bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental demonstration of diamond quantum vector magnetometer for deep-sea applications
Authors: Yu Ziyun , Zhu Yunbin , Zhang Wenzhe , Jing Ke , Wang Shuo , Chen Chuanxu , Xie Yijin , Rong Xing , Du Jiangfeng
Published: January 2025

Magnetometry plays an important role in exploring the deep sea, which is one of the Earth’s final unknown frontiers. However, the complexity of marine environment and the limitations of conventional magnetometers restricts its in-depth application. Nitrogen-Vacancy (NV) center in diamond offers a potential solution to encompass and transcend the conventional ocean magnetometers. Its unique advantages, such as precise vector measurement and tolerance to extreme environments, make it well-suited for deep-sea applications like navigation. This work introduces the first deep-sea quantum vector magnetometer based on NV centers. The performance of this magnetometer is effectively validated by a series of field tests on the manned submersible ShenhaiYongshi during a cruise in the South China Sea, including an experimental underwater navigation using the diamond quantum sensor as magnetic compass. This successful deep-sea application marks the milestone of transforming this promising solid-state spin quantum system into a practical sensor for real-world marine applications.
Identification of the Skip Phenomenon Among Patients With Staphylococcus lugdunensis Infective Endocarditis: A Retrospective Review
Authors: Crowley Patrick D , Gasca Luis R , Katragadda Silpita , Quintero-Martinez Juan , Baddour Larry M , DeSimone Daniel C
Published: January 2025

The skip phenomenon (SP) is a pattern where blood cultures are intermittently positive before final clearance. We report that one-third of patients with Staphylococcus lugdunensis infective endocarditis experienced the SP. Patients with the SP experienced both a longer duration of bacteremia and hospital stay, with a higher 1-year mortality rate.
Light-level geolocators and species distribution modeling reveal that the Vulnerable Sporophila cinnamomea (Chestnut Seedeater) migrates through the Paraná-Paraguay system to Central Brazil
Authors: Rosoni Jonas Rafael R , Fontana Carla S , Krammes Filho Hernandi F , Carlos Caio J
Published: January 2025

The movement ecology of migratory Sporophila seedeaters in the Neotropics, particularly their migratory routes and nonbreeding areas, remains poorly understood. This study aimed to fill this gap by providing a detailed description of these migratory routes, stopovers, and nonbreeding areas using light-level geolocators on Sporophila cinnamomea (Chestnut Seedeater), a vulnerable species that breeds in southern South America. Species distribution modeling was employed to estimate the probability of occurrence at distribution extremes. Over 3 breeding seasons (October to March 2018–2021), geolocators were affixed to 14 adult males. The overall device recovery rate was 64% (n = 9), and these 8 devices operated, on average, for 301 days. Autumn migration commenced on 24 February, lasting 46 days and spanning 1,679 km, with an average of 2.38 ± 0.92 stopovers—twice the number observed during spring migration (1.40 ± 0.89). We identified 8 nonbreeding areas utilized by the birds for an average of 145 days, primarily located between the northern and northeastern regions of the Paraná and Paraguay Rivers and the southern Tocantins River. Spring migration began in early September, lasted ~58 days, and covered 2,940 km. In both migrations, birds followed routes along the Paraná-Paraguay River valleys, with no significant difference in the number of stopovers detected between seasons. The nonbreeding period model indicated high habitat suitability in 2 regions within the Cerrado biome, particularly a larger area predominantly in the southern and then in the central regions of the Tocantins River. In the southern limit, the breeding model highlighted the most representative area, which is located in the central-eastern region of the Uruguay River. Our study offers valuable insights into the migratory patterns of S. cinnamomea. These findings should be used to inform the planning and establishment of protected areas aimed at conserving grassland species.
Improving the solubility of pseudo-hydrophobic chemicals through co-crystal formulation
Authors: Janilkarn-Urena Isis , Tse Amanda , Lin Jieye , Tafolla-Aguirre Bliss , Idrissova Alina , Zhang Mindy , Skinner Samantha G , Mostowfi Nader , Kim Jinah , Kalapatapu Nikhila , Chang Xinmin , Efthymiou Christina , Williams Christopher K , Magaki Shino D , Vinters Harry V , Gonen Tamir , Ahmed S Kaleem , Gukasyan Hovhannes J , Davies Daryl L , Seidler Paul M
Published: January 2025

