bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of nutrition in the pathogenesis of neglected tropical diseases: systematic review and meta-analysis
Authors: Loglo Aloysius , Aniagyei Wilfred , Vivekanandan Monika Mira , Agbanyo Abigail , Asamoah Evans Adu , Phillips Richard Odame , Annan Reginald , Engel Barbara , Simmonds Rachel E
Published: March 2024

Background: According to the WHO, neglected tropical diseases (NTDs) affect over 2 billion people worldwide. While the links between nutrition and many diseases have become clear over recent decade, NTDs have lagged behind and the linkage with nutrition is largely unknown. We conducted this systematic review with meta-analysis to determine the current status of research on the role of diet in the pathogenesis of NTDs.
Methodology: PubMed, Embase, Scopus and African Journal online databases were searched using predefined search terms. We included all original articles with a case-control design and at least one NTD. The studies had to compare the nutritional parameters between the infected and uninfected.  Articles that did not report original data were excluded. The quality of the studies was assessed using the Newcastle-Ottawa scale. Pooled estimates were conducted using the random-effects model. The publication bias of studies was determined by funnel plots.  Q and I2 statistics were used to assess the heterogeneity of the studies.
Results: After screening 1294 articles, only 16 qualified for the systematic review and 12 for meta-analysis. These predominately had a focus on soil-transmitted helminthiasis (ascariasis, hookworm diseases, trichuriasis) and schistosomiasis, with a minority concerning leishmaniasis and leprosy. Pooled estimates showed an association between intestinal parasites and stunting in children (OR= 1.38, 95%CI: 1.14-1.66, I2 = 0%). We also identified a moderate association established between blood iron deficiency (OR=4.67, 95%CI: 1.91-11.44) and intestinal parasites.
Conclusions/Significance: Of the 20 NTDs, the links between diet and disease have been explored only for a very few. There is a paucity of data from low and middle-income countries and least developed countries where the NTD burden is high. Therefore, more research into the role of nutrition in NTD infection is recommended.
Sex differences in symptoms following the administration of BNT162b2 mRNA Covid-19 Vaccine in Children below 5 Years of age in Germany (CoVacU5): a retrospective cohort study
Authors: Moor Jeanne , Toepfner Nicole , von Meißner Wolfgang C G , Berner Reinhard , Moor Matthias B. , Kublickiene Karolina , Strumann Christoph , Chao Cho-Ming
Published: March 2024

Background

Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany.

Methods

This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-<5 years for vaccination against SARS-CoV-2 in six private practices and/or two lay person-initiated vaccination campaigns. We analyzed the safety profiles of the first 3 doses of 3-10µg BNT162b2. Primary outcome was comparison in frequencies of 4 common post-vaccination symptom categories such as local, general, musculoskeletal symptoms and fever. Data were analyzed according to sex in bivariate analyses and regression models adjusting for age, weight, and dosage. Interaction between sex and BNT162b2 dosage was assessed. An active-comparator analysis was applied to compare post-vaccination symptoms after BNT162b2 versus non-SARS-CoV-2 vaccines.

Results

The dataset for the present analysis consisted of 7801 participants including 3842 females (49%) and 3977 males (51%) with an age of 3 years (median, interquartile: 2 years). Among individuals receiving 3µg BNT162b2, no sex differences were noted, but after a first dose of 5 or 10µg BNT162b2, local injection-site symptoms were more prevalent in girls compared to boys. In logistic regression, female sex was associated with higher odds of local symptoms, odds ratio (OR) of 1.33 (95% confidence interval [CI]: 1.15-1.55, p<0.05) and general symptoms with OR 1.21 (95% CI: 1.01-1.44, p<0.05). Following non-BNT162b2 childhood vaccinations, female sex was associated with a lower odds of post-vaccination musculoskeletal symptoms (OR: 0.29, 95% CI: 0.11-0.82, p<0.05). An active comparator analysis between BNT162b2 and non-SARS-CoV-2 vaccinations revealed that female sex positively influenced the association between BNT162b2 vaccine type and musculoskeletal symptoms.

Conclusions

Sex differences exist in post-vaccination symptoms after BNT162b2 administration even in young children. These are of importance for the conception of approval studies, for post-vaccination monitoring and for future vaccination strategies.

(German Clinical Trials Register ID: DRKS00028759).
3D culture of pancreatic cancer cellsin vitrorecapitulates an aberrant mitochondrial oxidative phosphorylation genotype observedin vivo
Authors: Kuś Krzysztof , Mark Treherne J. , Earnshaw David L. , Krzykawska Renata , Biesaga Beata , Statkiewicz Małgorzata , Unrug-Bielawska Katarzyna , Sandowska-Markiewicz Zuzanna , Mikula Michal , Alfaro Javier Antonio , Krzykawski Marcin Przemyslaw
Published: March 2024

