bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of GATA2 in the expression of the soluble decoy receptor ST2/IL1RL1 in human and mouse mast cells
Authors: Nagata Kazuki , Kasakura Kazumi , Ishii Kenta , Ito Naoto , Hara Mutsuko , Okumura Ko , Nishiyama Chiharu
Published: February 2025

TheST2/IL1RL1gene encodes a receptor subunit for IL-33. TheST2/IL1RL1gene is transcribed and translated to two splice variants, full-length ST2 (ST2L) and soluble ST2 (sST2). ST2L is expressed on cell surface as membrane bound molecule and forms a heterodimer with IL-1RAcP, which plays an important role in Th2 transduces a signaling of IL-33. In contrast, sST2 blocks the IL-33-signaling via functioning as a decoy receptor of IL-33. In this study, we analyzed the regulatory mechanisms of the gene expression of sST2 in mast cell, the major source of sST2. We found that a hematopoietic cell-specific transcription factor GATA2 is essential for sST2 expression in human mast cells (a cell line and primary cells) and mouse mast cells. Various assays including ChIP assay, reporter assay, and 3C assay revealed that GATA2 binding to the distal promoter of theIL1RL1gene transcriptionally activates proximal promoter-driven expression of sST2 through chromosomal conformation.
Diammonium glycyrrhizinate injection promotes zebrafish angiogenesis through the mTOR/HIF-1 signaling pathway
Authors: Yu Shuqing , Yu Jiahao , Sun Fengzhi , Zhang Xuanming , Sheng Wenlong , Liu Kechun , Li Xiaobin , Li Wei
Published: February 2025

(1)

Background

Glycyrrhizic acid (GA) is the main component of the traditional Chinese medicine Glycyrrhiza glabra. Many GA preparations in the pharmaceutical market have good efficacy in hepatoprotection and the treatment of liver diseases. However, the pro-angiogenic effects for GA-based agents have not been researched specifically. The aim of this study was to investigate the pro-angiogenic activity of GA preparations commonly used in clinical practice and screen the representative angiogenesis promotor to further elucidate the mechanism of action

(2)

Methods

A zebrafish vascular injury model induced by PTK787 was used to assess the pro-angiogenic effect of GA preparations. The pro-angiogenic activity of diammonium glycyrrhizinate injection (DGI) was further systematically evaluated by detecting the growth of the intersegmental vessels (ISVs) and subintestinal vein vessels (SIVs) in zebrafish. The underlying mechanism of action for DGI was explored by transcriptomics analysis and RT-qPCR validation;

(3)

Results

The results showed that magnesium isoglycyrrhizinate injection (MII), DGI, compound glycyrrhizinate tablets (CGT), and diammonium glycyrrhizinate enteric-coated capsules (DGEC) could demonstrate significantly pro-angiogenic effects. Among them, DGI exhibited the strongest activity. Transcriptomic analysis showed that the pro-angiogenic activity of DGI was closely associated with the mTOR signaling pathway. RT-qPCR results indicated that the expression levels of key genes of the mTOR/HIF-α pathway were significantly upregulated in DGI-treated zebrafish relative to the PTK787 group;

(4)

Conclusions

GA preparations have an obvious pro-angiogenic effect, in which DGI can exert particularly strong activity by activating the mTOR/HIF-1 signaling pathway. This study broadens the clinical application of GA agents and provides new insights into the pharmacodynamics and potential mechanisms of DGI as a candidate agent for treating ischemic diseases
A computational model elucidates the effect of oncogene induced expression alterations on the energy metabolism of neuroblastoma
Authors: Simon Mareike , Benary Uwe , Baum Katharina , Schramm Alexander , Wolf Jana
Published: February 2025

An altered energy metabolism is recognized as a hallmark of cancer. Experimental evidence shows that oncogenes play a key role in the reprogramming of metabolism. In neuroblastoma the oncogene MYCN, a main risk factor of poor prognosis, has been demonstrated to lead to expression changes in numerous glycolytic enzymes. Since it is not clear whether all these targets are required and how the overall metabolic response is shaped, we here dissect the effect of MYCN targets on the pathway individually and in combination using a computational modeling approach. We develop a first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that MYCN overexpression overall leads to Warburg-like flux alterations with characteristic changes for the individual MYCN targets highlighting that MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all described MYCN targets contribute to notable flux alterations, at least in glycolysis. Our model moreover predicts a potential bistability of the cellular metabolism with an occurrence of a low-flux state likely representing quiescence. Overall, our study highlights the importance of analysing perturbations such as expression changes in the context of realistic pathways capturing their specific interactions and complex regulations.
Swiftly squeaky clean: lessons learned from eradicating an overpopulation of rats on an island of constraints
Authors: Micheletti Tatiane , Mello Thayna J. , Verona Carlos , Gasparotto Vinicius P. O. , Krul Ricardo , Araujo Ricardo , Sampaio Thali , Mangini Paulo Rogerio
Published: February 2025