Natural products are ligands and in vitro inhibitors of Alzheimer’s disease (AD) tau. Dihydromyricetin (DHM) bears chemical similarity to known natural product tau inhibitors. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH, allowing the formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable co-crystalline solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All co-crystal formulations show better inhibitory activity against AD tau than the nonsalt form, with efficacies correlating to enhanced solubilities. In vitro and in vivo pharmacokinetic measures demonstrate that DHM co-crystals display enhanced absorption and distribution with altered rates of elimination, suggesting that co-crystal formulations could be strategically used to fine-tune delivery properties. These results underscore the role of structural chemistry in guiding the selection of solubilizing agents for chemical formulation. We propose DHM co-crystals are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding, although central nervous system (CNS) delivery remains a major limitation. DHM may be a suitable backbone for medicinal chemistry and possible development of pharmaceuticals with enhanced CNS exposure.
Glia: the cellular glue that binds circadian rhythms and sleep
Authors: Carvalhas-Almeida Catarina , Sehgal Amita
Published: January 2025

Glia are increasingly appreciated as serving an important function in the control of sleep and circadian rhythms. Glial cells in Drosophila and mammals regulate daily rhythms of locomotor activity and sleep as well as homeostatic rebound following sleep deprivation. In addition, they contribute to proposed functions of sleep, with different functions mapping to varied glial subtypes. Here, we discuss recent findings in Drosophila and rodent models establishing a role of glia in circadian or sleep regulation of synaptic plasticity, brain metabolism, removal of cellular debris, and immune challenges. These findings underscore the relevance of glia for benefits attributed to sleep and have implications for understanding the neurobiological mechanisms underlying sleep and associated disorders.
Effects of Scalp Nerve Block on Symptomatic Cerebral Hyperperfusion Syndrome After Combined Revascularization Surgery for Moyamoya Disease
Authors: Choi Seungeun , Park Jung Yeon , Jo Woo-Young , Shin Kyung Won , Park Hee-Pyoung , Lee Sung Ho , Cho Won-Sang , Kim Jeong Eun , Oh Hyongmin
Published: January 2025

Background:

Strict blood pressure control can be used to prevent or treat cerebral hyperperfusion syndrome. This study investigated whether scalp nerve block (SNB) is associated with a reduced risk of postoperative symptomatic cerebral hyperperfusion syndrome (SCHS) by reducing postoperative blood pressure in adult patients who underwent combined revascularization surgery for moyamoya disease.

Methods:

Patients were retrospectively divided into the SNB (n=167) and control (n=221) groups depending on whether SNB was performed immediately before placement of wound dressings at the end of surgery. Postoperative SCHS was defined as new-onset postoperative neurological deficits with a focal increase in cerebral blood flow at the perianastomosis site in the absence of infarction or hemorrhage on postoperative brain imaging. Inverse probability of treatment weighting was used to balance preoperative variables between the 2 groups.

Results:

The incidence of postoperative SCHS did not differ between the SNB and control groups (61 [36.5%] vs. 102 [46.2%], P=0.072), but its duration was shorter in the SNB group (4 [2–6] vs. 5 [3–7] days, P=0.021). Although of limited clinical relevance, the SNB group had lower postoperative pain scores and systolic blood pressures at postoperative days 0 to 1 and a shorter intensive care unit stay.

Conclusions:

Despite some potential benefits, SNB was not associated with a reduced incidence of postoperative SCHS in adult patients who underwent combined revascularization surgery for moyamoya disease.
Measurement of Ambient Millimeter Wave Exposure Levels around Small Base Stations
Authors: Bushberg Jerrold T. , Butcher Matthew J.
Published: January 2025

This study investigated the implementation and impact of fifth-generation (5G) wireless millimeter wave (mmW) technology. 5G offers significant advancements over previous generations and supports additional frequency bands, including mmW, to enhance mobile broadband with ultra-reliable, low-latency communications, supporting a high volume of diverse communications. This technology is expected to enable billions of new connections in the Internet of Things (IoT), fostering innovations in various sectors including healthcare, manufacturing, and education. This research contributes to the understanding and safe implementation of this transformative technology. Global adoption of 5G is rapidly increasing, with over 1.5 billion subscriptions as of 2024, projected to reach 58% of all wireless subscriptions by 2029. Despite its benefits, 5G mmW installations have raised concerns regarding exposure to electromagnetic fields. This study was conducted using a dual-polarized horn antenna and relatively inexpensive spectrum analyzers to measure typical ambient mmW radiofrequency field power densities near operational radio base stations (RBS) in urban and suburban environments. The measurements were taken at various times of the day and in different weather conditions to ensure a comprehensive understanding of the ambient mmW exposure. The study's results provide reassuring evidence that the ambient mmW exposure from RBSs is significantly lower than the safety limits set by the Federal Communications Commission (FCC) and other international standards. The exposure levels ranged from 0.0003% to 0.0082% of the public maximum permissible exposure (MPE), with the highest levels being more than 25,000 times lower than the allowed continuous public exposure. This study concludes that typical mmW exposure from 5G RBSs is minimal and substantially below established safety limits.
Which metabolites are removed by continuous renal replacement therapies: A prospective, observational, single-center study
Authors: Li Yue , Zeng Siyao , Peng Yahui , Li Tong , Yao Zhipeng , Wang Changsong , Han Qiuyuan
Published: January 2025

Background:

Despite considerable research on the loss of inorganic substances in continuous renal replacement therapy (CRRT), no relevant experimental studies have been conducted to determine whether and how much organic matter is lost and how such loss affects the body.