The treatment of many aggressive cancers remains a significant unmet medical need. An aberrant dependence of tumors on mitochondrial oxidative phosphorylation pathways has been well characterized in mediating the progression of pancreatic cancers, as well as some other malignancies. However, the discovery and development of new therapeutic strategies targeting or manipulating this pathway in pancreatic tumors has been relatively slow when compared with other cancers, limiting the current options for treating patients. One key technical challenge in discovering new therapies has been the limited ability of cancer cell lines when grown in 2D conditions to recapitulate the mitochondrial oxidative phosphorylation pathways in vitro that have been observed in vivo. In part, this is because 2D cultures fail to mimic the extracellular 3D tumoral environment. More generally, the translation of data based on 2D pancreatic cancer cell culture systems have also been constraining options for discovering new therapies. Conversely, 3D cultures can provide an improved technology platform in which pathologically relevant pathways in tumors can be recapitulated and analyzed in vitro. In this study, we have demonstrated in 3D cultures the reconstruction of the mitochondrial oxidative phosphorylation genotype in vitro, which more closely resembles that observed in vivo. Our study highlights the value of using transcriptomic readouts as a method to demonstrate the relevance and utility of 3D preclinical modelsin vitro, when grown in a more physiological extracellular environment. This key technological advance can now better enable the discovery and subsequent development of new therapeutic strategies targeting disease-relevant pathways found in pancreatic and other tumors.
ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF
Authors: Magnitov Mikhail D. , Maresca Michela , Saiz Noemí Alonso , Teunissen Hans , Braccioli Luca , de Wit Elzo
Published: March 2024

Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 degron line. Our results show that ZNF143/ZFP143 depletion has no effect on chromatin looping. Systematic analysis of ZNF143/ZFP143 occupancy data revealed that a commonly used antibody cross-reacts with CTCF, leading to its incorrect association with chromatin loops. Nevertheless, ZNF143/ZFP143 specifically activates nuclear-encoded mitochondrial genes and its loss leads to severe mitochondrial dysfunction. Using anin vitroembryo model, we find that ZNF143/ZFP143 is an essential regulator of organismal development. Our results establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by safeguarding mitochondrial activity.

Highlights

Acute degradation of ZFP143 leads to rapid and specific loss of gene transcription.

Molecular consequences of ZFP143 loss are inconsistent with a role in chromatin looping.

ZFP143 is a conserved transcriptional regulator of nuclear-encoded mitochondrial proteins.

ZFP143 regulation of mitochondrial homeostasis is critical for multicellular organismal development.

Graphical Abstract
Emergence of Orientation Pinwheels in a Self-Evolving Spiking Neural Network: Enhancing Visual Coding Efficiency and Reliability
Authors: Zhong Haixin , Wang Haoyu , Huang Mingyi , Dai Wei P , Huang Yuchao , An Mengyao , Roe Anna Wang , Yu Yuguo
Published: March 2024

Orientation preference maps (OPMs) in the primary visual cortex of primates organize orientation-tuned neurons into columnar structures, forming pinwheel-like patterns. However, lower-level animals like rodents typically exhibit a lack of OPMs, with neurons either randomly distributed or aggregated in small clusters. This distinction prompts an inquiry into whether more structured cortical columns correlate with improved visual computational or coding efficiency. To explore this, we propose a novel self-evolving spiking neural network (SESNN). To the best of our knowledge, the SESNN is the first spiking network, incorporating mechanisms of neural plasticity in forming neural connections without explicit objective functions. We reveal that the emergence of pinwheel structures is primarily driven by sparse coding constraints and local synaptic plasticity as fundamental mechanisms. Second, for higher mammals with expansive iso-orientation domains (IODs), the firing responses in pinwheel structures primarily emanate from pinwheel centers (PCs) and progressively extend toward the periphery, encompassing adjacent IODs. Third, the size and organization of these IODs across species are significantly influenced by the receptive fields’ ability to process overlapping visual information. Lastly, PCs within large IODs demonstrate enhanced robustness and population sparseness in detecting a variety of orientation features. These results indicate that the spatial pinwheel structure facilitates highly efficient and reliable coding performance.
Chloride intracellular channel 4 (CLIC4) is a global regulator of type 1 interferon signaling in Systemic Sclerosis (SSc) epithelial cells
Authors: Wasson Christopher W , Dibb Sophie L , Caballero-Ruiz Begoña , Clavane Eva M , Wells Rebecca , Kakkar Vishal , Lorenzis Enrico De , Ross Rebecca L , Bryon Jessica , Derrett-Smith Emma , Denton Christopher P , Meakin Paul J , Galdo Francesco Del
Published: March 2024

Objectives

Systemic sclerosis (SSc) is an autoimmune disease in which an immune-related injury induces fibrosis of the skin, progressing to affect the internal organs in the most serve cases. Type 1 interferon (IFN) signaling plays a major role in SSc disease progression. We have previously shown the chloride intracellular channel 4 (CLIC4) is upregulated in SSc skin fibroblasts and plays an important role in SSc fibrosis. In this study we investigated the role of CLIC4 in SSc keratinocyte biology.

Methods

healthy (HC) and SSc skin biopsies were analysed by immunohistochemistry for the expression of CLIC4. The skin keratinocyte cell line Hacats was stimulated with a range of type 1 IFN signaling agonists (POLY I:C, POLY dA:Dt, ODN 2216 and IFN-α). CLIC4 was inhibited with the chloride channel inhibitors NPPB and IAA-94 or siRNA. Conditioned media from HC or SSc fibroblasts was employed for indirect co-culture of Hacats and HUVECs.

