bluuebunny/crossref_metadata_2025 huggingface dataset:
Revascularization of arterial occlusions in posterior circulation acute ischemic stroke
Authors: Salerno Alexander , Michel Patrik , Strambo Davide
Published: December 2023

Purpose of review

This review highlights the latest advancements achieved in the revascularization of arterial occlusions associated with an acute ischemic stroke affecting the posterior circulation. It delves into the frequency and outcomes based on specific arterial segments and presents current evidence supporting revascularization treatments, including intravenous thrombolysis and endovascular thrombectomy.

Recent findings

Comprehensive evidence for treatment across major arterial segments of the posterior circulation -- vertebral artery, basilar artery, posterior cerebral artery, cerebellar arteries, and multilevel posterior occlusions -- is provided. Additionally, the latest findings from randomized clinical trials on basilar artery occlusion are explored alongside results from extensive retrospective analyses of isolated vertebral and posterior cerebral artery occlusions.

Current research supports the treatment decision in acute ischemic strokes of the posterior circulation using both intravenous thrombolysis and endovascular thrombectomy. This review also emphasizes existing knowledge gaps in the management of these strokes and advocates for more randomized clinical trials, notably concerning the posterior cerebral artery (currently ongoing), isolated vertebral artery, and multilevel posterior circulation occlusions.
Social identity bias and communication network clustering interact to shape patterns of opinion dynamics
Authors: Steiglechner Peter , Smaldino Paul E. , Moser Deyshawn , Merico Agostino
Published: December 2023

Social influence aligns people's opinions, but social identities and related in-group biases interfere with this alignment. For instance, the recent rise of young climate activists (e.g. ‘Fridays for Future’ or ‘Last Generation’) has highlighted the importance of generational identities in the climate change debate. It is unclear how social identities affect the emergence of opinion patterns, such as consensus or disagreement, in a society. Here, we present an agent-based model to explore this question. Agents communicate in a network and form opinions through social influence. The agents have fixed social identities which involve homophily in their interaction preferences and in-group bias in their perception of others. We find that the in-group bias has opposing effects depending on the network topology. The bias impedes consensus in highly random networks by promoting the formation of echo chambers within social identity groups. By contrast, the bias facilitates consensus in highly clustered networks by aligning dispersed in-group agents across the network and, thereby, preventing the formation of isolated echo chambers. Our model uncovers the mechanisms underpinning these opposing effects of the in-group bias and highlights the importance of the communication network topology for shaping opinion dynamics.
How visuomotor predictability and task demands affect tactile sensitivity on a moving limb during object interaction in a virtual environment
Authors: McManus Meaghan , Schütz Immo , Voudouris Dimitris , Fiehler Katja
Published: December 2023

Tactile sensitivity is decreased on a moving limb compared to the same static limb. This
tactile suppression
likely reflects an interplay between sensorimotor predictions and sensory feedback. Here, we examined how visuomotor predictability influences tactile suppression. Participants were instructed to hit an approaching virtual object, with the object either never rotating, or always rotating, or rotating unpredictably, prompting related movement adjustments. We probed tactile suppression by delivering a vibrotactile stimulus of varying intensities to the moving hand briefly after the object's rotation and asked participants to indicate if they had felt a vibration. We hypothesized that Unpredictable Rotations would require upweighting of somatosensory feedback from the hand and therefore decrease suppression. Instead, we found stronger suppression with unpredictable than Predictable Rotations. This finding persisted even when visual input from the moving hand was removed and participants had to rely solely on somatosensory feedback of their hand. Importantly, we found a correlation between task demand and tactile suppression in both experiments, indicating that task load can amplify tactile suppression, possibly by downweighting task-irrelevant somatosensory feedback signals to allow for successful task performance when visuomotor task demands are high.
RSYD-BASIC: a bioinformatics pipeline for Routine Sequence analYsis and Data processing of BActerial iSolates for clInical miCrobiology
Authors: Steinke Kat , Thomsen Karina Gravgaard , Hoegh Silje Vermedal , Larsen Sanne Løkkegaard , Kubel Vilhelmsen Karina , Jensen Thøger Gorm , Skov Marianne Nielsine , Sydenham Thomas Vognbjerg
Published: December 2023

Background
Whole genome sequencing of bacterial isolates is increasingly becoming routine in clinical microbiology; however, subsequent analysis often needs to be started by a bioinformatician even for comprehensive pipelines. To increase the robustness of our workflow and free up bioinformatician work hours for development and advanced analysis, we aimed to produce a robust, customizable bioinformatic pipeline for bacterial genome assembly and routine analysis results that could be initiated by non-bioinformaticians.
Results
 When tested on publicly available sequences, our pipeline yields comparable results in most cases. In routine use, it has already yielded clinically relevant results, allowing us to type a variety of bacterial pathogens isolated in our clinical laboratory and disprove a potential outbreak.
Conclusion
With the RSYD-BASIC pipeline, we present a reads-to-results analysis pipeline operated by non-expert users that greatly eases investigation of potential outbreaks. Results obtained with publicly available sequences are also promising, while underlining the importance of standardized methods.
Exploring the embodied mind: functional connectome fingerprinting of meditation expertise
Authors: Czajko Sebastien , Zorn Jelle , Daumail Loic , Chetelat Gael , Margulies Daniel , Lutz Antoine
Published: December 2023

