bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative analysis of spike-sorters in large-scale brainstem recordings
Authors: De Preter Caitlynn C , Leimer Elizabeth M , Sonneborn Alex , Heinricher Mary M
Published: November 2024

Recent technological advancements in high-density multi-channel electrodes have made it possible to record large numbers of neurons from previously inaccessible regions. While the performance of automated spike-sorters has been assessed in recordings from cortex, dentate gyrus, and thalamus, the most effective and efficient approach for spike-sorting can depend on the target region due to differing morphological and physiological characteristics. We therefore assessed the performance of five commonly used sorting packages, Kilosort3, MountainSort5, Tridesclous, SpyKING CIRCUS, and IronClust, in recordings from the rostral ventromedial medulla, a region that has been characterized using single-electrode recordings but that is essentially unexplored at the high-density network level. As demonstrated in other brain regions, each sorter produced unique results. Manual curation preferentially eliminated units detected by only one sorter. Kilosort3 and IronClust required the least curation while maintaining the largest number of units, whereas SpyKING CIRCUS and MountainSort5 required substantial curation. Tridesclous consistently identified the smallest number of units. Nonetheless, all sorters successfully identified classically defined RVM physiological cell types. These findings suggest that while the level of manual curation needed may vary across sorters, each can extract meaningful data from this deep brainstem site.

Significance Statement

High-density multichannel recording probes that can access deep brainstem structures have only recently become commercially available, but the performance of open-source spike-sorting packages applied to recordings from these regions has not yet been evaluated. The present findings demonstrate that Kilosort3, MountainSort5, Tridesclous, SpyKING CIRCUS, and IronClust can all be reasonably used to identify units in a deep brainstem structure, the rostral ventromedial medulla (RVM). However, manual curation of the output was essential for all sorters. Importantly, all sorters identified the known, physiologically defined RVM cell classes, confirming their utility for deep brainstem recordings. Our findings provide suggestions for processing parameters to use for brainstem recordings and highlight considerations when using high-density silicon probes in the brainstem.
Orchestrating the Acquisition of Oligodendrocyte Precursor Cell versus Olfactory Bulb Interneuron Fates throughOlig1/2during Mammalian Cortical Gliogenesis and Gliomagenesis
Authors: Tian Yu , Wang Ziwu , Yang Feihong , Zhang Wen , Li Jialin , Yang Lin , Fu Tongye , Zheng Wenhui , Xu Zhejun , Ma Tong , You Yan , Li Xiaosu , Song Jiangang , Xie Yunli , Yang Zhengang , Zhang Zhuangzhi
Published: November 2024

The hijacking of developmental gliogenesis programs is a hallmark of glioblastoma (GBM), in which glial precursor cells (GPCs) typically differentiate into both neurons and glial cells. In GBM, this process is disrupted, leading to the overproduction of proliferative glial-like cells. Our study demonstrates that the knockout ofOlig1/2in both normal development and gliomagenesis causes GPCs to shift from generating highly proliferative oligodendrocyte precursor cells to producing non-proliferative olfactory bulb interneurons. Mechanistically,Olig1/2play dual roles by orchestrating distinct transcriptional programs in GPCs, particularly inhibiting the expression ofGsx2through direct binding to its multiple enhancers. Additionally, we provide compelling evidence that human H3.3G34R/V-mutant tumors, a subtype of high-grade gliomas, originate from dorsal cortical-derived GPCs rather than from the previously assumed progenitors in the ventral basal ganglia. Collectively, our findings reveal a previously unrecognized role ofOlig1/2in both gliogenesis and gliomagenesis, offering deeper insights into the connections between normal neural development and tumorigenesis.

Graphical Abstract
Astroglial Dysfunction, Demyelination and Nodular inflammation in Necrotizing Meningoencephalitis
Authors: Hernandez Sara I , Assenmacher Charles A , Church Molly E , Alvarez Jorge I
Published: November 2024

Necrotizing Meningoencephalitis (NME), a form of Meningoencephalitis of Unknown Origin (MUO), is a progressive neuroinflammatory disease that primarily affects young, small-breed dogs. Due to limited understanding of its pathophysiology, early detection and the development of targeted therapies remain challenging. Definitive ante-mortem diagnosis is often unfeasible, and dogs with NME are frequently grouped under the broader MUO category. Our long-term objective is to identify distinct disease mechanisms within each MUO subtype to improve diagnostic accuracy, therapeutic approaches, and prognostic outcomes. To establish unique inflammatory patterns as they relate to neuropathologic changes in NME, we studied we studied the degree of immune cell infiltration, astrogliosis, demyelination, and microglial activation, comparing these factors with granulomatous meningoencephalomyelitis (GME), a closely related MUO subtype. We found that in the leptomeninges, NME is characterized by mild immune cell infiltration, in contrast to the prominent, B cell-rich aggregates seen in GME. In the neuroparenchyma, both diseases exhibit a comparable degree of lymphocyte infiltration; however, demyelination is more pronounced in NME, particularly within the subcortical white matter. Notably, areas of the brain affected by NME display a reduction in astrogliosis, which is associated with a marked decrease in the expression of the water channel protein aquaporin-4 (AQP4), a reduction not observed in GME. Additionally, we found that AQP4 expression levels correlate with the extent of microglial and macrophage activation. These findings suggest that astrocyte dysfunction in regions of microglial inflammation is a driver of NME and with adaptive immune responses likely playing a supportive role.
Information Theory of Composite Sequence Motifs: Mutational and Biophysical Determinants of Complex Molecular Recognition
Authors: Mascolo Elia , Erill Ivan
Published: November 2024

