investigated the nuclear role of TRiC/CCT. Inactivation of TRiC/CCT resulted in a significant increase in the production of nascent RNA leading to the accumulation of noncoding transcripts. The influence on transcription was not due to cytoplasmic TRiC/CCT-activities or other nuclear proteins as the effect was observed when TRiC/CCT was evicted from the nucleus and restricted to the cytoplasm. Rather, our data support a direct role of TRiC/CCT in regulating RNA polymerase II activity, as the chaperonin modulated nascent RNA production both in vivo and in vitro. Overall, our studies reveal a new avenue by which TRiC/CCT contributes to cell homeostasis by regulating the activity of nuclear RNA polymerase II.
Collaborative role of two distinct cilium-specific cytoskeletal systems in driving Hedgehog-responsive transcription factor trafficking
Authors: Ku Pei-I , Sreeja Jamuna S , Chadha Abhishek , Williams David S , Engelke Martin F , Subramanian Radhika
Published: September 2024

Calibrated transcriptional outputs in cellular signaling require fine regulation of transcription factor activity. In vertebrate Hedgehog (Hh) signaling, the precise output of the final effectors, the GLI (Glioma-associated-oncogene) transcription factors, depends on the primary cilium. In particular, the formation of the activator form of GLI upon pathway initiation requires its concentration at the distal cilium tip. However, the mechanisms underlying this critical step in Hh signaling are unclear. We developed a real-time imaging assay to visualize GLI2, the primary GLI activator isoform, at single particle resolution within the cilium. We observed that GLI2 is a cargo of Intraflagellar Transport (IFT) machinery and is transported with anterograde bias during a restricted time window following pathway activation. Our findings position IFT as a crucial mediator of transcription factor transport within the cilium for vertebrate Hh signaling, in addition to IFT’s well-established role in ciliogenesis. Surprisingly, a conserved Hh pathway regulator, the atypical non-motile kinesin KIF7, is critical for the temporal control of GLI2 transport by IFT and the spatial control of GLI2 localization at the cilium tip. This discovery underscores the collaborative role of a motile and a non-motile cilium-specific cytoskeletal system in determining the transcriptional output during Hh signaling.
Phospholipase D3 regulates TFEB/TFE3 metabolism to maintain lysosomal homeostasis
Authors: Wang Yongchao , Rieschick Paige , Romero-Fernandez Wilber , Appelbaum Nathan , Carvajal-Tapia Cristian , Shostak Alena , Schrag Matthew
Published: September 2024

A coding variant in Phospholipase D3 (PLD3) increases the risk of Alzheimer’s disease (AD). PLD3 is a lysosomal protein, and endosomal and lysosomal abnormalities are linked to AD; however, the role of PLD3 in lysosomal homeostasis and its implications in AD remain poorly understood. To address this knowledge gap, we conducted comprehensive studies integrating transcriptomics, proteomics, and cell biology approaches. We observed significant enlargement of lysosomes in neurons lacking PLD3, accompanied by increased endocytosis and autophagy, but a decline in lysosomal proteolytic activity. Lysosomes of PLD3-deficient cells underwent proteome remodeling, manifested by an enrichment of proteins involved in lysosomal biogenesis, endocytosis and calcium signaling. Mechanistically, we discovered that PLD3 mediates TFEB/TFE3 degradation through the proteasome, and as a result, PLD3 deficiency leads to increased TFEB/TFE3 levels, nuclear translocation, and transcriptional activities. Notably, variants in PLD3, e.g., V232M or K486R, do not alter its impact on TFEB/TFE3 metabolism. Transcriptomic profiling further confirmed the enrichment of transcripts involved in lysosomal biogenesis, endocytosis, autophagy, mTOR signaling and AD in response to PLD3 loss. Additionally, PLD3 ablation has synergistic effects with β-amyloid in causing lysosomal abnormalities and modifying TFEB/TFE3 signaling. In conclusion, our findings demonstrate that PLD3 is involved in regulating lysosomal biogenesis via TFEB/TFE3 signaling, and lysosomal abnormalities resulting from PLD3 deficiency are potentially a risk factor for AD.
Conserved role for spliceosomal component PRPF40A in microexon splicing
Authors: Choudhary Bikash , Norris Adam
Published: September 2024