Methods:

Based on gas chromatography-tandem time of flight mass spectrometry (GC-TOF-MS) metabolomics, the plasma and liquid in the waste liquid bags of acute kidney injury (AKI) patients before and after CRRT for 24 h were analyzed.

Results:

The expression of differential metabolites in the waste liquid samples of the 24 h after CRRT (WCRRT) group, the blood samples of the before CRRT (FCRRT) group, and the blood samples of the 24 h after CRRT (PCRRT) group is mainly composed of sugars, fatty acids, amino acids, lipids, and carnitine derivatives. The expression of differential metabolites in the plasma FCRRT and PCRRT groups mainly consists of fatty acids, lipids, carnitine derivatives, and other substances.

Conclusion:

In patients with AKI, CRRT can not only effectively reduce creatinine after 24 h but also lead to the loss of other metabolites, such as fatty acids, lipids, and carnitine derivatives.
Anatomic-Based Diagnosis and Filler Injection Techniques: Chin Augmentation and Jawline Contouring
Authors: Hong Gi-Woong , Wan Jovian , Yoon Song-Eun , Yi Kyu-Ho
Published: January 2025

Chin augmentation and jawline contouring have emerged as significant procedures in aesthetic medicine, addressing both structural and age-related changes in the lower face. This review explores anatomic-based diagnosis and filler injection techniques for these treatments. Ethnic variations in facial structure necessitate different approaches, with Western patients often seeking jawline definition, while Asian patients frequently require chin projection. The evolution of beauty standards and widespread orthodontic treatments have influenced treatment goals, emphasizing overall facial harmony. Successful outcomes rely on a thorough understanding of facial anatomy, including the complex interplay of muscles, fat layers, and soft tissue landmarks. The distinction between bony and soft tissue landmarks is crucial for optimal filler placement. Treatment techniques involve careful selection of filler consistency and injection depth, with high-viscosity fillers used for deep structural support and softer fillers for surface refinement. The use of cannulas in jawline treatments offers advantages in reducing complications and ensuring even distribution. Vascular anatomy knowledge is essential to avoid complications, particularly regarding the facial artery and its branches. Post-treatment management, including massage and follow-up assessments, is vital for achieving and maintaining desired results. This comprehensive approach ensures safe, effective, and aesthetically pleasing outcomes in chin and jawline enhancement procedures.
Association of pre- and postinjury mental health with long-term clinical and financial outcomes
Authors: Johnson Patrick L. , Hemmila Mark R. , Mullens Cody L. , Oliphant Bryant W. , Monahan Janessa R. , Kelm Julia D. , Jakubus Jill L. , Curtiss William J. , Mosher Benjamin D. , Kieninger Alicia N. , Scott John W.
Published: January 2025

BACKGROUND

As increased attention is placed on optimizing long-term outcomes of trauma patients by addressing mental health, little is known regarding the interplay of pre- and postinjury mental health on long-term financial and functional outcomes.

METHODS

Patients from 19 Level 1 and 2 trauma centers took part in serial surveys 1 to 24 months postdischarge. Preinjury mental health diagnoses were identified using trauma registry data and postinjury mental health symptoms from survey data. Outcomes included (1) health-related quality of life from the EuroQol-5D-5L and (2) elements of financial toxicity (e.g. medical debt, job/income loss, nonmedical bills, unaffordable care). Multivariable models were created, adjusting for patient, injury, and treatment factors, to evaluate the association of preinjury mental health diagnoses and postinjury mental health symptoms on health-related quality of life and financial toxicity.

RESULTS

A total of 1,017 patients completed 1,297 surveys from July 2021 to December 2023, at a median of 6 months postinjury. Forty-six percent were female, the median age was 67.5 years, and 89% had blunt injuries. Thirty-two percent of patients had a preinjury mental health diagnosis, and 49% had self-reported mental health symptoms postdischarge. Patients with preinjury mental health diagnoses had higher odds of postinjury mental health symptoms (adjusted odds ratio, 3.6 [2.6–4.9]; p < 0.001); however, 55% of those with postinjury symptoms had no preinjury diagnosis. Postinjury symptoms alone were associated with worse health-related quality of life or financial toxicity. Notably, patients with new postinjury mental health symptoms (no preinjury mental health diagnosis) had the highest rate of foregone postinjury care because of costs (26% vs. 14%, p < 0.01).