The recognition of nucleotide sequence patterns is a fundamental biological process that controls the start sites of replication, transcription and translation, as well as transcriptional and translational regulation. Foundational work on the evolution of biological information showed that the amount of information encoded in the target nucleotide sequence patterns, a quantity namedRsequence, evolves by natural selection to match a predictable quantity calledRfrequency. In this work, we propose a generalization of this canonical framework that can describe composite sequence motifs: motifs composed of a series of sequence patterns at some variable (not necessarily conserved) distance from each other. We find that some information can be encoded through the conservation of the distance between sequence patterns, a quantity we namedRspacer, and that - to be functional - biological systems require the sum ofRsequenceandRspacerto be constant. We empirically validate our mathematical results through evolutionary simulations. We apply this general framework to demonstrate that the pre-recruitment of regulatory complexes to target sites has intrinsic advantages over in situ recruitment in terms of energy dissipation and search efficiency, and that realistic values of protein flexibility co-evolve with the target composite motifs to match their spacer size variability. Lastly, we show that the relative advantage of encoding information in sequence patterns or in spacers depends on the balance between nucleotide substitutions and insertions/deletions, with known estimates for the rates of these mutation types favoring the evolution of composite motifs with highly conserved spacer length.
Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer
Authors: Armand Jessica , Kim Sungsoo , Kim Kibum , Son Eugene , Kim Minah , Yang Hee Won
Published: November 2024

The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence of resistance in most patients often leads to treatment discontinuation with no consensus on effective second-line therapies. The therapeutic benefits of maintaining CDK4/6i or incorporating CDK2 inhibitors (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained CDK4/6i therapy, either alone or combined with CDK2i, significantly suppresses the growth of drug-resistant HR+breast cancer. Continued CDK4/6i treatment induces a non-canonical pathway for retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting in diminished E2F activity and delayed G1 progression. Importantly, our data highlight that CDK2i should be combined with CDK4/6i to effectively suppress CDK2 activity and overcome resistance. We also identify cyclin E overexpression as a key driver of resistance to CDK4/6 and CDK2 inhibition. These findings provide crucial insights into overcoming resistance in HR+breast cancer, supporting the continued use of CDK4/6i and the strategic incorporation of CDK2i to improve therapeutic outcomes.
Decoding mesolimbic dopamine transmission in the olfactory tubercle and its contribution to methamphetamine responses through neurochemical sensing and chemogenetics
Authors: Bhimani Rohan V. , Pauly Ryan C. , Bass Caroline E. , Park Jinwoo
Published: November 2024

Central dopamine (DA) innervation of the olfactory tubercle (OT) from the ventral tegmental area (VTA) plays a critical role in encoding multisensory information and generating behavioral outputs necessary for survival. However, due to anatomical restrictions and the neurochemical heterogeneity of the VTA and OT, very little is known about the functional link between mesolimbic VTA-DA transmission in the OT and its role in mediating reward and drug seeking. In this study, we integratedin vivofast-scan cyclic voltammetry with chemogenetics to (1) characterize the effects of chemogenetic modulation (excitation and inhibition) of mesolimbic DA transmission in the OT of both anesthetized and awake-behaving wild-type rats and (2) demonstrate that inhibition of VTA-DA neurons is sufficient to suppress methamphetamine-induced DA transmission as well as its locomotor and rewarding effects. These results offer novel insights into mesolimbic DA transmission in the OT and its contribution to substance use disorders.
Activity-based selection for enhanced base editor mutational scanning
Authors: Kaplan Eleanor G , Steger Ryan J , Shah Spencer T , Drepanos Laura M , Griffith Audrey L , Reint Ganna , Doench John G
Published: November 2024

Base editing is a CRISPR-based technology that enables high-throughput, nucleotide-level functional interrogation of the genome, which is essential for understanding the genetic basis of human disease and informing therapeutic development. Base editing screens have emerged as a powerful experimental approach, yet significant cell-to-cell variability in editing efficiency introduces noise that may obscure meaningful results. Here, we develop a co-selection method that enriches for cells with high base editing activity, substantially increasing editing efficiency at a target locus. We evaluate this activity-based selection method against a traditional screening approach by tiling guide RNAs acrossTP53, demonstrating its enhanced capacity to pinpoint specific mutations and protein regions of functional importance. We anticipate that this modular selection method will enhance the resolution of base editing screens across many applications.
Urban greenspace connectivity drive shifts in host assemblages and tick-borne pathogen infection
Authors: VanAcker Meredith C. , Hofmeester Tim R. , Zhang-Sun Jeffrey , Goethert Heidi C. , Diuk-Wasser Maria A.
Published: November 2024