Short mindfulness-based interventions have gained traction in research due to their positive impact on well-being, cognition, and clinical symptoms across various settings. However, these short-term trainings are viewed as preliminary steps within a more extensive transformative path, presumably leading to long-lasting trait changes. Despite this, little is still known about the brain correlates of meditation traits. To address this gap, we investigated the neural correlates of meditation expertise in long-term Buddhist practitioners, comparing the large-scale brain functional connectivity of 28 expert meditators with 47 matched novices. Our hypothesis posited that meditation expertise would be associated with specific and enduring patterns of functional connectivity present during both meditative (open monitoring/open presence and loving-kindness compassion meditations) and non-meditative resting states, as measured by connectivity gradients. Our finding revealed a trend toward the overall contraction in the gradient cognitive hierarchy in experts versus novices during open presence meditation. The signature of expertise was further characterized by an increased integration of large-scale brain networks, including the somatomotor, dorsal and ventral attention, limbic and frontoparietal networks, which correlated with a higher ability to create psychological distance with thoughts and emotions. Applying a support vector classifier to states not included in training, we successfully decoded expertise as a trait, demonstrating that its non-state-dependent nature. Such heightened integration of bodily maps with affective and attentional networks in meditation experts could point toward a signature of the embodied cognition cultivated in these contemplative practices.
Inhibition of KLK8 promotes pulmonary endothelial repair by restoring VE-cadherin/Akt/FOXM1 pathway
Authors: Zhao Ying , Ji Hui , Han Feng , Xu Qing-Feng , Zhang Hui , Liu Di , Wei Juan , Xu Dan-Hong , Jiang Lai , Du Jian-Kui , Xu Ping-Bo , Liu Yu-Jian , Zhu Xiao-Yan
Published: December 2023

The tissue kallikrein-related peptidases (KLKs) are secreted serine proteases deeply involved in angiogenesis. However, whether KLKs are involved in the regulation of endothelial regeneration during sepsis remains unknown. By comparing the mRNA levels of 15 KLKs, we found that KLK8 was the highest induced KLK member in lung tissues or primary isolated mouse lung vascular endothelial cells (MLVECs) exposed to lipopolysaccharide (LPS). Adenovirus-mediated overexpression of KLK8 caused endothelial hyperpermeability bothin vitroandin vivo. Inhibition of KLK8, by either gene knockout or KLK8 neutralizing antibodies, alleviated sepsis-induced endothelial hyperpermeability, acute lung injury and mortality. Mechanistically, transcription profiling of KLK8-overexpressed endothelial cells revealed a central role of forkhead box M1 (FOXM1) downregulation in mediating the pro-injury and anti-proliferation effects of KLK8. KLK8 cleaved VE-cadherin and consequently suppressed FOXM1 expression by inactivation of the VE-cadherin/Akt pathway. KLK8 deficiency or blockade rescued VE-cadherin/Akt/FOXM1 pathway, thus promoting endothelium regeneration. This study reveals a critical role for KLK8-induced inactivation of VE-cadherin/Akt/FOXM1 pathway in mediating the impairment of endothelial regeneration and the consequent lung vascular leakiness in response to sepsis.

Highlights

Upregulated KLK8 mediates lung endothelial barrier dysfunction during sepsis

KLK8 inactivates VE-cadherin/Akt/FOXM1, thus impairing endothelium regeneration

KLK8 deficiency or blockade rescues VE-cadherin/Akt/FOXM1 signaling pathway

KLK8 deficiency or blockade promotes endothelium regeneration during sepsis

KLK8 deficiency or blockade attenuates sepsis-induced acute lung injury and mortality
Extensive remodeling of the ubiquitination landscape during aging inC. elegans
Authors: Koyuncu Seda , Vilchez David
Published: December 2023