Invasive rats threaten island biodiversity, disrupting ecosystems and endangering native species. While rat eradication has succeeded on many islands, tropical islands present unique management challenges. Strict regulations and financial constraints on some tropical islands further limit proven eradication methods, complicating rodent management. This study addresses these challenges by demonstrating a real-time active adaptive management (RAM) approach, providing a cautious, cost-efficient, scientifically grounded, and adaptive pathway to eradication, while adhering to strict environmental regulations. We implemented RAM on a Brazilian island at USD 3,300 per hectare, integrating rodenticide (brodifacoum) application, population monitoring, and iterative management adjustments. This approach eradicated a rat overpopulation within five months, with early population increases observed in the threatened masked booby and the endemic Noronha elaenia and Noronha skink. Despite logistical constraints, RAM proved effective and cost-efficient, marking its first application in a biological system. Our findings highlight the value of innovation, interdisciplinary collaboration, and adaptive decision-making when the application of best-practice methods is constrained.
Fiber photometry analysis of spontaneous dopamine signals: The z-scored data are not the data
Authors: Wallace Conner W , Slinkard Clare Y , Shaughnessy Rachael , Holleran Katherine M , Centanni Samuel W , Lapish Christopher C , Jones Sara R
Published: February 2025

Fluorescent sensors have revolutionized the measurement of molecules in the brain, and the dLight dopamine sensor has been used extensively to examine reward- and cue-evoked dopamine release, but only recently has the field turned its attention to spontaneous release events. Analysis of spontaneous events typically requires evaluation of hundreds of events over minutes to hours, and the most common method of analysis, z-scoring, was not designed for this purpose. Here, we compare the accuracy and reliability of three different analysis methods to identify pharmacologically induced changes in dopamine release and uptake in freely moving C57BL/6J mice. The D1-like receptor antagonist SCH23390 was used to prevent dLight sensors from interacting with dopamine in the extracellular space, while cocaine was used to inhibit uptake and raclopride to increase release of dopamine in the nucleus accumbens. We examined peak-to-peak frequency, peak amplitude, and width, the time spent above an established cutoff. The three methods were 1) the widely-used “Z-Score Method”, which automatically smooths baseline drift and normalizes recordings using signal-to-noise ratios, 2) a “Manual Method”, in which local baselines were adjusted manually and individual cutoffs were determined for each subject, and 3) the “Prominence Method” that combines z-scoring with prominence assessment to tag individual peaks, then returns to the preprocessed data for kinetic analysis. First, SCH23390 drastically reduced the number of signals detected as expected, but only when the Manual Method was used. Z-scoring failed to identify any changes, due to its amplification of noise when signals were diminished. Cocaine increased signal width as expected using the Manual and Prominence Methods, but not the Z-Score Method. Finally, raclopride- induced increases in amplitude were correctly identified by the Manual and Prominence Methods. The Z-Score Method failed to identify any of the changes in dopamine release and uptake kinetics. Thus, analysis of spontaneous dopamine signals requires assessment of the %ΔF/F values, ideally using the Manual Method, and the use of z- scoring is not appropriate.
Pericellular oxygen dynamics in human cardiac fibroblasts and iPSC-cardiomyocytes in high-throughput plates: insights from experiments and modeling
Authors: Li Weizhen , McLeod David , Antonevich Sarah , Li Zhenyu , Entcheva Emilia
Published: February 2025

Adequate oxygen supply is crucial for proper cellular function. The emergence of high-throughput (HT) expansion of human stem-cell-derived cells and HTin vitrocellular assays for drug testing necessitate monitoring and understanding of the oxygenation conditions, yet virtually no data exists for such settings. For metabolically active cells like cardiomyocytes, variations in oxygenation may significantly impact their maturation and function; conversely, electromechanical activity can drive oxygen demands. We used HT label-free optical measurements and computational modeling to gain insights about oxygen availability (peri-cellular oxygen dynamics) in syncytia of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and human cardiac fibroblasts (cFB) grown in glass-bottom 96-well plates under static conditions. Our experimental results highlight the critical role of cell density and solution height (oxygen delivery path) in peri-cellular oxygen dynamics. The developed 3D reaction-diffusion model with Michaelis-Menten kinetics, trained on the obtained comprehensive data set, revealed that time-variant maximum oxygen consumption rate, Vmax, is needed to faithfully capture the complex peri-cellular oxygen dynamics in the excitable hiPSC-CMs, but not in the cFB. For the latter, accounting for cell proliferation was needed. Interestingly, we found both hypoxic (< 2%) and hyperoxic (> 7%) conditions can easily emerge in these standard HT plates in static culture and that peri-cellular oxygen dynamics evolves with days in culture. Our results and the developed computational model can directly be used to optimize cardiac cell growth in HT plates to achieve desired physiological conditions, important in cellular assays for cardiotoxicity, drug development, personalized medicine and heart regeneration applications.
Topologically Optimized Intrinsic Brain Networks
Authors: Lewis Noah , Iraji Armin , Miller Robyn , Agcaoglu Oktay , Calhoun Vince
Published: February 2025