Habitat fragmentation is often highlighted as a driver of tick-borne disease hazard and spillover risk via reduction in biodiversity. However, habitat fragmentation can have divergent impacts on host, vector, and pathogen dynamics depending on the distribution of fragment sizes and the levels of connectivity to surrounding habitat, particularly when habitat fragments are embedded in an urban matrix. We examine how extreme habitat fragmentation influences host community composition in an urban landscape and determine its cascading impacts onIxodes scapularisvector abundance and infection prevalence with human pathogenicBorrelia burgdorferi,Babesia microti, andAnaplasma phagocytophilum. We utilize camera–trapping and live mammal–trapping methods to quantify the availability of vertebrate hosts to questing larval ticks and relate relative host activity to the resulting density of nymphs and nymphal infection prevalence; the combination of these metrics determines the tick–borne disease hazard (i.e. the density of infected questing nymphs — DIN). We found that increased habitat connectivity in urban areas shifted the composition of the host community from human–adapted to forest–dependent species, species which inhabit forested habitats for all or a portion of their lifecycles. The resulting increased encounter probability between ticks and forest–dependent species increased the density of nymphs and nymphal infection prevalence with host–limited pathogens,B. microtiandA. phagocytophilum, amplifying local tick-borne disease hazard. Host encounter probability of all species examined did not increaseB. burgdorferinymphal infection prevalence, likely due to the wider host range of this pathogen; whereas increased deer encounter probability decreased the nymphal infection prevalence ofB. burgdorferi. These findings emphasize the importance of host identity, rather than host diversity, in shaping the heterogenous distribution of tick–borne pathogen risk in highly fragmented urban forest patches and suggest a non–linear association between disease risk and host biodiversity.
Astrocytic connexin43 phosphorylation contributes to seizure susceptibility after mild Traumatic Brain Injury
Authors: Muñoz-Ballester Carmen , Leitzel Owen , Golf Samantha , Phillips Chelsea M , Zeitz Michael J , Pandit Rahul , Smyth James W. , Lamouille Samy , Robel Stefanie
Published: November 2024

Astrocytes play a crucial role in maintaining brain homeostasis through functional gap junctions (GJs) primarily formed by connexin43 (Cx43). These GJs facilitate electrical and metabolic coupling between astrocytes, allowing the passage of ions, glucose, and metabolites. Dysregulation of Cx43 has been implicated in various pathologies, including traumatic brain injury (TBI) and acquired epilepsy. We previously identified a subset of atypical astrocytes after mild TBI that exhibit reduced Cx43 expression and coupling and are correlated with the development of spontaneous seizures. Given that mild TBI affects millions globally and can lead to long-term complications, including post-traumatic epilepsy, understanding the molecular events post-TBI is critical for developing therapeutic strategies.

In the present study, we assessed the heterogeneity of Cx43 protein expression after mild TBI. In accordance with our previous findings, a subset of astrocytes lost Cx43 expression. As previously reported after TBI, we also found a significant increase in total Cx43 protein expression after mild TBI, predominantly in the soluble form, suggesting that while junctional Cx43 protein levels remained stable, hemichannels and cytoplasmic Cx43 were increased. We then investigated the phosphorylation of Cx43 at serine 368 after TBI, which is known to influence GJ assembly and function. Phosphorylation of Cx43 at serine 368 is elevated following TBI and Cx43S368Amutant mice, lacking this phosphorylation, exhibited reduced susceptibility to seizures induced by pentylenetetrazol (PTZ). These findings suggest that TBI-induced Cx43 phosphorylation enhances seizure susceptibility, while inhibiting this modification presents a potential therapeutic avenue for mitigating neuronal hyperexcitability and seizure development.

Significance statement

Connexin43 (Cx43) is the main protein of astrocyte gap junctions, mediating astrocyte coupling of astrocytes into cellular networks, but has also other non-junctional functions. Many pathologies present with altered Cx43 regulation. In this study, we studied Cx43 alterations after mild traumatic brain injury (TBI) in a mouse model. We found that while some astrocyte lost Cx43 expression, a subset of astrocytes experienced an increase in cytoplasmic and hemichannel Cx43. This increase correlated with an increase in phosphorylated Cx43 at serine 368. Cx43S368Amutant mice, lacking this phosphorylation, exhibited reduced susceptibility to seizures induced by pentylenetetrazol (PTZ). These findings suggest that TBI-induced Cx43 phosphorylation enhances seizure susceptibility.
Machine Learning Models for Predicting Multiple Myeloma Staging and MGUS Progression Using Gene Expression Data
Authors: Karathanasis Nestoras , Spyrou George M.
Published: November 2024

In this study, we developed and evaluated Machine Learning (ML) models aimed at predicting the stage of multiple myeloma (MM) and the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. Accurate staging of MM is critical for determining appropriate treatment strategies, and our models, employing algorithms such as ElasticNet, Random Forest, Boosting, and Support Vector Machines, demonstrated high efficacy in capturing the biological differences across disease stages. Among these, the ElasticNet model exhibited strong generalizability, achieving consistent multiclass AUC values across various datasets and data transformations.