Microexons (exons ≤30 nts) are important features of neuronal transcriptomes, but pose mechanistic challenges to the splicing machinery. We previously showed that PRP-40, a component of the U1 spliceosome, is globally required for microexon splicing inC. elegans. Here we show that the homologous PRPF40A is also globally required for microexon splicing in mouse neuroblastoma cells. We find that PRPF40A co-regulates microexons along with SRRM4, a neuron-specific regulator of microexon splicing. The relationship between exon size and dependence on PRPF40A/SRRM4 is distinct, with SRRM4-dependence exhibiting a size threshold (∼30 nts) and PRPF40A-dependence exhibiting a graded decrease as exon size increases. Finally, we show that PRPF40A knockdown causes an increase in productive splicing of its spliceosomal binding partnerLuc7lby skipping of a small “poison exon.” Similar homeostatic cross-regulation is often observed across paralogous RNA binding proteins. Here we find this concept likewise applies across evolutionarily unrelated but functionally and physically coupled spliceosomal components.
HuBMAPR: an R Client for the HuBMAP Data Portal
Authors: Hou Christine , Ghazanfar Shila , Marini Federico , Morgan Martin , Hicks Stephanie C.
Published: September 2024

The Human BioMolecular Atlas Program (HuBMAP) constructs the worldwide available platform to research the human body at the cellular level. The HuBMAP Data Portal encompasses a wide range of data resources measured on emerging experimental technologies at a spatial resolution. To broaden access to the HuBMAP Data Portal, we introduce an R client calledHuBMAPRavailable on Bioconductor. This gives an efficient and programmatic interface, enabling researchers to discover and retrieve HuBMAP data easier and faster.

Availability

This package is available on GitHub (https://github.com/christinehou11/HuBMAPR) and has been submitted to Bioconductor.
Dysregulation of the fluid homeostasis system by aging
Authors: Jang Heeun , Sharma Alexis B. , Dan Usan , Wong Jasmine H. , Knight Zachary A. , Garrison Jennifer L.
Published: September 2024

Chronic dehydration is a leading cause of morbidity for the elderly, but how aging alters the fluid homeostasis system is not well understood. Here, we used a combination of physiologic, behavioral and circuit analyses to characterize how fluid balance is affected by aging in mice. We found that old mice have a primary defect in sensing and producing the anti-diuretic hormone vasopressin, which results in chronic dehydration. Recordings and manipulations of the thirst circuitry revealed that old mice retain the ability to sense systemic cues of dehydration but are impaired in detecting presystemic, likely oropharyngeal, cues generated during eating and drinking, resulting in disorganized drinking behavior on short timescales. Surprisingly, old mice had increased drinking and motivation after 24-hour water deprivation, indicating that aging does not result in a general impairment in the thirst circuit. These findings reveal how a homeostatic system undergoes coordinated changes during aging.
Alternative mRNA Splicing and Polyadenylation Events are Synchronous with Podocyte Injury and Slit Diaphragm Dysregulation in Glomerular Disease Models
Authors: Das Monoj K , Webb Amy , Yarram Mahika , Reilly Christian , Bryant Claire , Govindarajan Rajgopal , Moore Claire , Agrawal Shipra
Published: September 2024

Background: Glomerular disease, often characterized by podocyte injury and proteinuria, can lead to chronic kidney disease and end stage kidney disease. We hypothesized that the glomerular pathophysiology is associated with alternative mRNA processing, such as alternative splicing (AS) and polyadenylation (APA), of glomerular genes and especially of critical podocyte, slit diaphragm and matrix genes that regulate the glomerular filtration barrier. Methods: Glomerular damage, accompanied with proteinuria, hypoalbuminemia and hypercholesterolemia was induced by puromycin aminonucleoside (PAN) or adriamycin (ADR) to mimic human minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), respectively. Glomerular RNA-seq analyses was performed followed by JunctionSeq and APATrap bioinformatics analyses to detect AS and APA events, respectively. Novel splice sites and poly(A) usage sites and differences in alternatively spliced and polyadenylated isoforms were queried in JunctionSeq and APATrap pipelines. Results: Altered glomerular mRNA processing by AS/APA was identified in 136/71 and 1875/746 genes in MCD and FSGS models, respectively. Transcript annotation and prioritization of significant AS and APA identified key events in genes with novel and established roles that cause disruption in the glomerular filtration barrier. These events localized in the regions of slit diaphragm (NPHS1, NPHS2, NEPH1, ZO1, ITM2B), glomerular basement membrane (COL4A3/4/5, LAMB2, LAMA5), podocyte mitochondria (COQ2), podocyte membrane (PODXL) and endothelial cells (INF2). Concomitantly, numerous polyadenylation and splicing factors which could serve as potential trans- factors that lead to AS and APA, were dysregulated in these two models of glomerular nephropathies. Additionally, beneficial proteinuria reducing treatment modalities, pioglitazone and GQ16 reversed many of these AS and APA events. Moreover, suggestive GWAS SNPs were identified in many of these genes from human nephrotic syndrome database, which could potentially serve as cis- factors that lead to AS and APA, and downstream functional effects. Conclusion: Findings from our studies shed light on a new landscape of research in glomerular pathophysiology, i.e., AS and APA of glomerular genes, many of which are crucial determinants of podocyte structure and function, slit diaphragm complex, and glomerular basement membrane. These findings present new implications for improved mechanistic understanding of glomerular disease and development of novel therapeutic intervention strategies.
Adaptation of retinal discriminability to natural scenes
Authors: Ding Xuehao , Lee Dongsoo , Melander Joshua B. , Ganguli Surya , Baccus Stephen A.
Published: September 2024