Results

SSc skin biopsies showed high levels of CLIC4 in SSc skin fibroblasts, keratinocytes and endothelial cells compared to HC. Co-culture of Hacats and Huvecs with SSc fibroblast media induced CLIC4 expression. CLIC4 played an important role in type 1 IFN signalling in keratinocytes. Inhibition of CLIC4 blocked TLR3, TLR9 and cGAS mediated activation of the type 1 IFN signaling pathway. Additionally, inhibition of CLIC4 prevented SSc fibroblast media from inducing a type 1 IFN response in keratinocytes.

Conclusions

The data presented in this study suggests CLIC4 is a global regulator of type 1 IFN signalling in SSc epithelial cells.

Key Messages

What is already known

SSc disease progression is driven in part by a Type 1 IFN signature and CLIC4 has previously been implicated in SSc fibroblast activation.

What this study adds

We show for the first time CLIC4 is a regulator of type 1 interferon signalling in epithelial cells and plays an important role in the signalling found in SSc skin.

How this study might affect research

Targeting CLIC4 in the context of SSc may disrupt the fibrosis and inflammation associated with SSc.
A genetic perspective on the recent demographic history of Ireland and Britain
Authors: Shanmugam Ashwini , Merrigan Michael , O’Reilly Seamus , Molloy Anne M. , Brody Lawrence , Hardiman Orla , McLaughlin Russell , Cavalleri Gianpiero L. , Byrne Ross , Gilbert Edmund
Published: March 2024

Background

While subtle yet discrete clusters of genetic identity across Ireland and Britain have been identified, their demographic history is unclear.

Methods

Using genotype data from 6,574 individuals with associated regional Irish or British ancestry, we identified Irish-like and British-like genetic communities using network community detection. We segregated Identity-by-Descent (IBD) and Runs-of-Homozygosity (ROH) segments by length and approximated their corresponding time periods. Through this, we inferred the regional Irish and British demographic histories in these time periods by (1) estimating genetic relatedness between communities, (2) estimating changes in effective population sizes, (3) inferring recent migration rates across Ireland and Britain, and (4) estimating changing affinities to regional European populations. For a subset of the Irish communities, we determined the enrichment/depletion of surnames within the genetic communities.

Results

Through patterns of IBD-sharing and ROH, we find evidence of recent population bottlenecks in the Orcadian, Manx and Welsh communities. While the structure in Ireland is subtler, the communities share relatively more IBD segments that are shorter in length, and the genetic differences between the Irish communities are more subtle on average, when compared to the British communities. Regional effective population size trajectories indicate a similar demographic history throughout the island of Ireland. Further, we observe a stable migration corridor between north-east Ireland and south-west Scotland while there is a recent migration barrier between South-Eastern Ireland and Western Ireland. We observed an enrichment of Anglo-Norman and English surnames in the Wexford community while within the West Ulster-Argyll community, we saw an enrichment of Gallowglass and Scottish surnames.

Conclusions

Using well-annotated Irish and British reference genotypes, we observed temporal changes in genetic affinities within and between genetic communities in Ireland and Britain. In addition, using effective population size estimates and levels of haplotype-sharing, we detected varying degrees of genetic isolation in some Irish and British genetic communities across time. Using these new insights into the regional demographic history of Ireland and Britain across different time periods, we hope to understand the driving forces of rare allele frequencies and disease risk association within these populations.
Chemotherapy-treated breast cancer cells activate the Wnt signaling pathway to enter a diapause-DTP state
Authors: El Laithy Youssef , Abreu De Oliveira Willy Antoni , Pabba Anirudh , Qualizza Alessandra , Richard François , Athanasouli Paraskevi , Luci Carla Rios , De Wispelaere Wout , Mourao Larissa , Hamer Siân , Moens Stijn , De Jaime-Soguero Anchel , Francesca Baietti Maria , Hutten Stefan J , Jonkers Jos , Sammut Stephen-John , Soenen Stefaan , Scheele Colinda LGJ , Bruna Alejandra , Desmedt Christine , Annibali Daniela , Lluis Frederic
Published: March 2024

The efficacy of chemotherapy is often hindered by the enrichment of a population of cancer cells that enter a drug-tolerant persister (DTP) state, mimicking embryonic diapause, yet the underlying mechanisms of this transition remain poorly understood. This study demonstrates that both parental and chemotherapy-induced Wnt-active (WntHigh) cells in Triple-negative breast cancer exhibit transcriptional and functional properties characteristic of DTP cells, including a diapause transcriptional signature, reduced MYC expression, reversible restricted proliferation, and pronounced chemoresistance. Our findings reveal that thede novoactivation of the Wnt signaling pathway, triggered by the transcriptional upregulation of components essential for canonical Wnt ligand-secretion and -activation, is critical for enriching the diapause-DTP (DTPDiap) population across various chemotherapy regimens. The diapause-DTP/WntHighpopulation can be selectively ablated by concomitant, rather than sequential, pharmacological inhibition of Wnt ligand-secretion alongside chemotherapy, highlighting new vulnerabilities in DTPDiapcell-emergence and potentially yielding a therapeutic opportunity against DTPs. This study shows that activation of Wnt signaling pathway is sufficient and necessary for the induction of a DTPDiapstate and enhances our understanding of the introductory mechanisms driving DTP cell-enrichment upon chemotherapy.
Why models underestimate West African tropical forest productivity
Authors: Zhang-Zheng Huanyuan , Stocker Benjamin , Thomson Eleanor , Aguirre-Gutiérrez Jesús , Deng Xiongjie , Ding Ruijie , Bredu Stephen Adu , Duah-Gyamfi Akwasi , Gvozdevaite Agne , Moore Sam , Oliveras Menor Imma , Prentice I. Colin , Malhi Yadvinder
Published: March 2024