CONCLUSION

More than one-in-two patients had peri-injury mental health conditions, and patients with postinjury mental health symptoms experienced worse financial and functional outcomes. Addressing postinjury mental health may potentially improve long-term health-related quality of life of trauma survivors; however, efforts are needed to ensure that patients can afford the care needed for optimal health.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
BCL6 Alleviates Hepatic Ischemia/Reperfusion Injury Via Recruiting SIRT1 to Repress the NF-κB/NLRP3 Pathway
Authors: Gu Yulei , Li Yue , Zhang Chao , Liu Yi , Shi Huiting , Tian Xiaoxu , Du Jiaqi , Zhang Hao , Cao Shengli , Gao Lu , Zhang Yanzhou , Zhao Guojun
Published: January 2025

Background.

Hepatic ischemia/reperfusion (I/R) injury (HIRI) is an intrinsic phenomenon observed in the process of various liver surgeries. Unfortunately, there are currently few options available to prevent HIRI. Accordingly, we aim to explore the role and key downstream effects of B-cell lymphoma 6 (BCL6) in hepatic I/R (HIR).

Methods.

BCL6 expression levels were measured in I/R liver tissue and primary hepatocytes stimulated by hypoxia/reoxygenation (H/R). Moreover, we ascertained the BCL6 effect on HIR in vivo using liver-specific BCL6 knockout mice and adenovirus-BCL6-infected mice. RNA-sequencing, luciferase, chromatin immunoprecipitation, and interactome analysis were combined to identify the direct target and corresponding molecular events contributing to BCL6 function. DNA pull-down was applied to identify upstream of BCL6 in the H/R challenge.

Results.

HIR represses BCL6 expression in vivo and in vitro. Hepatic BCL6 overexpression attenuates inflammation and apoptosis after I/R injury, whereas BCL6 deficiency aggravates I/R-induced liver injury. RNA-sequencing showed that BCL6 modulated nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 inflammasome signaling in HIRI. Mechanistically, BCL6 deacetylated nuclear factor kappa-B p65 lysine 310 by recruiting sirtuin 1 (SIRT1), thereby inhibiting the nuclear factor kappa-B/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 pathway. Moreover, overexpression of SIRT1 blocked the detrimental effects of BCL6 depletion. Moreover, EX 527, a SIRT1 inhibitor, vanished protection from BCL6 overexpression. Furthermore, transcription factor 7 was found to mediate the transcription regulation of BCL6 on H/R challenge.

Conclusions.

Our results provide the first evidence supporting BCL6 as an important protective agent of HIR. This suggests a potential therapeutic approach for HIR.
Electroconvulsive therapy in autism spectrum disorders: an update to the literature
Authors: Wachtel Lee , Luccarelli James , Falligant John Michael , Smith Joshua Ryan
Published: January 2025

Purpose of review

Over the last quarter century, the clinical evidence surrounding the use of electroconvulsive therapy (ECT) in individuals with autism spectrum disorder (ASD) has expanded. This review provides the most up-to-date findings on the usage of ECT in ASD and discusses these results within the historical context and direct patient care experience.

Recent findings

ECT is typically implemented for psychotropic-refractory catatonic, affective, psychotic, and combined pathology for individuals across the lifespan. Although highly stigmatized, ECT is well tolerated, efficacious, and potentially lifesaving for select individuals. A case presentation of an individual with autism as well as a summary of legal restrictions hampering his ECT access is presented.

ECT is increasingly used in individuals with ASD who present with a wide range of ECT-responsive psychopathology, as well as repetitive self-injury and late, autistic-like regression for which no cause is found. ECT is well tolerated and offers real hope for many ASD individuals with devastating, treatment-refractory conditions.
Dementia prevalence and dementia risk in Indigenous Peoples: recent findings, current developments, and future directions
Authors: Furlano Joyla A. , Okada de Oliveira Maira , Pintado-Caipa Maritza , Röhr Susanne
Published: January 2025

Purpose of review

To highlight recent findings on the prevalence and risk and protective factors for dementia in Indigenous Peoples, who are disproportionately affected by health inequities driven by social determinants of health and historical injustices. With increasing numbers of Indigenous individuals entering older age, there is a growing need for research to better understand dementia and opportunities for prevention in Indigenous Peoples.

Recent findings

Recent studies highlight a wide range of dementia prevalence across Indigenous Peoples, with estimates varying significantly by methodology, socio-cultural context, and region with stark gaps in regional representation. Studies suggested that Indigenous Peoples show distinct profiles of dementia risk factors, including higher rates of cardiovascular disease, lower educational attainment, and socioeconomic disadvantage. However, traditional lifestyles, strong social ties, and culturally grounded practices are suggested to offer protective effects against cognitive decline.