In previous work, we investigated ubiquitination changes during aging inC. elegans. We identified 2,163 peptides undergoing age-related ubiquitination changes in wild-type animals, corresponding to 1,050 proteins. While many lysine sites had increased ubiquitination with age, a larger number exhibited decreased ubiquitination. Longevity pathways, such as reduced insulin signaling and dietary restriction, prevented ubiquitination changes. Treatment with a broad-spectrum inhibitor of deubiquitinating enzymes (DUBs) or knockdown of specific DUBs ameliorated ubiquitination loss in old worms. Moreover, we identified proteins that accumulate with aging due to reduced ubiquitination and subsequent proteasomal degradation. Our conclusions were supported by multiple approaches, including ubiquitin and total proteomics, western blot, and ubiquitin-less mutations. Concerns were raised by a laboratory regarding the possibility of our protocol omitting insoluble proteins due to a centrifugation step after protein extraction and solubilization. To address these concerns, we have focused on proteins previously reported to become insoluble with aging inC. elegans. Our proteomics experiments successfully detected and quantified all these proteins in old worms. In many cases, the proteins that become insoluble with aging did not change or even increased at the total levels. However, they often exhibited ubiquitination changes, primarily a loss of ubiquitination. Independent work combining analysis of conformational changes with our datasets demonstrated that 92% of the age-dependent metastable proteins exhibit differential ubiquitination during aging. In addition, we performed experiments to confirm that the buffers used for proteomics and western blot efficiently solubilize most of the proteome. Importantly, the analysis of total homogenates combining clear lysates and the remaining debris after protein extraction also revealed decreased ubiquitination during aging, whereas DUB inhibitor treatment (4 h) in old worms restored ubiquitination levels. These data further support our previous conclusions regarding extensive ubiquitination changes during aging inC. elegans.
Systemic Inflammation and CT-Derived Coronary Plaque Characteristics Among Asymptomatic US Adults: The Miami Heart Study
Authors: Lahan Shubham , Hagan Kobina , Cainzos-Achirica Miguel , Valero-Elizondo Javier , Ali Shozab S. , Arias Lara , Saxena Anshul , Feldman Theodore , Blaha Michael J. , Shapiro Michael D. , Blankstein Ron , Sharma Garima , Al-Kindi Sadeer , Shah Svati , Cury Ricardo , Budoff Matthew J. , Fialkow Jonathan , Nasir Khurram
Published: December 2023

Objective

We aimed to evaluate the association between inflammatory markers and coronary plaque features on coronary computed tomography angiography (CCTA) among asymptomatic individuals.

Methods

Baseline data from Miami Heart Study — an ongoing prospective community-based study of a primary prevention cohort from the Greater Miami Area without prior known CAD — were used for this cross-sectional analysis. Independent variables included high-sensitivity C-reactive protein (hsCRP; <2 vs ≥ 2mg/L) and Interleukin-6 (IL–6; in tertiles). The outcomes of interest were CCTA-based plaque findings: any plaque, CAC>0, CAC>100, maximal stenosis >50%, and high-risk plaque. Multivariable logistic regression models were constructed to evaluate the association between inflammatory markers and coronary plaque features.

Results

We evaluated 2,342 participants (50.4% men; mean age 53.4±6.7 years, 47% Hispanic, 43% non-Hispanic White, 8.3% diabetes, 56% hypertension, 22% on statin therapy). After adjusting for age, sex, and race/ethnicity, hsCRP ≥2 mg/L was associated with increased odds of having any plaque on CCTA [odds ratio (OR), 1.31 (95% confidence interval [CI], 1.09–1.58)] and stenosis ≥ 50% [OR, 1.69 (95% CI, 1.18–2.41)]. participants with IL–6 levels in 3rdtertile were associated with higher odds of detecting any plaque [OR, 1.59 (95% CI, (1.27–1.99)], CAC >0 [OR, 1.34 (95% CI, 1.06–1.69)], ≥50% stenosis [OR, 2.41 (95% CI, 1.56–3.81)], and any high-risk plaque [OR, 2.41 (95% CI, 1.56–3.81)] Further adjustment for LDL, diabetes, hypertension, obesity, and tobacco use yielded nonsignificant associations.

Conclusion

Elevated levels of hsCRP and IL–6 are associated with the presence of coronary plaque and stenosis on CCTA when adjusted for demographics. However, these associations became nonsignificant after adjusting for additional cardiovascular risk factors. Our findings suggest a role of systemic inflammation as a mediator of the effect of cardiovascular risk factors on coronary plaque burden.
Reassessing the association of VDR and its polymorphisms with tuberculosis in global populations
Authors: Das Debashruti , Chaubey Gyaneshwer
Published: December 2023

Background

Vitamin D is a hormone that regulates the calcium homeostasis of the body. Besides this classical function, it is also regarded as an important immunomodulator. Most active Vitamin D actions are mediated through the Vitamin D receptor (VDR), a transcription factor and also a member of the nuclear receptor superfamily. In this study, we explored the phylogeographic attributes of the four most well-known polymorphisms of the VDR gene namely rs7975232 (ApaI), rs731235 (TaqI), rs1544410 (BsmI), rs2228570 (FokI) and also evaluated their association with the incidence of tuberculosis in global populations. This study integrated several in-silico approaches on population databases to evaluate the pattern of distribution, linkage and selection patterns of these SNPs.

Results

The ancestral alleles of rs7975232, rs731235, and rs1544410 are still present in over 50% frequency in modern human populations. These SNPs also have a very strong linkage disequilibrium among themselves in all population groups but no haplotype blocks are seen in South Asian populations constituting these polymorphisms. The selection results reveal a negative Tajima’s D value in West and East Eurasian populations suggesting positive selection in these regions… In correlation studies, we found no association between the incidence of tuberculosis and the allele or genotype frequency of these four SNPs.