Tropical forests dominate terrestrial photosynthesis, yet there are major contradictions in our understanding due to a lack of field studies, especially outside the tropical Americas. A recent field study indicated that West African forests have among the highest forests gross primary productivity (GPP) yet observed, contradicting models that rank them lower than Amazonian forests. Here, we explore possible reasons for this data-model mismatch. We found the in situ GPP measurements higher than multiple global GPP products at the studied sites in Ghana. The underestimation of GPP by models largely disappears when a standard photosynthesis model is informed by local field-measured values of (a) fractional absorbed photosynthetic radiation (fAPAR), and (b) photosynthetic traits. Satellites systematically underestimate fAPAR in the tropics due to cloud contamination issues. The study highlights the potential widespread underestimation of tropical forests GPP and carbon cycling and hints at the ways forward for model and input data improvement.

Related manuscript

The recent field study mentioned above is a manuscript currently accepted byNature Communications(manuscript id NCOMMS-23-37419), which is available as a preprinthttps://www.researchsquare.com/article/rs-3136892/v1

Codes and data availability

All data and codes underlying the study are currently shared viaGithub (link here)which will be made available through Zenodo upon acceptance.
A randomized, controlled, two-center preclinical trial assessing the efficacy of a new benzodiazepine–dihydropyridine hybrid molecule (JM-20) in rodent models of ischemic stroke
Authors: Ramírez-Sánchez Jeney , Rex André , McCann Sarah , Schulze Daniel , Wong-Guerra Maylin , Fonseca-Fonseca Luis A , García-Alonso Enrique , Ramírez-Abreu Ailín , Limonta Ricardo , Dopatka Monika , Mosch Larissa , Núñez-Figueredo Yanier , Dirnagl Ulrich
Published: March 2024

JM-20 is a novel multifunctional benzodiazepine molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide a robust preclinical evidence base for potential clinical development in stroke, we have performed a two-center preclinical trial with sufficiently large group sizes to detect relevant effects, minimizing biases in experimental design as much as possible (randomization, blinding, predefined in- and exclusion criteria) and increasing external and construct validities by performing experimental focal cerebral ischemia by different surgeons in two different laboratories on two continents, including two species (480 mice and 55 rats), different suppliers, young, young adult, and mature adult animals (range 2 -16 months) as well as comorbid animals (diabetes). While JM-20 improved functional outcomes after middle cerebral artery occlusion in young adult mice at day 7 and appeared to reduce mortality (not statistically significant), it had no effect in mature adult or comorbid (STZ-induced diabetes) mice. Effect sizes, where statistically significant, were modest, and much lower than those reported in the previous studies. Meta-analysis of all individual mouse data did not reveal statistically significant different functional outcomes or mortalities between vehicle- and JM-20-treated animals, although neuroscores and survival were slightly better in JM-20-treated animals. In the less severe model of permanent cortical focal cerebral ischemia in rats, JM-20 significantly reduced brain infarction. We conclude that we were able to confirm the neuroprotective potential of JM-20. However, effect sizes were substantially lower as previously described in small, monocentric trials. Further study is needed to determine whether JM-20 could be effective in less severe cases of focal cerebral ischemia or when used in combination with thrombolysis.
Predicting nanocarrier permeation across the human intestinein vitro: Model matters
Authors: Jung Nathalie , Schreiner Jonas , Baur Florentin , Vogel-Kindgen Sarah , Windbergs Maike
Published: March 2024