Despite growing research attention, significant limitations remain in understanding dementia in Indigenous Peoples. The available evidence points to the need for culturally sensitive approaches in research and dementia prevention, as well as greater consideration of the social and environmental factors shaping brain health. Future research should aim to incorporate Indigenous knowledge systems and address the social determinants of dementia risk in Indigenous Peoples.
Defining the limits of plant chemical space: challenges and estimations
Authors: Hart Chloe Engler , Gadiya Yojana , Kind Tobias , Krettler Christoph A. , Gaetz Matthew , Misra Biswapriya B. , Healey David , Allen August , Colluru Viswa , Domingo-Fernández Daniel
Published: January 2025

The plant kingdom, encompassing nearly 400,000 known species, produces an immense diversity of metabolites, including primary compounds essential for survival and secondary metabolites specialized for ecological interactions. These metabolites constitute a vast and complex phytochemical space with significant potential applications in medicine, agriculture, and biotechnology. However, much of this chemical diversity remains unexplored, as only a fraction of plant species have been studied comprehensively. In this work, we estimate the size of the plant chemical space by leveraging large-scale metabolomics and literature datasets. We begin by examining the known chemical space, which, while containing at most several hundred thousand unique compounds, remains sparsely covered. Using data from over 1,000 plant species, we apply various mass spectrometry-based approaches—a formula prediction model, a de novo prediction model, a combination of library search andde novoprediction, and MS2 clustering—to estimate the number of unique structures. Our methods suggest that the number of unique compounds in the metabolomics dataset alone may already surpass existing estimates of plant chemical diversity. Finally, we project these findings across the entire plant kingdom, conservatively estimating that the total plant chemical space likely spans millions, if not more, with the vast majority still unexplored.
Alprazolam induces anterograde amnesia for contextual fear memory and alters dorsoventral hippocampal neuronal ensembles in female mice
Authors: Kaplan Kameron , Toennies Lainey B. , Hunsberger Holly C.
Published: January 2025

Benzodiazepines (BZDs) are commonly prescribed anxiolytic drugs that act on GABAa receptors, and can result in anterograde amnesia, or the inability to form new memories. While BZDs have been used for decades, the brain regions and neuronal mechanisms responsible for this detrimental side effect are largely unknown at the systems neuroscience level. To analyze the effects of BZDs on long-term memory, activity-dependent ArcCreERT2x eYFP mice were injected with Alprazolam 30 minutes prior to a 3-shock contextual fear conditioning (CFC) procedure and encoding ensembles were tagged with eYFP. Mice were re-exposed to the same context 5 days later, and retrieval cell activation was analyzed using the immediate early gene (IEG), c-Fos, allowing us to determine which brain regions undergo changes after alprazolam injection. Additionally, we address the question of whether alprazolam induces state-dependent memory by altering the timelines of injection. We found that 1) alprazolam treated male and female mice exhibit a decrease in memory retention and, 2) alprazolam treated female and male mice show a decrease in memory retention with saline injection prior to re-exposure, 3) alprazolam treated female mice exhibit increased EYFP+ (encoding) activation in the dCA1 and enhanced engram activation in the dCA3, and 4) alprazolam treated females showed less c-Fos+ activation in the vCA1. These results suggest that alprazolam induces sex-specific ensemble activation throughout the hippocampus and will help us understand the long-term memory deficits associated with BZD use.
Sparse Sequencing permits accurate and efficient quantification of genome-wide cytosine modification levels
Authors: Loo Christian E. , Fowler Johanna M. , Zhu Heqiao , Krapp Christopher , Zhu Ruiyao , Bartolomei Marisa S. , Zhou Wanding , Kohli Rahul M.
Published: January 2025

5-methylcytosine (5mC) and 5-hydroxymethycytosine (5hmC) play crucial roles in epigenetic gene regulation, with dynamic levels in development and disease. While high-depth, base-resolution whole genome studies offer the most detailed view of epigenetic landscapes for individual samples, many open questions are answered by surveying changes in 5mC/5hmC levels genome-wide or at specific genomic elements across larger cohorts of samples. Nonetheless, current global quantification methods, including mass spectrometry and immunochemistry, are typically limited in accessibility, throughput, or accuracy. Here, using computational down-sampling of deeply sequenced data, we first demonstrate that sequencing base-resolution libraries to shallow depth can be sufficient for highly accurate quantification. Sparse sampling (<0.24% of the genome) can precisely measure genomic 5mC/5hmC levels (error <5%), even when levels are low (<0.3%). Using a combined chemical/enzymatic workflow, we then validate that Sparse-Sequencing (Sparse-Seq) shows high accuracy and less variability than mass spectrometry, while distinctively preserving genomic context. Applying Sparse-Seq to track developing mouse brains serially revealed an earlier emergence of 5hmCpG compared to 5mCpH and uncovered previously overlooked, genomic feature-specific differences in epigenetic dynamics. This work establishes a rigorous foundation for employing Sparse-Seq as a highly accessible approach for 5mC/5hmC quantification, allowing for economical and high-throughput analysis of epigenetic landscapes.
Robustness of Selection and Timing Inference under Model Variation in Population Genetics
Authors: Escabi Javier , Hormoz Sahand
Published: January 2025