Conclusion

The four SNPs of VDR behave differently in South Asian populations as compared to West and East Eurasian populations but no significant association was found with the incidence of tuberculosis in global populations.
stGCL: A versatile cross-modality fusion method based on multi-modal graph contrastive learning for spatial transcriptomics
Authors: Yu Na , Zhang Daoliang , Zhang Wei , Liu Zhiping , Qiao Xu , Wang Chuanyuan , Zhao Miaoqing , Chao Baoting , Li Wei , De Marinis Yang , Gao Rui
Published: December 2023

Advances in spatial transcriptomics (ST) technologies have provided unprecedented opportunities to depict transcriptomic and histological landscapes in the spatial context. Multi-modal ST data provide abundant and comprehensive information about cellular status, function, and organization. However, in dealing with the processing and analysis of spatial transcriptomics data, existing algorithms struggle to effectively fuse the multi-modal information contained within ST data. Here, we propose a graph contrastive learning-based cross-modality fusion model named stGCL for accurate and robust integrating gene expression, spatial information as well as histological profiles simultaneously. stGCL adopts a novel histology-based Vision Transformer (H-ViT) method to effectively encode histological features and combines multi-modal graph attention auto-encoder (GATE) with contrastive learning to fuse cross-modality features. In addition, stGCL introduces a pioneering spatial coordinate correcting and registering strategy for tissue slices integration, which can reduce batch effects and identify cross-sectional domains precisely. Compared with state-of-the-art methods on spatial transcriptomics data across platforms and resolutions, stGCL achieves a superior clustering performance and is more robust in unraveling spatial patterns of biological significance. Additionally, stGCL successfully reconstructed three-dimensional (3D) brain tissue structures by integrating vertical and horizontal slices respectively. Application of stGCL in human bronchiolar adenoma (BA) data reveals intratumor spatial heterogeneity and identifies candidate gene biomarkers. In summary, stGCL enables the fusion of various spatial modality data and is a powerful tool for analytical tasks such as spatial domain identification and multi-slice integration.
Structure-Aware Dual-Target Drug Design through Collaborative Learning of Pharmacophore Combination and Molecular Simulation
Authors: Chen Sheng , Xie Junjie , Ye Renlong , Xu David Daqiang , Yang Yuedong
Published: December 2023

Dual-target drug design has gained significant attention in the treatment of complex diseases, such as cancers and autoimmune disorders. A widely employed design strategy is combining pharmacophores to incorporate the knowledge of structure-activity relationships of both targets. Unfortunately, it often struggles with long and expensive trial and error, because protein pockets of two targets impose complex structural constraints on the pharmacophore combination. In this study, we propose AIxFuse, a structure-aware dual-target drug design method that learns pharmacophore fusion patterns to satisfy the dual-target structural constraints simulated by molecular docking. We utilize two self-play reinforcement learning (RL) agents to learn pharmacophore selection and fusion by comprehensive feedback including dual-target molecular docking scores. Collaboratively, the molecular docking scores are learned by active learning (AL). Through collaborative RL and AL, AIxFuse learns to generate molecules with multiple desired properties. AIxFuse is shown to outperform state-of-the-art methods in generating dual-target drugs against glycogen synthase kinase-3 beta (GSK3β) and c-Jun N-terminal kinase 3 (JNK3). When applied to another task against retinoic acid receptor-related orphan receptorγ-t (RORγt) and dihydroorotate dehydrogenase (DHODH), AIxFuse exhibits consistent performance while compared methods suffer performance drops, leading to a 5 times outperformance in success rate. Docking studies demonstrate that AIxFuse can generate molecules concurrently satisfying the binding mode required by both targets. Further free energy perturbation calculation indicates that the generated candidates have promising binding free energies against both targets.

Significance Statement

Complex diseases like cancers and autoimmune disorders are mostly caused by multiple genes. Designing dual-target drugs against two target proteins simultaneously can achieve synergistic effects and alleviate drug resistance. In this study, we present AIxFuse, which to our knowledge is the first structure-aware dual-target drug design method that learns pharmacophore fusion patterns to satisfy the dual-target structural constraints simulated by molecular docking. AIxFuse exhibits superior performance to previous state-of-the-art methods on comprehensive benchmarks. By generating diverse drug candidates with promising dualtarget binding free energies and other desired properties, AIxFuse holds promising prospects for accelerating the development of novel dual-target drugs for long-term therapeutic of complex diseases.
Senescence phenotype of lymph node stromal cells from patients with rheumatoid arthritis is partly restored by dasatinib treatment
Authors: de Jong T.A. , Semmelink J.F. , Bolt J.W. , Grasso C. , Hoebe R.A. , Krawczyk P.M. , van Baarsen L.G.M.
Published: December 2023

Objective

Cellular senescence is a state of proliferation arrest of cells occurring during aging. The persistence and accumulation of senescent cells has been implicated in the pathogenesis of age-related diseases like rheumatoid arthritis (RA). RA is a chronic autoimmune disease in which loss of immune tolerance and systemic autoimmunity precedes clinical onset of disease. Lymph node stromal cells (LNSCs) are important regulators of immune tolerance. Accordingly, accumulating senescent LNSCs may potentially lead to defective immune tolerance and the development of systemic autoimmune disease.