Sensory systems discriminate between stimuli to direct behavioral choices, a process governed by two distinct properties - neural sensitivity to specific stimuli, and neural variability that importantly includes correlations between neurons. Two questions that have received extensive investigation and debate are whether visual systems are optimized for natural scenes, and whether correlated neural variability contributes to this optimization. However, the lack of sufficient computational models has made these questions inaccessible in the context of the normal function of the visual system, which is to discriminate between natural stimuli. Here we take a direct approach to analyze discriminability under natural scenes for a population of salamander retinal ganglion cells using a model of the retinal neural code that captures both sensitivity and variability. Using methods of information geometry and generative machine learning, we analyzed the manifolds of natural stimuli and neural responses, finding that discriminability in the ganglion cell population adapts to enhance information transmission about natural scenes, in particular about localized motion. Contrary to previous proposals, correlated noise reduces information transmission and arises simply as a natural consequence of the shared circuitry that generates changing spatiotemporal visual sensitivity. These results address a long-standing debate as to the role of retinal correlations in the encoding of natural stimuli and reveal how the highly nonlinear receptive fields of the retina adapt dynamically to increase information transmission under natural scenes by performing the important ethological function of local motion discrimination.
Seed2LP: seed inference in metabolic networks for reverse ecology applications
Authors: Ghassemi Nedjad Chabname , Bolteau Mathieu , Bourneuf Lucas , Paulevé Loïc , Frioux Clémence
Published: September 2024

A challenging problem in microbiology is to determine nutritional requirements of microorganisms and culture them, especially for the microbial dark matter detected solely with culture-independent methods. The latter foster an increasing amount of genomic sequences that can be explored with reverse ecology approaches to raise hypotheses on the corresponding populations. Building upon genome scale metabolic networks (GSMNs) obtained from genome annotations, metabolic models predict contextualised phenotypes using nutrient information. We developed the toolSeed2LP, addressing the inverse problem of predicting source nutrients, orseeds, from a GSMN and a metabolic objective. The originality of Seed2LP is its hybrid model, combining a scalable and discrete Boolean approximation of metabolic activity, with the numerically accurate flux balance analysis (FBA). Seed inference is highly customisable, with multiple search and solving modes, exploring the search space of external and internal metabolites combinations. Application to a benchmark of 107 curated GSMNs highlights the usefulness of a logic modelling method over a graph-based approach to predict seeds, and the relevance of hybrid solving to satisfy FBA constraints. Focusing on the dependency between metabolism and environment, Seed2LP is a computational support contributing to address the multifactorial challenge of culturing possibly uncultured microorganisms. Seed2LP is available onhttps://github.com/bioasp/seed2lp.
Automated analysis of digital medical images in cervical cancer screening: A systematic review
Authors: Ledwaba Leshego , Saidu Rakiya , Malila Bessie , Kuhn Louise , Mutsvangwa Tinashe E.M.
Published: September 2024

Background

Cervical cancer screening programs are poorly implemented in LMICs due to a shortage of specialists and expensive diagnostic infrastructure. To address the barriers of implementation researchers have been developing low-cost portable devices and automating image analysis for decision support.

However, as the knowledge base is growing rapidly, progress on the implementation status of novel imaging devices and algorithms in cervical cancer screening has become unclear. The aim of this project was to provide a systematic review summarizing the full range of automated technology systems used in cervical cancer screening.

Method

A search on academic databases was conducted and the search results were screened by two independent reviewers. Study selection was based on eligibility in meeting the terms of inclusion and exclusion criteria which were outlined using a Population, Intervention, Comparator and Outcome framework.

Results

17 studies reported algorithms developed with source images from mobile device, viz. Pocket Colposcope, MobileODT EVA Colpo, Smartphone Camera, Smartphone-based Endoscope System, Smartscope, mHRME, and PiHRME. While 56 studies reported algorithms with source images from conventional/commercial acquisition devices. Most interventions were in the feasibility stage of development, undergoing initial clinical validations.