The estimation of brain networks is instrumental in quantifying and evaluating brain function. Nevertheless, achieving precise estimations of subject-level networks has proven to be a formidable task. In response to this challenge, researchers have developed group-inference frameworks that leverage robust group-level estimations as a common reference point to infer corresponding subject-level networks. Generally, existing approaches either leverage the common reference as a strict, voxel-wise spatial constraint (i.e., strong constraints at the voxel level) or impose no constraints. Here, we propose a targeted approach that harnesses the topological information of group-level networks to encode a high-level representation of spatial properties to be used as constraints, which we refer to as Topologically Optimized Intrinsic Brain Networks (TOIBN). Consequently, our method inherits the significant advantages of constraint-based approaches, such as enhancing estimation efficacy in noisy data or small sample sizes. On the other hand, our method provides a softer constraint than voxel-wise penalties, which can result in the loss of individual variation, increased susceptibility to model biases, and potentially missing important subject-specific information. Our analyses show that the subject maps from our method are less noisy and true to the group networks while promoting subject variability that can be lost from strict constraints. We also find that the topological properties resulting from the TOIBN maps are more expressive of differences between individuals with schizophrenia and controls in the default mode, subcortical, and visual networks.
Consequences of training data composition for deep learning models in single-cell biology
Authors: Nadig Ajay , Thoutam Akshaya , Hughes Madeline , Gupta Anay , Navia Andrew W. , Fusi Nicolo , Raghavan Srivatsan , Winter Peter S. , Amini Ava P. , Crawford Lorin
Published: February 2025

Foundation models for single-cell transcriptomics have the potential to augment (or replace) purpose-built tools for a variety of common analyses, especially when data are sparse. Recent work with large language models has shown that training data composition greatly shapes performance; however, to date, single-cell foundation models have ignored this aspect, opting instead to train on the largest possible corpus. We systematically investigate the consequences of training dataset composition on the behavior of deep learning models of single-cell transcriptomics, focusing on human hematopoiesis as a tractable model system and including cells from adult and developing tissues, disease states, and perturbation atlases. We find that (1) these models generalize poorly to unseen cell types, (2) adding malignant cells to a healthy cell training corpus does not necessarily improve modeling of unseen malignant cells, and (3) including an embryonic stem cell differentiation atlas during training improves performance on out-of-distribution tasks. Our results emphasize the importance of diverse training data and suggest strategies to optimize future single-cell foundation models.
Single-nuclei RNA Sequencing Reveals Distinct Transcriptomic Signatures of Rat Dorsal Root Ganglia in a Chronic Discogenic Low Back Pain Model
Authors: Caparaso Sydney M. , Sankaranarayanan Ishwarya , Lillyman David J. , Price Theodore J. , Wachs Rebecca A.
Published: February 2025

Chronic low back pain (LBP), often correlated with intervertebral disc degeneration, is a leading source of disability worldwide yet remains poorly understood. Current treatments often fail to provide sustained relief, highlighting the need to better understand the mechanisms driving discogenic LBP. During disc degeneration, the extracellular matrix degrades, allowing nociceptive nerve fibers to innervate previously aneural disc regions. Persistent mechanical and inflammatory stimulation of nociceptors can induce plastic changes within dorsal root ganglia (DRG) neurons, characterized by altered gene expression, enhanced excitability, and lowered activation thresholds. Although these transcriptional changes have been described in other pain states, including osteoarthritis, they remain underexplored in discogenic LBP. To address this gap, this study represents the first application of comprehensive single-nuclei RNA sequencing of DRG neurons in a rat model of chronic discogenic LBP. Eighteen distinct DRG subpopulations were identified and mapped to existing mouse and cross-species atlases revealing strong similarities in neuronal populations with the mouse. Differential expression analysis revealed increased expression of pain-associated genes, includingScn9aandPiezo2, and neuroinflammatory mediators such asFstl1andNgfr, in LBP animals. Axial hypersensitivity, measured using grip strength, significantly correlated with increased expression ofScn9a, Fstl1, and Ngfr,which suggests their role in maintaining axial hypersensitivity in this model. These findings establish a relationship between DRG transcriptomic changes and axial hypersensitivity in a discogenic LBP model, identifying potential molecular targets for non-opioid treatments and advancing understanding of discogenic LBP mechanisms.
Autophagy Suppresses CCL2 to Preserve Appetite and Prevent Lethal Cachexia
Authors: Ibrahim Maria , Gomez-Jenkins Maria , Scheinfeld Adina , Zhao Zhengqiao , Lopes Eduardo Cararo , Sawant Akshada , Hu Zhixian , Dharani Aditya , Sun Michael , Siddiqui Sarah , Mirek Emily T. , Abram-Saliba Johan , Lattime Edmund C. , Su Xiaoyang , Janowitz Tobias , Goncalves Marcus D. , Dunn Steven M. , Pritykin Yuri , Anthony Tracy G. , Rabinowitz Joshua D. , White Eileen
Published: February 2025

Macroautophagy (autophagy hereafter) captures intracellular components and delivers them to lysosomes for degradation and recycling1. In adult mice, autophagy sustains metabolism to prevent wasting by cachexia and to survive fasting, and also suppresses inflammation, liver steatosis, neurodegeneration, and lethality2,3. Defects in autophagy contribute to metabolic, inflammatory and degenerative diseases, however, the specific mechanisms involved were unclear4. Here we profiled metabolism and inflammation in adult mice with conditional, whole-body deficiency in an essential autophagy gene and found that autophagy deficiency altered fuel usage, and reduced ambulatory activity, energy expenditure, and food intake, and elevated circulating GDF15, CXCL10, and CCL2. While deletion ofGdf15orCxcl10provided no or mild benefit, deletion ofCcl2restored food intake, suppressed cachexia and rescued lethality of autophagy-deficient mice. To test if appetite suppression by CCL2 was responsible for lethal cachexia we performed single nucleus RNA sequencing of the hypothalamus, the center of appetite control in the brain. Notably, we found that autophagy deficiency was specifically toxic to PMCH and HCRT neurons that produce orexigenic neuropeptides that promote food intake, which was rescued by deficiency in CCL2. Finally, the restoration of food intake via leptin deficiency prevented lethal cachexia in autophagy-deficient mice. Our findings demonstrate a novel mechanism where autophagy prevents induction of a cachexia factor, CCL2, which damages neurons that maintain appetite, the destruction of which may be central to degenerative wasting conditions.