For clinical translation of oral nanocarriers, simulation of the complex intestinal microenvironment is crucial to evaluate interactions and transport across the intestinal mucosa for predicting the drug’s bioavailability. However, permeation studies are often conducted using simplistic cell culture models, overlooking key physiological factors such as tissue composition, morphology, and additional diffusion barriers as constituted by mucus. This oversight may potentially lead to an incomplete evaluation of the nanocarrier-tissue interactions and an overestimation of permeation. In this study, we systematically investigated different 3D tissue models of the human intestine under static cultivation and dynamic flow conditions with respect to tissue morphology, mucus production, and their impact on nanocarrier permeation. Our results revealed that the cell ratio between the different cell types (enterocytes and goblet cells), as well as the choice of culture conditions, had a notable impact on tissue layer thickness, mucus secretion, and barrier impairment, all of which were increased under dynamic flow conditions. Permeation studies with polymeric nanocarriers (PLGA and PEG-PLGA) elucidated that the amount of mucus present in the respective model was the limiting factor for the permeation of PLGA nanocarriers, while tissue topography represented the key factor influencing PEG-PLGA nanocarrier permeation. Furthermore, both nanocarriers exhibited diametrically opposite permeation kinetics in a direct comparison to soluble compounds. In summary, these findings reveal the critical role of the implemented test systems on permeation assessment and emphasize that, in the context of preclinical nanocarrier testing, the choice ofin vitromodel matters.
Key link between iron and the size structure of three main mesoplanktonic groups (Crustaceans, Rhizarians, and colonial N2-fixers) in the Global Ocean
Authors: Dugenne Mathilde , Corrales-Ugalde Marco , Luo Jessica Y. , Stemmann Lars , Irisson Jean-Olivier , Lombard Fabien , O’Brien Todd , Stock Charles ,   PSSdb data contributors consortium, Kiko Rainer
Published: March 2024

Size is commonly used as a master trait to characterize pelagic organisms as it affects a range of processes and impact marine biogeochemical cycles and services. Yet, a holistic understanding of what environmental factors shape size structure is lacking for most mesoplankton. As part of the Pelagic Size Structure database, we explore the linkages between environmental factors and global compilations of Rhizarian, colonial N2-fixer, and Crustacean size spectra measured from Underwater Vision Profilers or benchtop scanners. We found that iron, alongside temperature, plays a disproportionate role in shaping their spectral biogeography. Our results highlight the effect of dust on N2-fixers and Rhizarians while total iron, comprising organic and mineral compounds, explained most of the variance in Crustaceans size structure. Using machine learning models, we predicted their size structure at the global scale with relatively high R2of 0.93, 0.84, and 0.66. We hope our predictions can support further assessment of their role in biogeochemical processes under present and future forcings.
CytoSignal Detects Locations and Dynamics of Ligand-Receptor Signaling at Cellular Resolution from Spatial Transcriptomic Data
Authors: Liu Jialin , Manabe Hiroaki , Qian Weizhou , Wang Yichen , Gu Yichen , Yan Chu Angel Ka , Gadhvi Gaurav , Song Yuxuan , Ono Noriaki , Welch Joshua D.
Published: March 2024

Nearby cells within tissues communicate through ligand-receptor signaling interactions. Emerging spatial transcriptomic technologies provide a tremendous opportunity to systematically detect ligand-receptor signaling, but no method operates at cellular resolution in the spatial context. We developed CytoSignal to infer the locations and dynamics of cell-cell communication at cellular resolution from spatial transcriptomic data. CytoSignal is based on the simple insight that signaling is a protein-protein interaction that occurs at a specific tissue location when ligand and receptor are expressed in close spatial proximity. Our cellular-resolution, spatially-resolved signaling scores allow several novel types of analyses: we identify spatial gradients in signaling strength; separately quantify the locations of contact-dependent and diffusible interactions; and detect signaling-associated differentially expressed genes. Additionally, we can predict the temporal dynamics of a signaling interaction at each spatial location. CytoSignal is compatible with nearly every kind of spatial transcriptomic technology including FISH-based protocols and spot-based protocols without deconvolution. We experimentally validate our resultsin situby proximity ligation assay, confirming that CytoSignal scores closely match the tissue locations of ligand-receptor protein-protein interactions. Our work addresses the field’s current need for a robust and scalable tool to detect cell-cell signaling interactions and their dynamics at cellular resolution from spatial transcriptomic data.
A knockoff calibration method to avoid over-clustering in single-cell RNA-sequencing
Authors: DenAdel Alan , Ramseier Michelle L. , Navia Andrew W. , Shalek Alex K. , Raghavan Srivatsan , Winter Peter S. , Amini Ava P. , Crawford Lorin
Published: March 2024

Standard single-cell RNA-sequencing (scRNA-seq) pipelines nearly always include unsupervised clustering as a key step in identifying biologically distinct cell types. A follow-up step in these pipelines is to test for differential expression between the identified clusters. When algorithms over-cluster, downstream analyses will produce inflatedP-values resulting in increased false discoveries. In this work, we presentcallback(CalibratedClustering viaKnockoffs): a new method for protecting against over-clustering by controlling for the impact of reusing the same data twice when performing differential expression analysis, commonly known as “double-dipping”. Importantly, our approach can be applied to a wide range of clustering algorithms. Using real and simulated data, we show thatcallbackprovides state-of-the-art clustering performance and can rapidly analyze large-scale scRNA-seq studies, even on a personal laptop.
Graph Contrastive Learning of Subcellular-resolution Spatial Transcriptomics Improves Cell Type Annotation and Reveals Critical Molecular Pathways
Authors: Lu Qiaolin , Ding Jiayuan , Li Lingxiao , Chang Yi , Tang Jiliang , Qiu Xiaojie
Published: March 2024