1

In population genetics, accurately inferring the selection coefficient and the time of onset of advantageous mutations from genetic data is fundamental for understanding evolutionary processes. Here, we investigate how mismatches between the true evolutionary process and the inference model—specifically in the reproductive variance (σ2) and the number of generations (L)—affect the posterior distributions of the selection coefficient and the time of onset. Using the Kolmogorov forward and backward equations, we model the stochastic dynamics of gene frequencies under selection and drift. We show that while the posterior distribution of the selection coefficient remains unaffected by changes inσ2andL, this invariance does not apply to the time of onset. By framing the problem as a first passage time issue, we derive explicit expressions for the offsets in the posterior mean and variance of the time of onset that result from incorrect assumptions aboutσ2andL. Our analysis reveals that these offsets are related to the mean and variance of the first passage time required for the allele frequency to reach a certain threshold, starting from an initial frequency determined by the model parameters. Under the assumption of a uniform prior for the time of onset, we find that the offset in the inferred mean is given by the difference in the effective generation duration (Δ = 1/σ2) between the true process and the inference model. We validate our theoretical findings through simulations, demonstrating that the empirical offsets closely match our predictions. Furthermore, we generalize our results to accommodate non-uniform prior distributions, such as exponential priors, and provide numerical methods for calculating offsets under arbitrary priors. Stochastic fluctuations due to genetic drift, which are influenced by the reproductive variance and generational structure, can introduce significant biases in the posterior distribution of time of onset of advantageous mutations. By quantifying these biases, our framework enables more accurate adjustments to inferences drawn from genetic data, thereby enhancing our understanding of evolutionary dynamics and improving the reliability of population genetic analyses.
PixlMap: A generalisable pixel classifier for cellular phenotyping in multiplex immunofluorescence images
Authors: Pennie Rachel Louise , Mason David , Rakovic Kai , Ballantyne Fiona , Powley Ian R , Georgakopoulou Anastasia , Bird Thomas G , Officer-Jones Leah , Le Quesne John
Published: January 2025

Multiplexed methods for the detection of protein expression generate extremely data-rich images of intact tissue sections. These images are invaluable for the quantification and analysis of complex biology and biomarker development. However, their interpretation presents a considerable analytical challenge.

Cell segmentation from images is a key bottleneck and a major focus of research activity in artificial intelligence. Most current methods depend initially on the use of a nuclear counterstain to identify nuclear boundaries, which is a relatively straightforward task. The cellular boundary is then assigned either by expansion of the nuclear outline, or by the use of membrane or cytoplasm-specific stains to delineate cell boundaries, or by some combination of the two. The task is critical, as inaccurate segmentation leads to information loss and data contamination from neighbouring cells. Increasingly sophisticated methods are being developed to address these issues, but each has its own shortcomings. We present an alternative method which is inspired by the fact that the assignation of a cellular phenotype ‘by eye’ does not depend upon the accurate identification of cell boundaries. We present an easy-to-use deep learning-based cellular phenotyping method which leverages this human capacity to assign phenotypes without segmenting the entire cell, and which can accurately phenotype cells based on nuclear segmentation alone.

Using human ground truth annotations of entire cellular regions, we developed a classifier leveraging the U-Net architecture within a commercially available deep learning image analysis platform, but the principle is transferrable to any deep-learning framework. Crucially, training requires only a single example of each compartmental stain (nuclear/cytoplasmic/membranous). The resulting algorithm assigns class identities to cells with nuclear labelling alone, without the need for whole cell expansion. The method is highly novel, broadly generalisable, and comparable in accuracy to intensity-based phenotyping methods, bridging the gap between inaccurate cellular segmentation and accurate phenotype generation.
Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity
Authors: Moore Zachery , Storey Claire , Brown Daniel V. , Valkovic Adam , Spiteri Montana , Pignatelli Jasmine F. , Oliver Shannon J. , Fakhri Alana , Drummond Katharine J. , Malinowski Seth , Ligon Keith L. , Sieber Oliver M. , Whittle James R. , Freytag Saskia , Best Sarah A.
Published: January 2025