Key points of paper

1) Autophagy-deficient mice have reduced food intake, systemic inflammation, and cachexia

2) CCL2, but not GDF15 or CXCL10, induces lethal cachexia caused by autophagy defect

3) Autophagy-deficient mice have CCL2-dependent destruction of appetite-promoting neurons in the hypothalamus

4) Leptin deficiency restores appetite and rescues lethal cachexia in autophagy-deficient mice

5) Autophagy-deficient mice die from cachexia mediated by appetite loss

6) Degenerative conditions due to impaired autophagy are caused by the inflammatory response to the damage

7) Targeting CCL2 may be a viable approach to prevent degenerative wasting disorders
Loss of Sarm1 Mitigates Axonal Degeneration and Promotes Neuronal Repair After Ischemic Stroke
Authors: Wang Jack T. , Toh Brian , An Jennifer , Komuro Yutaro , Godoy Marlesa I. , Putman Jennifer , Carmichael S. Thomas , Damoiseaux Robert , Hinman Jason D.
Published: February 2025

Axonal degeneration is a core feature of ischemic brain injury that limits functional recovery (1). The pro-degenerative molecule Sarm1 is required for Wallerian axon degeneration after traumatic and chemotoxic nerve injuries (2), however it is unclear if a similar mechanism mediates axonal degradation after ischemic injury. Here we show that loss of Sarm1 results in profound attenuation of axonal degeneration after focal ischemia to the subcortical white matter. Moreover, absence of Sarm1 significantly promotes the survival of neurons remote from but connected to the infarct after ischemic injuries to the subcortical white matter as well as to the cortex. To further understand the mechanism ofSarm1-/-mediated neuronal protection, we performed differential gene expression analyses of wildtype andSarm1-/-stroke-injured neurons and found that the loss of Sarm1 activates a pro-growth molecular program that promotes new axon and synapse formation after white matter ischemia. Using a functional genomics approach to recapitulate such a molecular program inSarm1-/-neurons, we identify molecular compounds sufficient to enhance cortical neurite outgrowthin vitro, and all of which elicit a conserved epigenetic signature promoting axonogenesis. These results indicate that Sarm1 promotes axonal degeneration and concurrently inhibits an axonal reparative program encoded at the level of the epigenome that can be modulated pharmacologically. Our findings thus reveal a novel role for Sarm1 as a crucial regulator of both axonal degeneration and axonal remodeling after ischemic stroke.

SIGNIFICANCE STATEMENT

Axon degeneration is a pivotal event following ischemic stroke, however the mechanism of white matter loss in stroke is unknown. We demonstrate that the pro-degenerative molecule Sarm1 is required for axonal and neuronal degeneration after ischemic injuries, and that loss of Sarm1 surprisingly induces the activation of a reparative program driving new axon and synapse formation. Using functional genomics, we uncover molecular candidates that phenocopy this pro-growth molecular signature inSarm1-/-neurons, and show that these compounds are sufficient to promote de novo axonal growth via an epigenetic mechanism. Our results thus reveal a novel role for Sarm1 as a regulator of both axonal degeneration and axonal remodeling after ischemia, and identify pharmacologic candidates to promote axonal repair in stroke.
PARP inhibitors affect the replisome and replication fork progression during a single S phase
Authors: Briu Lina-Marie , Maric Chrystelle , Valentin Nicolas , Panara Nicolas , Chevreux Guillaume , Baldacci Giuseppe , Cadoret Jean-Charles
Published: February 2025

Poly(ADP-ribosyl)ation (PARylation) is a protein modification mostly synthesised and degraded by PARP1/2 and PARG enzymes, respectively. PARylation is involved in many covalent and non-covalent protein-protein interactions in the nucleus, making it a powerful form of molecular signaling in DNA metabolism. PARP inhibitors (PARPi) have shown efficacy in the treatment of Homologous Recombination (HR)-deficient cancers, yet the full range of molecular mechanisms underlying the activity of these drugs is not fully understood. Here, we decipher the direct consequences of PARPi-induced loss of PARylation on DNA replication. First, PARPi treatment during a single S phase induces replicative stress, delays S phase progression and causes genome-wide replication timing changes of disease-associated regions. These DNA replication alterations appear to be caused by an accumulation of SSBs in the DNA replicative template when PARylation is inhibited, which then seems to lead to one-ended DSBs and fork collapse during S phase. Second, PARPi deplete FANCD2-I, BRCA, monoubiquitinated PCNA and RAD18 proteins from the replisomes. The two PARPi tested then appear to modulate the choice of fork restart mechanisms and influence replisome dynamics in different ways. Taken together, our study highlights the common and unique primary effects of two PARPi on unperturbed DNA replication in human cells.