Methods

Human LNSCs were isolated and cultured from inguinal lymph node needle biopsies from individuals at risk of developing RA (RA-risk individuals), RA patients and seronegative healthy volunteers. Senescence hallmarks and the effect of dasatinib treatment were assessed using quantitative PCR, flow cytometry, microscopy and live-cell imaging.

Results

Cell size, granularity and autofluorescence were significantly higher in RA LNSCs compared with control LNSCs. Stainings indicate more senescence associated β-galactosidase activity, more lipofuscin positive granules and increased DNA damage in RA-risk and RA LNSCs compared with control LNSCs. Moreover, we found altered gene expression levels of senescence associated genes in LNSCs from RA patients. Strikingly, the capacity to repair irradiation induced DNA damage was significantly lower in RA-risk and RA LNSCs compared with control LNSCs. Treating LNSCs with dasatinib significantly improved cell size and DNA repair capacity of cultured LNSCs.

Conclusion

We observed multiple senescent hallmarks in RA LNSCs and to lesser extent already in RA-risk LNSCs, which could partly be restored by dasatinib treatment.

KEY MESSAGES

What is already known on this topic?

–

Synovial fibroblasts from RA patients display a senescent phenotype and accumulate in inflamed synovial tissue.

What does this study add?

–

Lymph node stromal cells (LNSCs) from RA patients, and to a lesser extent from RA-risk, display key hallmarks of senescence.

–

Bothex vivoandin vitroLNSCs from RA patients have an increased cell size compared with control LNSCs.

–

RA and RA-risk LNSCs have an impaired ability to repair DNA damage

–

Treating LNSCs with dasatinib significantly improved cell size and DNA repair capacity of LNSCs.

How might this study impact on clinical practice or future developments?

–

These hallmarks of senescence in LNSCs may indicate premature aging and loss of function of the immunomodulatory lymph node stromal compartment during RA development. Dasatinib treatment of LNSCs shows that senolytics may be an effective preclinical drug to restore cell function early in disease.
Studying social anxiety without triggering it: Establishing an age-controlled cohort of social media users for observational studies
Authors: Schmidt Ana Lucia , O’Connor Karen , Gonzalez Hernandez Graciela , Rodriguez-Esteban Raul
Published: December 2023

Background

Patients of certain diseases are less likely to approach the healthcare system but remain active in social media. Young Social Anxiety Disorder (SAD) patients, in particular, are a hard-to-reach population due to disease symptomatology, unmet need and age-related barriers, which makes obtaining first-hand access to patient perspectives challenging.

Objective

To create a curated cohort of patients from social media that report their age in the range of 13 to 25 years old and confirm having a SAD diagnosis or having received therapy for SAD, and to assess the value of the content posted by these users for observational studies of SAD.

Methods

We collected 535k posts by 118k Reddit users from the r/SocialAnxiety subreddit. We then developed precise regular expressions to extract age, diagnosis and therapy mentions. We manually annotated the full set of expressions extracted and double-annotated 5% of the age mentions and 10% of the diagnosis and therapy mentions. Using similar methodology, we identified mentions of comorbidities and substance use.

Results

Our validated cohort includes 37,073 posts by 1,102 users that meet the inclusion criteria. The age, diagnosis, and therapy mention detection had a precision of 68%, 31%, and 44%, respectively, with an inter-annotator agreement of 0.96, 0.96, and 0.78. Sixty-one percent of the users in the cohort report having one or more comorbidities on top of their SAD diagnosis (Fleiss’s Kappa=0.79) and 13% report a concerning use of drugs or alcohol (Fleiss’s Kappa=0.87). We compared the characteristics of our social media cohort to the published literature on SAD.

Conclusions

Patients with SAD post actively on Reddit and their perspectives can be captured and studied directly from these data. Extracting age, therapy, substance abuse and comorbidities (and potentially other patient data) can address realworld data source biases. Thus, social media is a valuable source to create cohorts of hard-to-reach patient populations that may not enter the healthcare system.
Newly Sequenced Genomes Reveal Patterns of Gene Family Expansion in Select Dragonflies (Odonata: Anisoptera)
Authors: Tolman Ethan R. , Beatty Christopher D. , Frandsen Paul B. , Bush Jonas , Bruchim Or R. , Driever Ella Simone , Harding Kathleen M. , Jordan Dick , Kohli Manpreet K. , Park Jiwoo , Park Seojun , Reyes Kelly , Rosario Mira , Ryu Jisong L. , Wade Vincent , Suvorov Anton , Ware Jessica L.
Published: December 2023

Gene family expansions play a key role in shaping patterns of biodiversity across the tree of life. In Insecta, expanded gene families have broadly been tied to diet, pesticide resistance, immune response and survival in extreme environments. Patterns of gene family evolution are of particular interest in Odonata (dragonflies and damselflies), which are the first lineage to fly, and are one of the most exceptional predators. In Odonata, expansions of opsin genes are correlated with the diversification of the herbivorous insects that Odonata prey upon, but general trends in gene family expansion and contraction have not been studied in this order. Here, we show that two families of Anisoptera (dragonflies), Libellulidae and Petaluridae, have expanded gene families related to their unique life history and diversification patterns.