Predicting MGUS progression to MM presents a significant challenge due to the scarcity of MGUS cases that have progressed. We employed a two-pronged approach to address this: developing models using a limited dataset containing progressing MGUS patients and training models on combined MGUS and MM datasets. The models achieved AUC values slightly above 0.8, particularly with ElasticNet, Boosting and Support Vector Machines, indicating their potential in stratifying MGUS patients by progression risk. This study is original in integrating MM data with MGUS cases to enhance the predictive accuracy of MGUS progression, offering a novel methodology with potential clinical applications in patient monitoring and early intervention.

Our feature selection and enrichment analyses further revealed that the identified genes are involved in key signaling pathways, including PI3K-Akt, MAPK, Wnt, and mTOR, all of which play crucial roles in MM pathogenesis. These findings align with established biological knowledge, suggest possible therapeutic targets and increase the explainability of our models.
Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord
Authors: Tuddenham John F. , Fujita Masashi , Khairallah Anthony , Harbison Claire , Flowers Xena E. , Coronas-Samano Guillermo , Maniatis Silas , Daly Aidan , Schneider Julie A. , Teich Andrew F. , Vonsattel Jean Paul G. , Sims Peter A. , Elyaman Wassim , Bradshaw Elizabeth M. , Phatnani Hemali , Shneider Neil , Bennett David A. , De Jager Philip L. , Przedborski Serge , Menon Vilas , Olah Marta
Published: November 2024

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.
Visual training induced occipital fast sleep spindle clustering in humans revealed by full-night HD-EEG recordings
Authors: Gerván Patrícia , Bocskai Gábor , Berencsi Andrea , Gombos Ferenc , Kovács Ilona
Published: November 2024

This study investigates the impact of extensive visual procedural training on the temporal organisation of sleep spindles in healthy young adults. We selected 39 participants aged 16-20 and employed high-density electroencephalography to assess spindle characteristics during two full nights of sleep, with daytime practising in a contour integration task in between the two nights. We utilised linear mixed models to comprehensively analyse the effects of age and training on basic, clustering- and rhythmicity-related spindle parameters. Our findings indicate no significant age effects in this age-range, and no significant change between the two nights with respect to slow spindles. Fast spindles demonstrated a significant increase in density after training, and we observed significant changes in spindle clustering and rhythmicity parameters as well. Local spindle density, train density, and the ratio of clustered spindles have increased, and inter-train interval decreased by the second night. These results contribute to the growing literature on sleep-dependent memory consolidation by demonstrating that spindle reorganisation occurs not only in motor tasks but also in visual learning contexts. The absence of age-related differences further highlights the robustness of these mechanisms across developmental stages. Our study emphasises the importance of spindle dynamics in procedural learning and suggests promising possibilities for future research into the neurophysiological basis of memory consolidation. By revealing the relationship between training and sleep spindle characteristics, our findings provide valuable insights into how sleep supports learning and memory processes in young adults, potentially informing interventions aimed at enhancing memory performance through sleep-related strategies.
Integrating Machine Learning with Flow-Imaging Microscopy for Automated Monitoring of Algal Blooms
Authors: Khan Farhan , Gincley Benjamin , Busch Andrea , Tolofari Dienye L , Norton John W , Varga Emily , Mckay R Michael , Fuentes-Cabrera Miguel , Slawecki Tad , Pinto Ameet J.
Published: November 2024

Real-time monitoring of phytoplankton in freshwater systems is critical for early detection of harmful algal blooms so as to enable efficient response by water management agencies. This paper presents an image processing pipeline developed to adapt ARTiMiS, a low-cost automated flow-imaging device, for real-time algal monitoring specifically in freshwater and environmental systems. This pipeline addresses several challenges associated with autonomous imaging of aquatic samples such as flow-imaging artifacts (i.e., out-of-focus and background objects), as well as specific challenges associated with monitoring of open environmental systems (i.e., identification of novel objects). The pipeline leverages a Random Forest model to identify out- of-focus particles with an accuracy of 89% and a custom background particle detection algorithm to identify and remove particles that erroneously appear in consecutive images with >97±2.8% accuracy. Furthermore, a convolutional neural network (CNN), trained to classify distinct classes comprising both taxonomical and morphological categories, achieved 94% accuracy in a closed dataset. Nonetheless, the supervised closed-set classifiers struggled with the accurate classification of objects when challenged with debris and novel particles which are common in complex open environments; this limits real-time monitoring applications by requiring extensive manual oversight. To mitigate this, three methods incorporating classification with rejection were tested to improve model precision by excluding irrelevant or unknown classes. Combined, these advances present a fully integrated, end-to-end solution for real-time HAB monitoring in open environmental systems thus enhancing the scalability of automated detection in dynamic aquatic environments.

Highlights

Random Forest model is more generalizable than Convolutional Neural Networks to remove out-of-focus particles.

A two-stage clustering algorithm is effective at removing background particles in flow imaging microscopy.

Closed-set CNN classifier performance deteriorates when challenged with unknown particles.