GRAPHICAL ABSTRACT
Morphine self-administration induces region-specific brain volume changes and microglial phenotypic alterations without affecting neuronal density in male Wistar rats
Authors: Elizarrarás-Herrera Ana Débora , Medina-Sánchez David , Serrano-Ramírez Mariana Stefania , Angeles-Valdez Diego , Trujillo-Villarreal Luis A. , Carbajo-Mata María Antonieta , Carranza-Aguilar César J. , Garza-Villarreal Eduardo A.
Published: February 2025

Addiction to opioids, including morphine, is a major public health crisis in the U.S. It has been associated with brain volume changes in reward-related regions, neuronal death, and neuroinflammation. However, the link between structural changes and neuroinflammation is not well understood. In this study, we used operant conditioning to induce morphine self-administration in rats and examined brain volume and cellular changes, focusing on microglial phenotypes. Male Wistar rats were conditioned to morphine self-administration (0.01 mg/kg) for 20 days under a fixed-ratio 1 schedule. In vivo structural Magnetic Resonance Imaging (MRI) scans were conducted at the beginning and end of self-administration. Brains were stained for Iba1 and NeuN proteins, and confocal images were analyzed for cell counts and microglial morphology. We used Deformation-Based Morphometry for MRI volume analysis and Principal Component Analysis with K-means clustering for microglial phenotyping. Our results showed that morphine self-administration led to volume changes in addiction-related brain regions, including increased globus pallidus and decreased insular cortex volume. Additionally, morphine caused widespread neuroinflammation, evidenced by elevated microglial density in the caudate-putamen, dentate gyrus, globus pallidus, and insular cortex, without affecting neuron counts. Finally, we observed region-specific variations in microglial phenotypes, suggesting region-specific neuroinflammatory roles. In conclusion, our study shows that morphine self-administration induces structural and microglial changes in addiction-related brain regions without neuronal loss, highlighting the role of neuroinflammation in opioid-induced adaptations. The variability in microglial phenotypes underscores their complexity, emphasizing the need to study their progression in addiction and their potential as therapeutic targets.
Dopaminergic Modulation of Short-Term Associative Memory inCaenorhabditis elegans
Authors: McMillen Anna , Minervini Caitlin , Green Renee , Johnson Michaela E. , Ansaar Radwan , Chew Yee Lian
Published: February 2025

Forgetting, the inability to retrieve previously encoded memories, is an active process involving neurotransmission, second messenger signalling, and cytoskeletal modifications. Forgetting is thought to be essential to remove irrelevant memories and to increase the capacity to encode new memories. Therefore, identifying key regulators of active forgetting is crucial to advance our understanding of neuroplasticity. In this study, we utilised the compact and tractableCaenorhabditis elegansmodel to investigate the role of the neurotransmitter dopamine in forgetting. We conducted butanone associative learning assays based on an established protocol and used mutant strains deficient in dopamine synthesis (tyrosine hydroxylase CAT-2 and dopamine transporter DAT-1) and signalling (G protein-coupled receptors DOP-1, DOP-2, and DOP-3) to assess the impact on learning and memory retention. Learning was measured immediately post-training, and memory retention was evaluated every 0.5 hours up to 2 hours. Our results show that animals lacking dopamine display a modest enhancement in learning relative to wild-type, with the learned association persisting for at least 2 hours after training. We also found that the D2-like receptors DOP-2 and DOP-3 function together to modulate the forgetting process, with D1-like receptor DOP-1 having an antagonistic effect. Furthermore, re- expression of CAT-2 tyrosine hydroxylase in ADE or CEP neurons showed that dopamine synthesis in both neuron types is essential for short-term memory retention, albeit at different time points after learning. These findings highlight the critical role of dopamine in forgetting, consistent with findings inDrosophila, and suggest potential relevance for understanding memory retention during healthy ageing and in conditions with dopamine imbalances such as Parkinson’s disease.
Comparison of Nanopore with Illumina Whole Genome Assemblies of the Epstein-Barr Virus in Burkitt Lymphoma
Authors: Kim Isaac E. , Fola Abebe A. , Puig Enrique , Maina Titus K. , Hui Sin Ting , Ma Hongyu , Zuckerman Kaleb , Agwati Eddy , Leonetti Alec , Crudale Rebecca , Luftig Micah A. , Moormann Ann M. , Oduor Cliff , Bailey Jeffrey A.
Published: February 2025