Libellulidae share expanded gene families related to immune response, desiccation response, and processing free radicals, which are all related to the success of Libellulidae in low quality water bodies. The Petaluridae have expanded gene families involved in sensory perception, which can be tied to the unique semi-terrestrial lifestyle of the nymphs of this family. Furthermore, Odonata as a whole has a remarkably high (λ=.19) level of gene turnover compared to other insect orders, a phenomenon that will merit further exploration. These results are an important step towards understanding why Libellulidae is, generally, a species rich family of short lived species that are highly tolerant to poor water quality, while Petaluridae is a species poor family of habitat and behavioral specialists.
MUFFIN : A suite of tools for the analysis of functional sequencing data
Authors: de Langen Pierre , Ballester Benoit
Published: December 2023

The large diversity of functional genomic assays allows for the characterization of non-coding and coding events at the tissue level or at a single-cell resolution. However, this diversity also leads to protocol differences, widely varying sequencing depths, substantial disparities in sample sizes, and number of features. In this work, we have specifically designed a suite of tools for exploring the non-coding genome, particularly for identifying consensus peaks in peak-called assays, as well as linking non-coding genomic regions to genes and performing Gene Set Enrichment Analyses. We demonstrate that a generic but flexible count modelling approach can be utilised to compare different conditions across a broad range of genomic assay such as ENCODE H3K4Me3 ChIP-seq, scRNA-seq and TCGA ATAC-seq. Our Python package, MUFFIN, offers a suite of tools to address common issues associated with high-dimensional genomic data, such as normalisation, count transformation, dimensionality reduction, differential expression, and clustering. Additionally, our tool integrates with the popular Scanpy ecosystem and is available on Conda and athttps://github.com/pdelangen/Muffin.
α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
Authors: Geibl Fanni F. , Henrich Martin T. , Xie Zhong , Zampese Enrico , Tkatch Tatiana , Wokosin David L. , Nasiri Elena , Grotmann Constantin A. , Dawson Valina L. , Dawson Ted M. , Chandel Navdeep S. , Oertel Wolfgang H. , Surmeier D. James
Published: December 2023

Background

Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain.

Methods

aSYN PPFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell- type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser- scanning microscopy of genetically encoded sensors for bioenergetic and redox status.

Results

In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure.

Conclusions

Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
“Flower power”: how flowering affects spectral diversity metrics and their relationship with plant diversity
Authors: Perrone Michela , Conti Luisa , Galland Thomas , Komárek Jan , Lagner Ondřej , Torresani Michele , Rossi Christian , Carmona Carlos P. , Bello Francesco de , Rocchini Duccio , Moudrý Vítězslav , Šímová Petra , Bagella Simonetta , Malavasi Marco
Published: December 2023

Biodiversity monitoring is constrained by cost- and labour-intensive field sampling methods. Increasing evidence suggests that remotely sensed spectral diversity (SD) is linked to plant diversity, holding promise for monitoring applications. However, studies testing such a relationship reported conflicting findings, especially in challenging ecosystems such as grasslands, due to their high temporal dynamism and variety. It follows that a thorough investigation of the key factors, such as the metrics applied (i.e., continuous, categorical) and phenology (e.g., flowering), influencing such a relationship is necessary. Thus, this study aims to assess the applicability of SD for plant diversity monitoring at the local scale by testing six different SD metrics while considering the effect of the presence of flowering on the relationship and resampling the original data to assess how spatial resolution affects the results. Taxonomic diversity was calculated based on data collected in 159 plots with 1.5 m ×1.5 m experimental mesic grassland communities. Spectral information was collected using a UAV-borne sensor measuring reflectance across six bands in the visible and near-infrared range at ∼2 cm spatial resolution. Our results show that, in the presence of flowering, the relationship is significant and positive only when SD is calculated using categorical metrics. Despite the observed significance, the variance explained by the models had very low values, with no evident differences when resampling spectral data to coarser pixel sizes. Such findings suggest that new insights into the possible confounding effects on the SD∼plant diversity in grassland communities are needed to use SD for monitoring purposes.
Globally abundant birds disproportionately inhabit anthropogenic environments
Authors: Carroll Tadhg , Hatfield Jack H. , Thomas Chris D.
Published: December 2023

Research into biodiversity change predominantly focuses on rarity and declines, but many ecological processes are governed by abundant species. Analysing 3,146 terrestrial bird species across 5,454 field-sampled sites, we find that three times more species in the top quartile for global abundance are more likely to occur in ecosystems characterised by major human land-cover modification (croplands, plantation forest, urban areas and pasture), compared with species in the bottom quartile. The likelihood of inhabiting human-modified environments consistently increases with global abundance across species with different dietary requirements, whereas low abundance species tend to have increased probabilities of occurrence (within their ranges) in relatively unmodified environments. Our findings suggest that human modification of the Earth’s land surface has favoured ‘anthrophilic’ species able to thrive in widespread anthromes.