The intra- and inter-tumoral heterogeneity of glioblastoma represents a significant therapeutic challenge, as well as difficulty in generating reliable models forin vitrostudies. Historical 2D adherent cell lines do not recapitulate this complexity, whereas both patient-derived neurospheres (PDN) and organoids (PDO) demonstrate intra-tumoral heterogeneity. Here, we quantify the tumor cell composition from matched models established from the same primary tumor using a series of multi-omic interrogations. We find that both patient-derived models recapitulate the genomic, epigenomic and tumor cell heterogeneity of the primary tissue. Furthermore, single-nuclei RNA sequencing revealed a subset of organoids containing small numbers of non-malignant cells from neuron and immune cell lineages. Harnessing the intra-tumoral heterogeneity of PDN models, we reveal the impact of temozolomide chemotherapy on individual cell states, altering composition of tumors over time in response to treatment. Our data confirms that both patient-derived models recapitulate patient intra-tumoral heterogeneity providing a platform for tumor cell state refined therapeutic studies.

Key Points

Generation of matched patient-derived neurosphere and organoid models from resected GBM tissue

Neurosphere models exhibit greater proliferative signatures

Both patient-derived models recapitulate genomic and epigenomic features of the primary tissue

Single-nuclei RNA sequencing reveals both models recapitulate intra-tumoral heterogeneity of the primary tissue

Neurosphere models enable interrogation of therapeutic responses in the context of heterogeneity

Importance of study

Patient derived models can be powerful tools when they faithfully recapitulate the tumor tissue from which they are derived. In glioblastoma, patient derived neurospheres (PDN) and organoids (PDO) have both been used in studies, however the differences between these models and the recapitulation of patient heterogeneity remain to be fully characterized. To address this, we performed multi-omic profiling of PDN and PDO models generated from the same tumor tissue. We find that that across a range of data modalities, both model systems exhibit a high level of resemblance to tissue, and critically, maintain heterogeneity and tumor cell composition. The importance of modeling heterogeneity was demonstrated in PDN models, where temozolomide treatment specifically alters the abundance of MES-like and AC-like tumor cells. Our findings demonstrate that neurosphere and organoid models effectively preserve cellular heterogeneity, genomic alterations, methylation signatures and transcriptomic features, both highly suitable to model glioblastoma’s complex cellular landscape.
A Technical Evaluation of Plasma Proteomics Technologies
Authors: Beimers William F. , Overmyer Katherine A. , Sinitcyn Pavel , Lancaster Noah M. , Quarmby Scott T. , Coon Joshua J.
Published: January 2025

Plasma proteomic technologies are rapidly evolving and of critical importance to the field of biomedical research. Here we report a technical evaluation of six notable plasma proteomic technologies – unenriched (Neat), Acid depletion, PreOmics ENRICHplus, Mag-Net, Seer Proteograph XT, Olink Explore HT. The methods were compared on proteomic depth, reproducibility, linearity, tolerance to lipid interference, and limit of detection/quantification. In total we performed 618 LC-MS/MS experiments and 93 Olink Explore HT assays. The Seer method achieved the greatest proteomic depth (∼4,500), while Olink detected ∼2,600 proteins. Other MS-based methods ranged from ∼500-2,200. Neat, Mag-Net, Seer, and Olink had strong reproducibility, while PreOmics and Acid showed higher variability. All MS methods showed good linearity with spiked-in C-Reactive Protein (CRP); CRP was surprisingly not in the Olink assay. None of the methods were affected by lipid interference. Seer had more than double the number of quantifiable proteins (4,800) for both LOD and LOQ than the next best method. Olink was comparable to Neat and Mag-Net for LOD, but worse for LOQ. Finally, we tested the applicability of these methods for detecting differences between healthy and cancer groups in a non-small cell lung cancer (NSCLC) cohort.
Back Home: A Machine Learning Approach to Seashell Classification and Ecosystem Restoration
Authors: Valverde Alexander , Solano Luis
Published: January 2025

In Costa Rica, an average of 5 tons of seashells are extracted from ecosystems annually. Confiscated seashells, cannot be returned to their ecosystems due to the lack of origin recognition. To address this issue, we developed a convolutional neural network (CNN) specifically for seashell identification. We built a dataset from scratch, consisting of approximately 19000 images from the Pacific and Caribbean coasts. Using this dataset, the model achieved a classification accuracy exceeding 85%.

The model has been integrated into a user-friendly application, which has classified over 36,000 seashells to date, delivering real-time results within 3 seconds per image. To further enhance the system’s accuracy, an anomaly detection mechanism was incorporated to filter out irrelevant or anomalous inputs, ensuring only valid seashell images are processed.