Endemic Burkitt lymphoma (eBL) is one of the most prevalent cancer in children in sub-Saharan Africa, and while prior studies have found that Epstein-Barr virus (EBV) type and variation may alter the tumor driver genes necessary for tumor survival, the precise relationship between EBV variation and EBV-associated tumorigenesis remains unclear due to lack of scalable, cost-effective, viral whole-genome sequencing from tumor samples. This study introduces a rapid and cost-effective method of enriching, sequencing, and assembling accurate EBV genomes in BL tumor cell lines through a combination of selective whole genome amplification (sWGA) and subsequent 2-tube multiplex polymerase chain reaction along with long-read sequencing with a portable sequencer. The method was optimized across a range of parameters to yield a high percentage of EBV reads and sufficient coverage across the EBV genome except for large repeat regions. After optimization, we applied our method to sequence 18 cell lines and 3 patient tumors from fine needle biopsies and assembled them with median coverages of 99.62 and 99.68%, respectively. The assemblies showed high concordance (99.61% similarity) to available Illumina-based assemblies. The improved method and assembly pipeline will allow for better understanding of EBV variation in relation to BL and is applicable more broadly for translational research studies, especially useful for laboratories in Africa where eBL is most widespread.
At-Home Movement State Classification Using Totally Implantable Bidirectional Cortical-Basal Ganglia Neural Interface
Authors: Ramesh Rithvik , Fekri Azgomi Hamid , Louie Kenneth H. , Balakid Jannine P. , Marks Jacob H. , Wang Doris D.
Published: February 2025

Movement decoding from invasive human recordings typically relies on a distributed system employing advanced machine learning algorithms programmed into an external computer for state classification. These brain-computer interfaces are limited to short-term studies in laboratory settings that may not reflect behavior and neural states in the real world. The development of implantable devices with sensing capabilities is revolutionizing the study and treatment of brain circuits. However, it is unknown whether these devices can decode natural movement state from recorded neural activity or accurately classify states in real-time using onboard algorithms. Here, using a totally implanted bidirectional neurostimulator to perform long-term, at-home recordings from the motor cortex and pallidum of four subjects with Parkinson’s disease, we successfully identified highly sensitive and specific personalized signatures of gait state, as determined by wearable sensors. Additionally, we demonstrated the feasibility of using these neural biomarkers to drive adaptive stimulation with the classifier embedded onboard the neurostimulator. These findings offer a pipeline for ecologically valid movement biomarker identification that can advance therapy across a variety of diseases.
Delay-related harm: direct and indirect impacts of boarding medical patients in the Emergency Department on the urgent and emergency care pathway. A retrospective observational cohort study
Authors: Howlett Nicholas C , Cameron James A , Wood Richard M
Published: February 2025

Background

Previous studies have indicated that crowding within the Emergency Department (ED) is associated with longer lengths of stay in the ED and higher mortality. Boarding, the time patients spend waiting for an inpatient bed after ED assessment, represents a clinically unproductive delay, and occupies scarce ED resources. We aimed to explore the impact of medical patients boarding not only on their outcomes but also indirectly on other patients in the ED and in and awaiting ambulances.

Methods

A retrospective cohort study using routine data for 3 EDs in England from June 2021 to May 2024 was performed. Direct outcomes of medical patient boarding time were investigated: inpatient length of stay, 30-day readmission rate and mortality. Indirect outcomes of medical patient boarding levels consisted of time in ED for non-admitted patients, ambulance handover times, and ambulance response times. Regression analysis was used to model each relationship while controlling for other potentially confounding variables.

Results

In all, data on 223,856 ambulance responses, 117,800 ambulance handovers, 367,985 non-admitted ED patients, and 46,976 medical admissions were studied. Medical patients, covering two-thirds of ED admissions, constituted 82% of total ED boarding time. Regression analysis showed that for a typical 25-bed ED, each additional five medical boarders was associated with an extra 12 and 39 minutes for Category 2 and 3 ambulance response times (p<0.001) and an extra 20 minutes for ambulance handover times (p<0.001). For admitted medical patients, each additional 4 hours of boarding time was associated with an extra 13 hours inpatient length of stay (p<0.001) and a 6% increase in odds of 30-day mortality (p<0.01).

Conclusion

Boarding of medical patients in the ED is associated with direct harm for those patients, and indirect harms for other patients in the ED and awaiting ambulances.

What is already known on this topic

A prolonged length of stay in the Emergency Department is known to increase mortality for those patients.

What this study adds

Medical admissions make up 85% of boarding time in the ED waiting for an inpatient bed. This delay affects them directly with increased mortality, readmission and length of stay. It affects other patients with delayed ambulance offload and ambulance response times for other patients.

How this study might affect research, practice or policy

The boarding delay for medical patients in the ED results in a longer inpatient length of stay and therefore fewer beds available for future patients. Stopping this practice would free up much needed hospital capacity, improve ambulance response times, and reduce mortality.
Comparison of methods for characterizing skin pigment diversity in research cohorts
Authors: Lipnick Michael S. , Chen Danni , Law Tyler , Moore Kelvin , Lester Jenna C. , Monk Ellis P. , Hendrickson Carolyn M. , Chou Yu , Hughes Caroline , Behnke Ella , Elmankabadi Seif , Ortiz Lily , Negussie Fekir , Leeb Gregory , Ehie Odinakachukwu , Auchus Isabella , Igaga Elizabeth N. , Bisegerwa Ronald , Okunlola Olubunmi , Bickler Philip , Feiner John , Shmuylovich Leonid
Published: February 2025

Background

Some pulse oximeters perform worse in people with darker skin, and this may be due to inadequate diversity of skin pigment in device development study cohorts. Guidance is needed to accurately and equitably characterize skin pigment to ensure diversity in research cohorts. We tested multiple methods for characterizing skin pigment to assess comparability and impact on cohort diversity.