Conclusion

Researchers have proven superior prediction performance of computer aided diagnostics (CAD) in colposcopy (>80% accuracies) versus manual analysis (<70.0% accuracies). Furthermore, this review summarized evidence of the algorithms which are being created utilizing portable devices, to circumvent constraints prohibiting wider implementation in LMICs (such as expensive diagnostic infrastructure). However clinical validation of novel devices with CAD is not yet implemented adequately in LMICs.
Genetics-driven risk predictions leveraging the Mendelian randomization framework
Authors: Sens Daniel , Shilova Liubov , Gräf Ludwig , Grebenshchikova Maria , Eskofier Bjoern M. , Casale Francesco Paolo
Published: September 2024

Accurate predictive models of future disease onset are crucial for effective preventive healthcare, yet longitudinal data sets linking early risk factors to subsequent health outcomes are limited. To overcome this challenge, we introduce a novel framework,PredictiveRisk modeling usingMendelianRandomization (PRiMeR), which utilizes genetic effects as supervisory signals to learn disease risk predictors without relying on longitudinal data. To do so, PRiMeR leverages risk factors and genetic data from a healthy cohort, along with results from genome-wide association studies of diseases of interest. After training, the learned predictor can be used to assess risk for new patients solely based on risk factors. We validate PRiMeR through comprehensive simulations and in future type 2 diabetes predictions in UK Biobank participants without diabetes, using follow-up onset labels for validation. Moreover, we apply PRiMeR to predict future Alzheimer's disease onset from brain imaging biomarkers and future Parkinson's disease onset from accelerometer-derived traits. Overall, with PRiMeR we offer a new perspective in predictive modeling, showing it is possible to learn risk predictors leveraging genetics rather than longitudinal data.
Heralding entangled optical photons from a microwave quantum processor
Authors: Haug Trond Hjerpekjøn , Kockum Anton Frisk , Van Laer Raphaël
Published: September 2024

Exploiting the strengths of different quantum hardware components may increase the capabilities of emerging quantum processors. Here we propose and analyze a quantum architecture that leverages the nonlocal connectivity of optics, along with the exquisite quantum control offered by superconducting microwave circuits, to produce entangled optical resource states. In contrast to previous proposals on optically distributing entanglement between superconducting microwave processors, we use squeezing between microwaves and optics to produce microwave-optical Bell pairs in a dual-rail encoding from a single microwave quantum processor. Moreover, the microwave quantum processor allows us to deterministically entangle microwave-optical Bell pairs into larger cluster states, from which entangled optical photons can be extracted through microwave measurements. Our scheme paves the way for small microwave quantum processors to create heralded entangled optical resource states for optical quantum computation, communication, and sensing using imperfect microwave-optics transducers. We expect that improved isolation of the superconducting processor from stray optical fields will allow the scheme to be demonstrated with currently available hardware.

Published by the American Physical Society
2024
Lattice QCD estimates of thermal photon production from the QGP
Authors: Ali Sajid , Bala Dibyendu , Francis Anthony , Jackson Greg , Kaczmarek Olaf , Turnwald Jonas , Ueding Tristan , Wink Nicolas ,   HotQCD Collaboration
Published: September 2024

Thermal photons produced in heavy-ion collision experiments are an important observable for understanding quark-gluon plasma (QGP). The thermal photon rate from the QGP at a given temperature can be calculated from the spectral function of the vector current correlator. Extraction of the spectral function from the lattice correlator is known to be an ill-conditioned problem, as there is no unique solution for a spectral function for a given lattice correlator with statistical errors. The vector current correlator, on the other hand, receives a large ultraviolet contribution from the vacuum, which makes the extraction of the thermal photon rate difficult from this channel. We therefore consider the difference between the transverse and longitudinal part of the spectral function, only capturing the thermal contribution to the current correlator, simplifying the reconstruction significantly. The lattice correlator is calculated for light quarks in quenched QCD at T=470  MeV (∼1.5Tc), as well as in 2+1 flavor QCD at T=220  MeV (∼1.2Tpc) with mπ=320  MeV. In order to quantify the nonperturbative effects, the lattice correlator is compared with the corresponding NLO+LPMLO estimate of correlator. The reconstruction of the spectral function is performed in several different frameworks, ranging from physics-informed models of the spectral function to more general models in the Backus-Gilbert method and Gaussian process regression. We find that the resulting photon rates agree within errors.

Published by the American Physical Society
2024
Testing for coherence and nonstandard neutrino interactions in COHERENT data
Authors: Liao Jiajun , Marfatia Danny , Zhang Jiajie
Published: September 2024

We analyze data from the CsI, liquid Ar and Ge detectors of the COHERENT experiment and confirm within 1.5σ that the measured elastic neutrino-nucleus scattering cross section is proportional to the square of the number of neutrons in the nucleus, as expected for coherent scattering in the standard model. We also show how various degeneracies involving nonstandard neutrino interaction parameters are broken in a combined analysis of the three datasets.

Published by the American Physical Society
2024