One-Sentence Summary

The world’s most abundant birds disproportionately inhabit croplands, plantation forests, urban areas and pastures.
Characterization ofStreptococcus uberisCas9 (SuCas9) – a Type II-A Ortholog Functional in Human Cells
Authors: Selkova Polina , Vasileva Aleksandra , Arseniev Anatolii , Abramova Marina , Musharova Olga , Malysheva Polina , Khodorkovskii Mikhail , Severinov Konstantin
Published: December 2023

Type II CRISPR-Cas9 RNA-guided nucleases are commonly used for genome engineering. To date, all characterized Cas9-based genome editors, including the widely used SpCas9, have limitations such as their relatively large size and restriction of targets flanked by a specific PAM sequence. Here, we biochemically characterized more compact SpCas9 ortholog, SuCas9, fromStreptococcus uberis, a bacterium inhabiting the mammary glands of dairy cattle. SuCas9 recognizes a novel 5′-NNAAA-3′ PAM, efficiently cleaves DNAin vitro, and is active in human cells. The study of SuCas9 has the potential to expand the range of applications of CRISPR-Cas9 enzymes in medicine and biotechnology.
Postnatal FGFR-signaling establishes gradients of secretory cell identities along the proximal-distal axis of the lung airways
Authors: Sountoulidis Alexandros , Firsova Alexandra B. , Liontos Andreas , Theelke Jonas , Koepke Janine , Millar-Büchner Pamela , Mannerås-Holm Louise , Björklund Åsa , Fysikopoulos Athanasios , Gaengel Konstantin , Bäckhed Fredrik , Betsholtz Christer , Seeger Werner , Bellusci Saverio , Samakovlis Christos
Published: December 2023

Secretory cells are major structural and functional constituents of the lung airways. Their spatial organization and specification mechanisms are partially understood. Here, we labelled major secretory airway cell types and analysed them at single-cell resolution. We found opposing, partially overlapping gene-expression gradients along the proximal-distal airway axis superimposed on a general gene program encoding detoxification. One graded program is elevated proximally and relates to innate immunity, whereas the other is enriched distally, encoding lipid metabolism and antigen presentation. Intermediately positioned cells express low levels of both graded programs and show increased clonogenic potency in vitro, relating cell-plasticity to location in each branch. Single-cell RNA-sequencing following lineage-tracing revealed the sequential and postnatal establishment of the gradients in common epithelial progenitors. Fgfr2b is distally enriched and its postnatal inactivation reduces distal gene expression and expands proximal genes into distally located cells. This suggests a central role of FGFR-signaling in tissue-scale airway patterning.
Climate change has desynchronized insect and vegetation phenologies across Europe
Authors: Huang Yanru , Wu Chaoyang , Huang Wenjiang , Liu Yang , Qi Man , Bai Jie , Dong Yingying , Gascoigne Samuel J L , Ciais Philippe , Peñuelas Josep , Salguero-Gómez Roberto
Published: December 2023

Climate change is drastically affecting the phenologies of species worldwide, including shifts in development1–3. The potential impact of climate change on the synchronicity of plant-insect phenology is particularly concerning since the stability of pollination networks and food chains depends on their tight temporal dependencies4–6. Furthermore, the recently reported “insect armageddon”7makes it urgent to establish trends and identify primary drivers of plant-insect phenological synchrony. Here, coupling high-resolution remote sensing and citizen science data across Europe over 34 years, we examine the differences in occurrence dates of 1,584 herbivorous insects across four orders and the corresponding dates of leaf unfolding. We find that 61.2% of the vegetation and insect phenologies have become highly asynchronous, with vegetation phenology advancing four-fold faster than insect phenology. These trends were modulated by insects’ life-cycles and taxonomic order. A primary driver of this phenological mismatch is the higher sensitivity of vegetation phenology than insect phenology to climate, which has prevented insects from matching the pace of plant phenological advance in the growing season. Our analyses provide a unique continental overview and underlying mechanisms of the asynchronicity between vegetation and insect phenologies, thus enhancing our ability to predict and manage its potential cascading ecological effects.
Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types
Authors: Lin Yao , Li Jingyi , Liang Shuaiyi , Chen Yaxin , Li Yueqi , Cun Yixian , Tian Lei , Zhou Yuanli , Chen Yitong , Chu Jiemei , Chen Hubin , Luo Qiang , Zheng Ruili , Wang Gang , Liang Hao , Cui Ping , An Sanqi
Published: December 2023