Imaging based spatial transcriptomics (iST), such as MERFISH, CosMx SMI, and Xenium, quantify gene expression level across cells in space, but more importantly, they directly reveal the subcellular distribution of RNA transcripts at the single-molecule resolution. The subcellular localization of RNA molecules plays a crucial role in the compartmentalization-dependent regulation of genes within individual cells. Understanding the intracellular spatial distribution of RNA for a particular cell type thus not only improves the characterization of cell identity but also is of paramount importance in elucidating unique subcellular regulatory mechanisms specific to the cell type. However, current cell type annotation approaches of iST primarily utilize gene expression information while neglecting the spatial distribution of RNAs within cells. In this work, we introduce a semi-supervised graph contrastive learning method called Focus, the first method, to the best of our knowledge, that explicitly models RNA’s subcellular distribution and community to improve cell type annotation. Focus first constructs gene neighborhood networks based on the subcellular colocalization relationship of RNA transcripts. Next, the subcellular graph of each cell can be augmented by adding important edges and nodes or removing trivial edges and nodes. Focus then aims to maximize the similarity between positive pairs from two augmented views of the same cell and minimize the similarity between negative pairs from different cells within a common batch. Guided by a limited amount of labeled data, Focus is capable of assigning cell type identities for the entire datasets at high accuracy. Extensive experiments demonstrate the effectiveness of Focus compared to existing state-of-the-art approaches across a range of spatial transcriptomics platforms and biological systems. Furthermore, Focus enjoys the advantages of revealing intricate cell type-specific subcellular spatial gene patterns and providing interpretable subcellular gene analysis, such as defining the gene importance score. Importantly, with the importance score, Focus identifies genes harboring strong relevance to cell type-specific pathways, indicating its potential in uncovering novel regulatory programs across numerous biological systems. Focus is freely accessible athttps://github.com/OmicsML/focus.
Compensatory Mechanisms for Preserving Speech-in-Noise Comprehension Involve Prefrontal Cortex in Older Adults
Authors: Li Zhuoran , Liu Yi , Zhang Xinmiao , Kou Nuonan , Zhao Xiaoying , Jiang Xiangru , Engel Andreas K. , Zhang Dan , Wang Shuo
Published: March 2024

The capacity of comprehending others amidst noise is essential for human communication. However, it presents significant challenges for the elderly who often face progressive declines in the peripheral auditory system and the whole brain. While previous studies have suggested the existence of neural reserve and neural compensation as potential mechanisms for preserving cognitive abilities in aging, the specific mechanisms supporting speech-in-noise comprehension among the elderly remain unclear. To address this question, the present study employs an inter-brain neuroscience approach by analyzing the neural coupling between brain activities of older adults and those of speakers under noisy conditions. Results showed that the neural coupling encompassed more extensive brain regions of older listeners compared to young listeners, with a notable engagement of the prefrontal cortex. Moreover, the neural coupling from prefrontal cortex was coordinated with that from classical language-related regions. More importantly, as background noise increases, the older listener’s speech comprehension performance was more closely associated with the neural coupling from prefrontal cortex. Taken together, this study reveals the compensatory recruitment of neurocognitive resources, particularly within the prefrontal cortex, to facilitate speech processing in the aging brain, and further highlights the critical role of prefrontal cortex in maintaining the elderly’s ability to comprehend others in noisy environments. It supports the neural compensation hypothesis, extending the knowledge about the neural basis that underlies cognitive preservation in the aging population.
Nonlinear Elastic Bottlebrush Polymer Hydrogels Modulate Actomyosin Mediated Protrusion Formation in Mesenchymal Stromal Cells
Authors: Ohnsorg Monica L. , Mash Kayla M. , Khang Alex , Rao Varsha V. , Kirkpatrick Bruce E. , Bera Kaustav , Anseth Kristi S.
Published: March 2024

The nonlinear elasticity of many tissue-specific extracellular matrices is difficult to recapitulate without the use of fibrous architectures, which couple strain-stiffening with stress relaxation. Herein, bottlebrush polymers are synthesized and crosslinked to form poly(ethylene glycol)-based hydrogels and used to study how strain-stiffening behavior affects human mesenchymal stromal cells (hMSCs). By tailoring the bottlebrush polymer length, the critical stress associated with the onset of network stiffening is systematically varied, and a unique protrusion-rich hMSC morphology emerges only at critical stresses within a biologically accessible stress regime. Local cell-matrix interactions are quantified using 3D traction force microscopy and small molecule inhibitors are used to identify cellular machinery that plays a critical role in hMSC mechanosensing of the engineered, strain-stiffening microenvironment. Collectively, this study demonstrates how covalently crosslinked bottlebrush polymer hydrogels can recapitulate strain-stiffening biomechanical cues at biologically relevant stresses and be used to probe how nonlinear elastic matrix properties regulate cellular processes.
Effectiveness and efficiency: label-aware hierarchical subgraph learning for protein-protein interaction
Authors: Zhou Yuanqing , Lin Haitao , Huang Yufei , Wu Lirong , Li Stan Z. , Chen Wei
Published: March 2024