Classification with rejection improves both precision and accuracy for environmental samples.
Disruptive changes in tissue microenvironment prime oncogenic processes at different stages of carcinogenesis in lung
Authors: Venkat Vignesh , Hu Xiaoju , Biswas Antara , Saxena Ankit , Malhotra Jyoti , Reidlinger Gregory , De Subhajyoti
Published: November 2024

Carcinogenesis is characterized not only by the uncontrolled growth of malignant cells but also by the disruption of the normal balance of cellular processes and intercellular interactions in the microenvironment that overcome the constraints of tissue homeostasis and support malignant growth. We profiled benign pulmonary dysplasia, carcinoma in situ, and invasive lung carcinomas at single-cell resolution to identify composite changes in cellular processes, signaling, and interactions among tumor-immune-stromal cells in the microenvironment in progressively advanced disease stages. We developed OncoTerrain, a hyperparameter-tuned model that captured synergistic multimodal signatures of an increasingly perturbed microenvironment in malignant disease stages and identified composite microenvironmental changes that supported cancer hallmarks. Key cancer-related changes in transcriptional states, cellular processes, and intercellular interactions involving immune, fibroblast, and stromal cell types preceded tumor initiation and were often synergistic. The microenvironment of increasingly malignant tissues was characterized by immune avoidance, ECM remodeling, and altered cell mobility. There were changes in cell states in fibroblasts, macrophages, and their inter-cellular interactions with other cell types, whereas T-cell activation occurred late. The in-situ carcinomas showed variations in the composite microenvironmental states that corroborated their pathology, which was not apparent at the genome level. A subset of those harbored populations of tumor and non-tumor cells with aggressive characteristics in some but not all aspects of hallmarks of carcinogenesis in the lung. We suspect that the variation in the coordination of microenvironmental cues may influence why some but not all in-situ tumors progress to the advanced stages.
iModMix: Integrative Module Analysis for Multi-omics Data
Authors: Narváez-Bandera Isis , Lui Ashley , Mekonnen Yonatan Ayalew , Rubio Vanessa , Sulman Noah , Wilson Christopher , Ackerman Hayley D. , Ospina Oscar E. , Gonzalez-Calderon Guillermo , Flores Elsa , Li Qian , Chen Ann , Fridley Brooke , Stewart Paul
Published: November 2024

The integration of metabolomics with other omics (“multi-omics”) offers complementary insights into disease biology. However, this integration remains challenging due to the fragmented landscape of current methodologies, which often require programming experience or bioinformatics expertise. Moreover, existing approaches are limited in their ability to accommodate unidentified metabolites, resulting in the exclusion of a significant portion of data from untargeted metabolomics experiments. Here, we introduceiModMix - Integrative Module Analysis for Multi-omics Data, a novel approach that uses a graphical lasso to construct network modules for integration and analysis of multi-omics data.iModMixuses a horizontal integration strategy, allowing metabolomics data to be analyzed alongside proteomics or transcriptomics to explore complex molecular associations within biological systems. Importantly, it can incorporate both identified and unidentified metabolites, addressing a key limitation of existing methodologies.iModMixis available as a user-friendly R Shiny application that requires no programming experience (https://imodmix.moffitt.org), and it includes example data from several publicly available multi-omic studies for exploration. An R package is available for advanced users (https://github.com/biodatalab/iModMix).

Availability and implementation

Shiny application:https://imodmix.moffitt.org. The R package and source code:https://github.com/biodatalab/iModMix.
Capacity building needed to reap the benefits of access to biodiversity collections
Authors: Groom Quentin , Meeus Sofie , Barrios Sara , Childs Catherine , Clubbe Colin , Corbett Ernestine , Francis Sarita , Gray Alan , Harding Luke , Jackman Annick , Machin Rebecca , McGovern Andrew , Pienkowski Mike , Ryan Delmaude , Sealys Chris , Wensink Catherine , Peyton Jodey
Published: November 2024

This research examines biodiversity specimens from two areas of the Caribbean to understand patterns of collection and the roles of the people involved. Using open data from the Global Biodiversity Information Facility (GBIF) and Wikidata, we aimed to uncover geographic and historical trends in specimen use. This study aims to provide concrete evidence to guide collaboration between collection-holding institutions and the communities that need their resources most.

We analysed biodiversity specimens from Montserrat and the Cayman Islands in three steps. First, we extracted specimen data from GBIF, disambiguated collector names, and linked them to unique biographical entries. Next, we connected collectors to their publications and specimens. Finally, we analysed the modern use of these specimens through citation data, mapping author affiliations and research themes.

Specimens are predominantly housed in the Global North and were initially used by their collectors, whose focus was largely on taxonomy and biogeography. With digitisation, use of these collections remains concentrated in the Global North and covers a broader range of subjects, although Brazil and China stand out as significant users of digital collection data compared to other similar countries.

The availability of open digital data from collections in the Global North has led to a substantial increase in the reuse of these data across biodiversity science. Nonetheless, most research using these data is still conducted in the Global North. For the non-monetary benefits of digitisation to extend to the countries of origin, capacity building in the Global South is crucial, Open Data alone are insufficient.