Objectives

Assess reliability and comparability of common skin pigment measurement methods

Compare findings from different anatomical sites

Demonstrate that pigment cannot be assumed from US National Institutes for Health (NIH) race categories

Methods

We used three subjective methods (perceived Fitzpatrick pFP, Monk Skin Tone MST and Von Luschan VL) and two objective methods (Konica Minolta CM-700d spectrophotometer and Delfin Skin Color Catch DSCC colorimeter) for individual typology angle (ITA), across multiple measurement sites in adults. We calculated ΔE to estimate operator perceptibility thresholds for subjective methods and to determine reproducibility for objective methods. We used each method to categorize participants as ‘light, medium, or dark’ and compared the impact of method selection on cohort diversity.

Results

We studied 789 participants, with 33,856 assessments. The MST had the widest luminosity range, and VL had the least discernible adjacent categories. With ‘dark’ defined as ITA <-30°, 14% of participants were categorized ‘dark’ as compared to 26% by pFP or 16% by MST. Approximately half of the ‘dark’ cohort had an ITA <-50°. With an ITA threshold <-50°, only 7% of the cohort was categorized as ‘dark.’ When ‘Black or African American’ self-identification was used to define ‘dark’, 23% of the cohort was categorized as such. Each self-assigned NIH race category included a wide range of ITA and subjective scale categories. Both ITA and L* from the KM-700d and DSCC demonstrated strong correlation (⍴ > 0.7).

Conclusion

Common methods for skin pigment characterization, especially the use of race or subjective scales, have significant limitations. When applied to the same cohort, different methods yield significantly different results, and some may overestimate diversity. Previously published ITA thresholds for defining ‘dark’ skin are too light and lead to underrepresentation of people with darker skin.
Saccadic Suppression Enhances Saliency of Prey-Like Stimuli in the Optic Tectum
Authors: Soto Giulia , Thomas Carina , Hladnik Tim C. , Dehmelt Florian A. , Hafed Ziad M. , Arrenberg Aristides B.
Published: February 2025

Saccadic suppression, a reduction in visual sensitivity around the time of a rapid eye movement, is a robust perceptual phenomenon, extensively studied in primate psychophysics. However, the mechanisms and purpose of saccadic suppression are still debated in the field. Here, we demonstrate saccadic suppression in zebrafish, and trace its origins not only in retinal circuits, but also in downstream visual and motor-related neurons of the optic tectum. Using electrophysiology, we first established that retinal ganglion cells jumpstart saccadic suppression, in a spatial frequency dependent manner. Calcium imaging of the optic tectum, combined with 360° visual stimulation and behavioral tracking, revealed that motor signals enhance peri-saccadic suppression strength up to 0.5 s after the saccade. Notably, vision-mediated saccadic suppression lasts more than 3 s. Suppression strength depends on saccade size. Interestingly, we found much weaker saccadic suppression in the optic tectum for stimuli related to hunting behavior than for behaviorally less relevant global flashes, suggesting a selectivity of saccadic suppression aimed at increasing the salience of particular types of visual stimuli after saccades. These findings demonstrate that saccadic suppression in zebrafish integrates visual and motor signals to optimize sensory processing within neural constraints, providing insights into evolutionarily conserved visual strategies.
Experimental evidence of stress-induced critical state in schooling fish
Authors: Lin Guozheng , Escobedo Ramón , Li Xu , Xue Tingting , Han Zhangang , Sire Clément , Guttal Vishwesha , Theraulaz Guy
Published: February 2025

How do animal groups dynamically adjust their collective behavior in response to environmental changes is an open and challenging question. Here, we investigate the mechanisms that allow fish schools to tune their collective state under stress, testing the hypothesis that these systems operate near criticality, a state maximizing sensitivity, responsiveness, and adaptability. We combine experiments and data-driven computational modeling to study how group size and stress influence the collective behavior of rummy-nose tetras (Hemigrammus rhodostomus). We quantify the collective state of fish schools using polarization, milling, and cohesion metrics and use a burst-and-coast model to infer the social interaction parameters that drive these behaviors. Our results indicate that group size modulates stress levels, with smaller groups experiencing higher baseline stress, likely due to a reduced social buffering effect. Under stress, fish adjust the strength of their social interactions in a way that leads the group into a critical state, thus enhancing its sensitivity to perturbations and facilitating rapid adaptation. However, large groups require an external stressor to enter the critical regime, whereas small groups are already near this state. Unlike previous studies suggesting that fish adjust their interaction network structure under risk, our results suggest that the intensity of social interactions, rather than network structure, governs collective state transitions. This simpler mechanism reduces cognitive demands while enabling dynamic adaptation. By revealing how stress and group size drive self-organization toward criticality, our study provides fundamental insights into the adaptability of collective biological systems and the emergent properties in animal groups.
A humanized mouse model system mimics prenatal Zika infection and reveals premature differentiation of neural stem cells
Authors: Horvath Allison R. , Abdelmalek Clara M. , Park Eunbin , Alexander Aubrey P. , Maheswaran Sadhana A. , Patel Arnav H. , Patel Nandi G. , Ruan Janet E. , Adeyemo Ademide T. , Li Erin C. , Helmicki Katherine E. , Lin Stephen , Wang Paul C. , Li Zhen , Wang Li , Gordish-Dressman Heather A. , Haydar Tarik F. , Mansour Tamer A. , Kousa Youssef A.
Published: February 2025