Protein-protein interactions (PPIs) are crucial in various biological processes and their study has significant implications for drug development and disease diagnosis. Existing deep learning methods for PPIs prediction, including graph neural networks (GNNs), have been widely employed as the solutions, while they usually suffer from performance degradation under complex real-world scenarios. We claim that the topological shortcut is one of the key problems contributing negatively to the performance, according to our analysis. By modeling the PPIs as a graph with protein as nodes and interactions as edge types, the prevailing models tend to learn the pattern of nodes’ degrees rather than intrinsic sequence-structure profiles, leading to the problem termed topological shortcut. In addition, with the emergence of high-throughput experimental methods such as mass spectrometry and protein chip technology, the amount of available PPI data is exploding. The huge data growth leads to intensive computational costs and challenges computing devices, causing infeasibility in practice. To address the discussed problems, we propose alabel-aware hierarchical subgraphlearning method (laruGL-PPI) that can effectively infer PPIs while being both interpretable and generalizable. Specifically, we introduced edge-based subgraph sampling to effectively alleviate the problems of topological shortcuts and high computing costs. Besides, the inner-outer connections of PPIs are modeled as a hierarchical graph, together with the dependencies between interaction types constructed by a label graph. Extensive experiments on PPI datasets of different scales demonstrate that laruGL-PPI outperforms state-of-the-art PPI prediction methods, particularly in the testing of unseen proteins. Also, our model can recognize crucial sites of proteins, such as surface sites for binding and active sites for catalysis.
Choroid plexus enlargement in acute neuroinflammation is tightly interrelated to the tyrosine receptor signalling
Authors: Luessi Felix , Schiffer Julia , Gonzalez-Escamilla Gabriel , Fleischer Vinzenz , Engel Sinah , Ciolac Dumitru , Koeck Thomas , Wild Philipp S. , Gruchot Joel , Ruck Tobias , Othmann Ahmed , Bittner Stefan , Meuth Sven G. , Zipp Frauke , Stüve Olaf , Groppa Sergiu
Published: March 2024

The choroid plexus (ChP) plays a crucial function in neuroinflammation of the central nervous system and in the immune response of the brain during neurodegeneration. Recent studies described a massive ChP enlargement in patients with multiple sclerosis (MS) and active disease courses, but also in several other neuroinflammatory and neurodegenerative conditions. Nevertheless, the exact basis and pathophysiology behind ChP hypertrophy remains unclear. This study was designed to evaluate the association of cerebrospinal fluid (CSF) proteomic spectra with brain MRI-derived volumetric measures of ChP in two independent cohorts of MS patients, and to translationally validate the related molecular mechanisms in the transcriptomic analysis of the ChP properties in a mouse model of experimental autoimmune encephalomyelitis (EAE). Our analysis revealed five enriched proteins(NTRK2, ADAM23, SCARB2, CPM, CNTN5)significantly associated with the ChP volumes in both of the MS cohorts. These proteins relate closely to mechanisms of cellular communication, function (e.g. transmembrane tyrosine receptor signalling (RTK) and vascular endothelial growth) and pathways involved in the regulation of cellular plasticity (e.g. neuron differentiation, axonal remodelling and myelin regulation) as depicted by molecular function analysis and validation of the results in the transcriptome from ChP tissue specific for EAE. This work provides conclusive new evidence for the role of ChP in the context of neuroinflammation and neurodegeneration, demonstrating the intriguing relationships between ChP enlargement, CSF dynamics, and the development of neuroinflammatory and neurodegenerative diseases. Our results are encouraging for the development of new therapeutic avenues (i.e. targeting RTK signalling).

One sentence summary

Tyrosine receptor signalling is tightly associated with choroid plexus enlargement and is key in CSF dynamics during a neuroinflammatory attack in MS
Human-in-the-loop approach to identify functionally important residues of proteins from literature
Authors: Vollmar Melanie , Tirunagari Santosh , Harrus Deborah , Armstrong David , Gaborova Romana , Gupta Deepti , Afonso Marcelo Querino Lima , Evans Genevieve Laura , Velankar Sameer
Published: March 2024

We present a novel system that leverages curators in the loop to develop a dataset and model for detecting residue-level functional annotations and other protein structure features from standard publication text. Our approach involves the integration of data from multiple resources, including PDBe, EuropePMC, PubMedCentral, and PubMed, combined with annotation guidelines from UniProt, while employing LitSuggest and Huggingface models as tools in the annotation process. A team of seven annotators manually curated ten articles for named entities, which we utilized to train a starting PubmedBert model from Huggingface. Using a human-in-the-loop annotation system, we developed the best model with commendable performance metrics of 0.90 for precision, 0.92 for recall, and 0.91 for F1-measure. Our proposed system showcases a successful synergy of machine learning techniques and human expertise in curating a dataset for residue-level functional annotations and protein structure features. The results demonstrate the potential for broader applications in protein research, bridging the gap between advanced machine learning models and the indispensable insights of domain experts.
Single-character insertion-deletion model preserves long indels in ancestral sequence reconstruction
Authors: Jowkar Gholamhossein , Pěcerska Jūlija , Gil Manuel , Anisimova Maria
Published: March 2024

Insertions and deletions (indels) play a significant role in genome evolution across species. Realistic modelling of indel evolution is challenging and is still an open research question. Several attempts have been made to explicitly model multi-character (long) indels, such as TKF92, by relaxing the site independence assumption and introducing fragments. However, these methods are computationally expensive