Societal Impact Statement

Digital biodiversity data from herbaria and museums hold significant potential for nature conservation in the Global South, yet many regions, like Montserrat and the Cayman Islands in the Caribbean, are, for multiple reasons, unable to fully leverage this information. This lack of skills and resources limits local conservation efforts, showing the need for more investment in training, facilities, and expertise. Although past funding has helped improve coordination and build skills, our findings show that more work is needed to make sure conservation in these biodiverse areas can continue in the long term.
TopLib: Building and searching top-down mass spectral libraries for proteoform identification
Authors: Li Kun , Tang Haixu , Liu Xiaowen
Published: November 2024

Mass spectral library search is a widely used approach for spectral identification in mass spectrometry (MS)-based proteomics. While numerous methods exist for building and searching bottom-up mass spectral libraries, there is a lack of software tools for top-down mass spectral libraries. To fill the gap, we introduce TopLib, the first software package designed for building and searching top-down spectral libraries. TopLib utilizes an efficient spectral representation technique to reduce database size and improve query speed and performance. We systematically evaluated various spectral representation techniques and scoring functions for top-down spectral clustering and search. Our results demonstrated that TopLib is 140 times faster and achieves better reproducibility in proteoform identification compared with conventional database search methods in top-down MS.
Midbrain dopamine D2R regulates the salience of threat-related events
Authors: Castell Laia , Rogliardo Angelina , Borgne Tinaig Le , Naon Claire , Cathala Adeline , Puighermanal Emma , Makrini Leila , Mashhour Nejmeh , Petit Chloé P. , Bernat Claire , Nouvian Régis , Cutando Laura , Revest Jean-Michel , Faure Philippe , Besnard Antoine , Bellone Camilla , Monteil Arnaud , Gangarossa Giuseppe , Marti Fabio , Valjent Emmanuel
Published: November 2024

Salience attributed to stimuli predicting rewarding or aversive outcomes is critical for adaptive behavior. Dopamine (DA)-neurons play a central role in this process by modulating responses to both rewarding and aversive cues. DA-neurons are tightly and readily modulated by DA D2 autoreceptors (autoD2Rs), but their role in regulating responses to aversive stimuli remains unclear. In this study, we investigated the role of autoD2R in regulating the activity of VTA DA-neurons in response to salient aversive stimuli. UsingDrd2Slc6a3mice, in whichDrd2is selectively deleted in DA-neurons, we observed enhanced excitatory and inhibitory responses of VTA DA-neurons to aversive stimuli, suggesting that autoD2R acts as a critical regulatory brake. Importantly, this modulation occurred independently of either the pacemaker activity of DA-neurons or their coupling to the non-selective sodium leak channel NALCN. Behaviorally,Drd2Slc6a3male mice showed enhanced discrimination between threat-predicting and non-predicting cues that persisted during extinction learning, highlighting a sex-biased role of autoD2R in threat processing. Our results provide new mechanistic insights through which autoD2R influence behavioral responses to aversive stimuli, with implications for understanding neuropsychiatric disorders characterized by maladaptive threat processing.
LTB4is converted into a potent human neutrophil NADPH oxidase activator via a receptor transactivation mechanism in which the BLT1receptor activates the free fatty acid receptor 2
Authors: Wu Yanling , Dahlgren Claes , Forsman Huamei , Sundqvist Martina
Published: November 2024

The endogenous neutrophil chemoattractant leukotriene B4(LTB4) is a biased signalling agonist that potently increases the intracellular concentration of free calcium ions ([Ca2+]i), but alone is a weak activator of the neutrophil superoxide anion (O2-)-generating NADPH oxidase. However, in this study we show that an allosteric modulator of the free fatty acid 2 receptor (FFA2R) converts LTB4into a potent NADPH oxidase activating agonist. While an allosteric modulation of FFA2R was required for LTB4receptor 1 (BLT1R)-mediated activation of the NADPH oxidase, the LTB4-induced increase in [Ca2+]iwas not affected by the modulator. Thus, the biased BLT1R signalling pattern was altered in the presence of the allosteric FFA2R modulator, being biased with a preference towards the signals that activate the NADPH oxidase relative to an increase in [Ca2+]i. Both BLT1R and FFA2R belong to the family of G protein-coupled receptors (GPCRs), and our results show that a communication between the activated BLT1R and the allosterically modulated FFA2Rs generates signals that induce NADPH oxidase activity. This is consistent with a previously described receptor transactivation (crosstalk) model whereby the function of one neutrophil GPCR can be regulated by receptor downstream signals generated by another GPCR. Furthermore, the finding that an allosteric FFA2R modulator sensitises not only the response induced by orthosteric FFA2R agonists but also the response induced by LTB4, violates the receptor restriction properties that normally define the selectivity of allosteric GPCR modulators.
AIP56, an AB toxin secreted byPhotobacterium damselaesubsp.piscicida, has tropism for myeloid cells
Authors: Freitas Inês Lua , Macedo Fátima , Oliveira Liliana , Oliveria Pedro , do Vale Ana , dos Santos Nuno M.S.
Published: November 2024