Zika, a mosquito-borne flavivirus, has been found in 87 countries and territories. Global outbreaks peaked in 2016. Prenatal infection of Zika virus was found to be associated with microcephaly, arthrogryposis, intracranial calcifications, fetal growth restriction, and fetal demise. The most severely affected children were diagnosed with congenital Zika syndrome, which impacts thousands worldwide. With no approved treatment or preventative measures for Zika, future viral outbreaks have the potential to cause epidemic levels of prenatal brain injury, as seen over the past 70 years. Therefore, there is a great need for a reliable and clinically translational experimental system that mimics the human condition of prenatal Zika infection. To this end, we developed a humanized, immunocompetent mouse model system of virally induced brain injury from prenatal Zika infection, which ranges from mild to severe. Here, we describe the extent to which this system mirrors the human phenotypic spectrum. Using our thorough preclinical system, we find that prenatal Zika infection of mice impacts survival rate, anthropometric measurements, tissue formation, and neurological outcomes, all of which are typical of prenatal infection. Single-cell RNA sequencing of the Zika-infected cerebral cortex reveals severely disrupted transcriptome profiles and suggests that these injuries are a result of a depletion of neural stem cells. Current and future applications include the identification of genetic or environmental modifiers of brain injury, molecular or mechanistic studies of pathogenesis, and preclinical evaluation of future therapies.
Hyper-ovulation in an ovarian-specific transgenic mouse model
Authors: Muñiz Luis C. , Reilly James , Spigelman Melissa , Molina Carlos A.
Published: February 2025

Ovulation is a fundamental prerequisite for achieving successful reproduction. In vertebrates, ovulation is controlled by the cyclical action of hormones, particularly the gonadotropins such as follicle stimulating hormone (FSH) and luteinizing hormone (LH). A critical component of the intracellular activity of these two hormones is relayed by the second messenger cAMP. Although it is well established that a family of transcription factors facilitate cAMP mediated gene expression, it remains unknown how these factors directly affect ovulation. In particular, the Inducible cAMP Early Repressor (ICER) has been implicated in the transcriptional repression of FSH inducible genes during folliculogenesis. Here we show, using an ovarian-specific transgenic mouse model that ICER potentiates ovulation. We observed a twofold rate increase in ovulation for transgenic mice when compared to the wild type in response to exogenous gonadotropin treatment. Furthermore, mature cycling transgenic mice display a significantly enhanced ovulation rate compared to the wild-type. The observed changes in ovulation in the transgenic females are accompanied by altered gonadotropins production and gene expression. Most significantly, the expression of inhibin alpha subunit (INHA) was found to be about 5-fold higher in the transgenic mice. These observations may aid in unraveling some of the molecular mechanisms underlying ovulation and be relevant to the development of novel reproductive technologies.

Summary Sentence

Generation of an FSH inducible ovarian specific FLAG-ICER-II© Tg Mice results in hyper-ovulation upon gonadotropin stimulation.
Unconscious Neural Activity Predicts Overt Attention in Visual Search
Authors: Nadra John G. , Bengson Jesse J. , Mangun George R.
Published: February 2025

Unconscious neural activity has been shown to precede both motor and cognitive acts. In the present study, we investigated the neural antecedents of overt attention during visual search, where subjects make voluntary saccadic eye movements to search a cluttered stimulus array for a target item. Building on studies of both overt self-generated motor actions (Lau et al., 2004, Soon et al., 2008) and self-generated cognitive actions (Bengson et al., 2014, Soon et al., 2013), we hypothesized that brain activity prior to the onset of a search array would predict the direction of the first saccade during unguided visual search. Because both spatial attention and gaze are coordinated during visual search, both cognition and motor actions are coupled during visual search. A well-established finding in fMRI studies of willed action is that neural antecedents of the intention to make a motor act (e.g., reaching) can be identified seconds before the action occurs. Studies of the volitional control ofcovertspatial attention in EEG have shown that predictive brain activity is limited to only a few hundred milliseconds before a voluntary shift of covert spatial attention. In the present study, the visual search task and stimuli were designed so that subjects could not predict the onset of the search array. Perceptual task difficulty was high, such that they could not locate the target using covert attention alone, thus requiring overt shifts of attention (saccades) to carry out the visual search. If the first saccade to the array onset in unguided visual search shares mechanisms with willed shifts of covert attention, we expected predictive EEG alpha-band activity (8-12 Hz) immediately prior to the array onset (within 1 sec) (Bengson et al., 2014; Nadra et al., 2023). Alternatively, if they follow the principles of willed motor actions, predictive neural signals should be reflected in broadband EEG activity (Libet et al., 1983) and would likely emerge earlier (Soon et al., 2008). Applying support vector machine decoding, we found that the direction of the first saccade in an unguided visual search could be predicted up to two seconds preceding the search array’s onset in the broadband but not alpha-band EEG. These findings suggest that self-directed eye movements in visual search emerge from early preparatory neural activity more akin to willed motor actions than to covert willed attention. This highlights a distinct role for unconscious neural dynamics in shaping visual search behavior.