As the most abundant mRNA modification in mRNA,N6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the function and role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A-seq and RNA-seq samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called “m6A-express”, we predicted m6A– regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulatorCAPRIN1controls the m6A level ofTP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A for cancer precision medicine for patients with different cancer types.
scPharm: identifying pharmacological subpopulations of single cells for precision medicine in cancers
Authors: Tian Peng , Zheng Jie , Xu Yue , Wu Tao , Chen Shuting , Zhang Yinuo , Zhang Bingyue , Qiao Keying , Fan Yuxiao , Ambrogio Chiara , Wang Haiyun
Published: December 2023

Intratumour heterogeneity is a major challenge that limits the effectiveness of anticancer therapies, thus compromising treatment outcomes. Single-cell RNA sequencing (scRNA-seq) technology offers a means to capture gene expression profiles at a single-cell resolution, while drug perturbation experiments yield valuable pharmacological data at the bulk cell level. Here, we introduce “scPharm”, a computational framework to integrate large-scale pharmacogenomics profiles with scRNA-seq data, for identifying pharmacological subpopulations within a tumour and prioritizing tailored drugs. scPharm assesses the distribution of the identity genes of single cell (Cell-ID) within drug response-determined gene list, which is accomplished using the normalized enrichment score (NES) obtained from Gene Set Enrichment Analysis (GSEA) as the statistic. One key strength of scPharm is rooted in the robust positive correlation between NES statistics and drug response values at single-cell resolution. scPharm successfully identifies sensitive subpopulations in ER-positive and HER2-positive human breast cancer tissues, discovers dynamic changes in resistant subpopulation of human PC9 cells treated with Erlotinib, and expands its prediction capabilities to a mouse model. By a thoroughly comparative evaluation with other single-cell prediction tools, scPharm presents the superior predictive performance and computational efficiency. Furthermore, scPharm offers a unique feature by predicting combination strategies, gauging compensation effects or booster effects between two drugs through the Set covering method, as well as evaluating drug toxicity on healthy cells within the tumour microenvironment. Together, scPharm provides a novel approach to uncover therapeutic heterogeneity within tumours at single-cell resolution and facilitates precision medicine in cancers.
AlphaFold2-Enabled Atomistic Modeling of Epistatic Binding Mechanisms for the SARS-CoV-2 Spike Omicron XBB.1.5, EG.5 and FLip Variants: Convergent Evolution Hotspots Cooperate to Control Stability and Conformational Adaptability in Balancing ACE2 Binding and Antibody Resistance
Authors: Raisinghani Nishank , Alshahrani Mohammed , Gupta Grace , Xiao Sian , Tao Peng , Verkhivker Gennady
Published: December 2023

In this study, we combined AI-based atomistic structural modeling and microsecond molecular simulations of the SARS-CoV-2 Spike complexes with the host receptor ACE2 for XBB.1.5+L455F, XBB.1.5+F456L(EG.5) and XBB.1.5+L455F/F456L (FLip) lineages to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and physics-based rigorous computations of binding affinities, we identified binding energy hotspots and characterized molecular basis underlying epistatic couplings between convergent mutational hotspots. Consistent with the experiments, the results revealed the mediating role of Q493 hotspot in synchronization of epistatic couplings between L455F and F456L mutations providing a quantitative insight into the mechanism underlying differences between XBB lineages. Mutational profiling is combined with network-based model of epistatic couplings showing that the Q493, L455 and F456 sites mediate stable communities at the binding interface with ACE2 and can serve as stable mediators of non-additive couplings. Structure-based mutational analysis of Spike protein binding with the class 1 antibodies quantified the critical role of F456L and F486P mutations in eliciting strong immune evasion response. The results of this analysis support a mechanism in which the emergence of EG.5 and FLip variants may have been dictated by leveraging strong epistatic effects between several convergent revolutionary hotspots that provide synergy between the improved ACE2 binding and broad neutralization resistance. This interpretation is consistent with the notion that functionally balanced substitutions which simultaneously optimize immune evasion and high ACE2 affinity may continue to emerge through lineages with beneficial pair or triplet combinations of RBD mutations involving mediators of epistatic couplings and sites in highly adaptable RBD regions.
Statistical models of hospital patient fatality rates after accidental falls in children
Authors: Rossant Cyrille , Schneps Leila
Published: December 2023

Pediatric traumatic brain injuries represent a public health concern globally. Epidemiological studies are essential to understand their extent, uncover risk factors and outcome predictors, and establish efficient prevention policies. Etiological investigations also benefit from epidemiological data. In young, pre-linguistic children, distinguishing between accidental and non-accidental trauma is often challenging for frontline clinicians. Classification errors can have severe repercussions for children and their families. Past influential epidemiological studies have drawn general conclusions about the etiology of pediatric traumatic brain injuries based on specific statistical information, such as hospital patient fatality rates after reported accidental falls. In this article, we use simple mathematical models to revisit one of these studies and discuss the reliability of its conclusion. We show that apparent paradoxical discrepancies, such as hospital patient fatality rates that are higher after short versus long falls, may have mathematical justification and do not necessarily justify seeking alternative etiological explanations such as non-accidental trauma.