The AB-type toxin AIP56 is a key virulence factor ofPhotobacterium damselaesubsp.piscicida(Phdp), inducing apoptosis in fish immune cells. The discovery of AIP56-like and AIP56-related toxins in diverse organisms, including human-associatedVibriostrains, highlights the evolutionary conservation of this toxin family, suggesting that AIP56 and its homologs may share conserved receptors across species. These toxins have potential for biotechnological applications, such as therapeutic protein delivery and immune modulation. Herein, the cell specificity of AIP56 for immune cells in sea bass, mice, and humans was characterized. Whether AIP56 interacts directly or indirectly with sea bass neutrophils was never investigated and it was shown that only a small population of sea bass neutrophils internalized AIP56, indicating that most of the neutrophilic destruction duringPhdpinfection and/or AIP56 intoxication does not result from the direct toxicity of the toxin. Moreover, the cellular tropism of AIP56 for myeloid cells was observed in the three species, including its preference for macrophages. Further, mouse and human M0 and M2-like macrophages internalized more toxin than M1-like macrophages. Despite the limited interaction of lymphoid cells with AIP56, mouse B1-cells were able to internalize the toxin, possibly due to its myeloid features. These findings are relevant for both pathogenicity and biomedical contexts.
Single-cell analyses reveal that monocyte gene expression profiles influence HIV-1 reservoir size in acutely treated cohorts
Authors: Ehrenberg Philip K. , Geretz Aviva , Volcic Meta , Izumi Taisuke , Yum Lauren , Waickman Adam , Shangguan Shida , Paquin-Proulx Dominic , Creegan Matthew , Bose Meera , Machmach Kawthar , McGraw Aidan , Narahari Akshara , Currier Jeffrey R. , Sacdalan Carlo , Phanuphak Nittaya , Apps Richard , Corley Michael , Ndhlovu Lishomwa C. , Slike Bonnie , Krebs Shelly J. , Anonworanich Jintanat , Tovanabutra Sodsai , Robb Merlin L. , Eller Michael A. , Laird Gregory M. , Cyktor Joshua , Daar Eric S. , Crowell Trevor A. , Mellors John W. , Vasan Sandhya , Michael Nelson L. , Kirchhoff Frank , Thomas Rasmi
Published: November 2024

Elimination of latent HIV-1 is a major goal of AIDS research but the host factors determining the size of these reservoirs are poorly understood. Here, we investigated whether differences in host gene expression modulate the size of the HIV-1 reservoir during suppressive ART. Peripheral blood mononuclear cells (PBMC) from fourteen individuals initiating ART during acute infection who demonstrated effective viral suppression but varying magnitude of total HIV-1 DNA were characterized by single-cell RNA sequencing (scRNA-seq). Differentially expressed genes and enriched pathways demonstrated increased monocyte activity in participants with undetectable HIV-1 reservoirs.IL1Bexpression in CD14+ monocytes showed the greatest fold difference. The inverse association ofIL1Bwith reservoir size was validated in an independent cohort comprised of 38 participants with different genetic backgrounds and HIV-1 subtype infections, and further confirmed with intact proviral DNA assay (IPDA®) measurements of intact HIV-1 proviruses in a subset of the samples. Modeling interactions with cell population frequencies showed that monocyteIL1Bexpression associated inversely with reservoir size in the context of higher frequencies of central memory CD4+ T cells, implicating an indirect effect ofIL1Bvia the cell type well established to be a reservoir for persistent HIV-1. Signatures consisting of co-expressed genes includingIL1Bwere highly enriched in the “TNFα signaling via NF-κB” geneset. Functional analyses in cell culture revealed that IL1B activates NF-κB, thereby promoting productive HIV-1 infection while simultaneously suppressing viral spread, suggesting a natural latency reversing activity to deplete the reservoir in ART treated individuals. Altogether, unbiased high throughput scRNA-seq analyses revealed that monocyteIL1Bvariation could decrease HIV-1 proviral reservoirs in individuals initiating ART during acute infection.
SNR-Efficient Whole-Brain Pseudo-Continuous Arterial Spin Labeling Perfusion Imaging at 7 Tesla
Authors: Woods Joseph G. , Ji Yang , Li Hongwei , Hess Aaron , Okell Thomas W.
Published: November 2024

Purpose

To optimize pseudo-continuous arterial spin labeling (PCASL) parameters to maximize SNR efficiency for RF power constrained whole brain perfusion imaging at 7 T.

Methods

We used Bloch simulations of pulsatile laminar flow to optimize the PCASL parameters for maximum SNR efficiency, balancing labeling efficiency and total RF power. The optimization included adjusting the inter-RF pulse spacing (TRPCASL), mean B1+(B1 ave), slice-selective gradient amplitude (Gmax), and mean gradient amplitude (Gave). In vivo data were acquired from four volunteers at 7 T to validate the optimized parameters. Dynamic B0-shimming and flip angle adjustments were utilized to avoid needing to make the PCASL parameters robust to B0/B1+variations.

Results

The optimized PCASL parameters achieved a significant (3.1x) reduction in RF power while maintaining high labeling efficiency. This allowed for longer label durations and minimized deadtime, and resulted in a 126% improvement in SNR efficiency in vivo compared to a previously proposed protocol. Additionally, the static tissue response was improved, reducing the required distance between labeling plane and imaging volume.