On the other hand, the Poisson Indel Process (PIP) assumes site independence but allows one to infer single-character indels on the phylogenetic tree, distinguishing insertions from deletions. PIP’s marginal likelihood computation has linear time complexity, enabling ancestral sequence reconstruction (ASR) with indels in linear time. Recently, we developed ARPIP, an ASR method using PIP, capable of inferring indel events with explicit evolutionary interpretations

Here, we investigate the effect of the single-character indel assumption on reconstructed ancestral sequences on mammalian protein orthologs and on simulated data. We show that ARPIP’s ancestral estimates preserve the gap length distribution observed in the input alignment. In mammalian proteins the lengths of inserted segments appear to be substantially longer compared to deleted segments. Further, we confirm the well-established deletion bias observed in real data

To date, ARPIP is the only ancestral reconstruction method that explicitly models insertion and deletion events over time. Given a good quality input alignment, it can capture ancestral long indel events on the phylogeny
Non-apoptotic caspase events and Atf3 expression underlie direct neuronal differentiation of adult neural stem cells
Authors: Rosa Frédéric , Dray Nicolas , Bally-Cuif Laure
Published: March 2024

Neural stem cells (NSCs) are key physiological components of adult vertebrate brains, generating neurons over a lifetime. In the adult zebrafish pallium, NSCs persist at long term through balanced fate decisions that include direct neuronal conversions, i.e., delamination and neurogenesis without a division. The characteristics and mechanisms of these events remain unknown. Here we reanalyze intravital imaging data of adult pallial NSCs and observe shared delamination dynamics between NSCs and committed neuronal progenitors. In a candidate approach for mechanisms predicting NSC decisions, we build an NSC-specific genetic tracer of Caspase3/7 activation (Cas3*/Cas7*)in vivoand show that non-apoptotic Cas3*/7* events occur in adult NSCs and are biased towards neuronal conversion under physiological conditions. We further identify the transcription factor Atf3 as necessary to express this fate. Finally, we show that the Cas3*/7*/Atf3 pathways are part of the processes engaged when NSCs are recruited for neuronal regeneration. These results provide evidence for the non-apoptotic caspase events occurring in vertebrate adult NSCs and link these events with the NSC fate decision of direct conversion, important for long-term NSC population homeostasis.
Inferring allele-specific copy number aberrations and tumor phylogeography from spatially resolved transcriptomics
Authors: Ma Cong , Balaban Metin , Liu Jingxian , Chen Siqi , Ding Li , Raphael Benjamin J.
Published: March 2024

A key challenge in cancer research is to reconstruct the somatic evolution within a tumor over time and across space. Spatially resolved transcriptomics (SRT) measures gene expression at thousands of spatial locations in a tumor, but does not directly reveal genetic aberrations. We introduce CalicoST, an algorithm to simultaneously infer allele-specific copy number aberrations (CNAs) and a spatial model of tumor evolution from SRT of tumor slices. By modeling CNA-induced perturbations in both total and allele-specific gene expression, CalicoST identifies important types of CNAs – including copy-neutral loss of heterozygosity (CNLOH) and mirrored subclonal CNAs– that are invisible to total copy number analysis. On SRT data from nine patients from the Human Tumor Atlas Network (HTAN) with matched whole exome sequencing (WES) data, CalicoST achieves an average accuracy of 86%, approximately 21% higher than existing methods. On two patients with SRT data from multiple adjacent slices, CalicoST reconstructs a tumor phylogeography that describes the spread of cancerous clones in three-dimensional space. CalicoST analysis of multiple SRT slices from a cancerous prostate organ reveals five spatially coherent clones, with mirrored subclonal CNAs distinguishing clones on the two sides of the prostate, forming a bifurcating phylogeography in both genetic and physical space.
Detection of spatial chromatin accessibility patterns with inter-cellular correlations
Authors: Chen Xiaoyang , Li Keyi , Wu Xiaoqing , Li Zhen , Jiang Qun , Wu Yanhong , Jiang Rui
Published: March 2024

Recent advances in spatial sequencing technologies enable simultaneous capture of spatial location and chromatin accessibility of cells within intact tissue slices. Identifying peaks that display spatial variation and cellular heterogeneity is the first and key analytic task for characterizing the spatial chromatin accessibility landscape of complex tissues. Here we propose an efficient and iterative model, Descartes, for spatially variable peaks identification based on the graph of inter-cellular correlations. Through the comprehensive benchmarking for spatially variable peaks identification, we demonstrate the superiority of Descartes in revealing cellular heterogeneity and capturing tissue structure. In terms of computational efficiency, Descartes also outperforms existing methods with spatial assumptions. Utilizing the graph of inter-cellular correlations, Descartes denoises and imputes data via the neighboring relationships, enhancing the precision of downstream analysis. We further demonstrate the ability of Descartes for peak module identification by using peak-peak correlations within the graph. When applied to spatial multi-omics data, Descartes show its potential to detect gene-peak interactions, offering valuable insights into the construction of gene regulatory networks.