Conclusion

These optimized PCASL parameters provide a robust and efficient approach for whole brain perfusion imaging at 7 T, with significant improvements in SNR efficiency and reduced SAR burden.
Wound state monitoring by multiplexed, electrochemical, real-time, localized, inflammation-tracking nitric oxide sensor (MERLIN)
Authors: Wang Liyang , Wang Yingqiao , Bartlett Mabel , San Roman Daniel , Balakrishnan Gaurav , Gershanok Samuel , Khan Reem , Skillen Clint , Butler Shanae , Kulkarni Mangesh , Cohen-Karni Devora , Brown Bryan , Cohen-Karni Tzahi
Published: November 2024

Nitric oxide (NO) released endogenously by induced nitric oxide synthase (iNOS) in macrophages is a key regulatory biomarker for wound inflammation. Detecting NO directly on the wound bed is challenging due to its short half-life time (6 – 50 s), low physiological concentration (nM - µM) and interferences in the complex wound environment. Existing NO sensors suffer from limitations such as rigid substrates, single point of detection and complex measurement setup. Here we present a compliant, multiplexed, electrochemical, real-time, localized, inflammation-tracking nitric oxide sensor (MERLIN) array for in vivo spatiotemporal measurement of NO, with high sensitivity (15.6 ± 5.0 nA/μM for 1.5 mm diameter electrodes), selectivity against nitrites (ca. 27900-fold), ascorbic acid (ca. 3800-fold), and uric acid (ca. 6900-fold), and low limit of detection (8.00 nM). We developed a robust device fabrication protocol, comprehensive and highly reproducible in vitro characterization yielding a consistent device performance deployed for wound healing diagnostics. MERLIN spatiotemporally tracked NO on rat skin wounds for 7 days and results indicated that NO peaks on day 3, in line with previously reported iNOS activity. MERLIN allows spatial mapping of the NO gradient across the wound bed, which can be used to provide diagnostic information to assist wound care.
Attention-dependent attribute comparisons underlie multi-attribute decision-making in orbitofrontal cortex
Authors: Perkins Aster Q. , Rich Erin L.
Published: November 2024

Economic decisions often require weighing multiple dimensions, or attributes. The orbitofrontal cortex FC) is thought to be important for computing the integrated value of an option from its attributes and comparing lues to make a choice. Although OFC neurons are known to encode integrated values, evidence for value mparison has been limited. Here, we used a multi-attribute choice task for monkeys to investigate how OFC eurons integrate and compare multi-attribute options. Attributes were represented separately and eye tracking as used to measure attention. We found that OFC neurons encode the value of attended attributes, dependent of other attributes in the same option. Encoding was negatively weighted by the value of the same tribute in the other option, consistent with a comparison between the two like attributes. These results indicate at OFC computes comparisons among attributes rather than integrated values, and does so dynamically, ifting with the focus of attention.
Urinary Proteome Characterization of Stroke-Prone Spontaneously Hypertensive Rats
Authors: Meng Wenshu , Gao Youhe
Published: November 2024

Background: Hypertension is a multifactorial, complex disease related to genetic and environmental factors and has become the most serious public health problem. This study aimed to explore the changes of hypertension based on urinary proteome. Methods: The stroke-prone spontaneously hypertensive rats (SHRSPs) model was used to examined urinary proteome changes during hypertension development. Urine proteome at months 1, 4, 8, 10, 12, and 14 was profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Considered the degree of disease progression may differ, each rat was compared before and after hypertension developed to screen for differential proteins. Results: The differential proteins in each rat can be enriched into some important biological processes and pathways associated with hypertension, such as regulation of systemic arterial blood pressure by renin-angiotensin, renin-angiotensin signaling, response to glucocorticoid and glucocorticoid receptor signaling, calcium transport I, aldosterone adipocyte signaling pathway, apelin adipocyte signaling pathway and oxidative stress response. The biological processes and pathways enriched at the same time point in the progression of hypertension differed significantly among different rat individuals. Conclusions: This study showed that the changes of hypertension can be reflected in urine proteins. The urine proteomics has the potential to be used to study the mechanisms of hypertension, discovery new drug targets, and provide personalized antihypertensive treatment strategies.
scTrace+: enhance the cell fate inference by integrating the lineage-tracing and multi-faceted transcriptomic similarity information
Authors: Guo Wenbo , Chen Zeyu , Li Xinqi , Huang Jingmin , Hu Qifan , Gu Jin
Published: November 2024

Deciphering the cell state dynamics is crucial for understanding biological processes. Single-cell lineage tracing technologies provide an effective way to track the single-cell lineages by heritable DNA barcodes, but the high missing rates of lineage barcodes and the intra-clonal heterogeneity bring great challenges for dissecting the mechanisms of cell fate decision. Here, we systematically evaluate the feature of single-cell lineage tracing data, and then develop an algorithm scTrace+ to enhance the cell dynamic traces by incorporating multi-faceted transcriptomic similarities into lineage relationships via a Kernelized Probabilistic Matrix Factorization model. We assess its feasibility and performance by conducting ablation and benchmarking experiments on multiple real datasets, and show scTrace+ can accurately predict the fates of cells. Further, scTrace+ effectively identifies some important driver genes implicated in cellular fate decision of diverse biological processes, such as the cell differentiation or the tumor drug responses.