Abstract Figure
A high-quality reference genome and comparative genomics of the widely-farmed banded cricket (Gryllodes sigillatus) identifies selective breeding targets
Authors: Zhang Shangzhe , Duffield Kristin R. , Foquet Bert , Ramirez Jose L. , Sadd Ben M. , Sakaluk Scott K. , Hunt John , Bailey Nathan W.
Published: January 2025

Farmed insects have gained attention as an alternative, sustainable source of protein with a lower carbon footprint than traditional livestock. We present a high-quality reference genome for one of the most commonly farmed insects, the banded cricketGryllodes sigillatus. In addition to its agricultural importance,G. sigillatusis also a model in behavioural and evolutionary ecology research on reproduction and mating systems. We report comparative genomic analyses that clarify the banded cricket′s evolutionary history, identify gene family expansions and contractions unique to this lineage, associate these with agriculturally important traits, and identify targets for genome-assisted breeding efforts. The high-qualityG. sigillatusgenome assembly plus accompanying comparative genomic analyses serve as foundational resources for both applied and basic research on insect farming and behavioural biology, enabling researchers to pinpoint trait-associated genetic variants, unravel functional pathways governing those phenotypes, and accelerate selective breeding efforts to increase the efficacy of large-scale insect farming operations.
Tissular glucocorticoid reactivating enzyme 11β-HSD1 drives pathogenic myofibroblast differentiation in chronic kidney disease
Authors: Arnoux Grégoire , Legouis David , Tihy Matthieu , Yvon Raphaël , Liaudet Nicolas , Moser Seraina O. , Poinot Hélène , Sassi Ali , Lempke Olga M. , Fernandez Marylise , Monnay Isabelle , Chassot Alexandra , Bourquin Carole , Moll Solange , Somm Emmanuel , Rutkowski Joseph , Wenger Roland H. , Naesens Maarten , Odermatt Alex , Khodo Stellor Nlandu , Pommier Aurélien , Feraille Eric
Published: January 2025

Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality and morbidity. Irrespective of its underlying cause, tubulointerstitial fibrosis (TIF) is a hallmark of CKD progression, with myofibroblasts being the primary effectors of renal fibrosis.

Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a critical driver of pathogenic myofibroblast differentiation and fibrosis in CKD. Using genetic deletion and pharmacological inhibition of 11β-HSD1 in mouse models, we demonstrate a marked reduction in TIF severity and improved renal function, linked to the suppression of a regulatory myofibroblast (Reg-MF) subpopulation.

Single-cell and spatial transcriptomics data reveal that 11β-HSD1 is essential for the activation and expansion of Reg-MFs, which is conserved across species and predicts worse outcomes in CKD patients and kidney allograft recipients.

These findings establish a direct link between 11β-HSD1 activity and renal fibrogenesis, highlighting its role during the transition from pericytes to pathogenic Reg-MFs. Our results support 11β-HSD1 inhibition as a promising therapeutic strategy to mitigate CKD progression, offering both mechanistic insights and translational potential for improving patient outcomes.
Endogenous gene tagging with FnCas9 to track and sort neural lineages from 3D cortical organoids
Authors: Kumar Manoj , Torras Berta Terre , Guillemot François , Chakraborty Debojyoti
Published: January 2025

Neural lineage tracing, or molecular dissection of lineage-specific brain cell types, is used in many labs to learn how neurons grow and mature. However, these studies depend on the growth and characterization of pure cultures, which takes a long time because of biochemical or fluorescence-based isolation through cell surface markers that overlap. These lineage-specific cells, however, can be efficiently sorted using endogenously expressed, fluorescently labeled marker genes. The labeled cell lines can be used not only to differentiate and purify different types of neurons but also to study the long-term development of neural lineages in two- and three-dimensional development models. In this study, we used an orthogonal Cas protein to generate human embryonic stem cell (hESC) lines with genetically labeled fluorescent barcodes for discrete neural lineages. We use these lines to successfully demonstrate spatial and temporal tracing of DCX-positive neuroblasts and immature neuronal cells within 2D neural cultures and 3D cortical organoids derived from human embryonic stem cells. This allowed the purification of endogenously tagged live neural cells from heterogeneous cortical organoids across multiple stages of development.
Simultaneous stabilizing feedback control of linear and angular momentum in human walking
Authors: van Dieen Jaap H. , Bruijn Sjoerd M. , Lemaire Koen K. , Kistemaker Dinant A.
Published: January 2025

Stabilizing bipedal gait is mechanically challenging. Previous studies have used the assumption that the linear momentum of the body center of mass (CoM) is controlled to analyze how gait is stabilized. In these studies, the position of the center of pressure (CoP) or of the foot relative to the COM is often used as an indicator of corrections of the CoM state. Mechanically, neither of these variables is directly related to changes in linear momentum, whereas they do directly affect whole-body angular momentum (WBAM), which has also been suggested to be a controlled variable. We show that, in human walking, linear and angular momentum follow quasi-periodic functions with similar periodicity and phase. Combining the equations of linear and rotational motion for a system of linked rigid segments shows that, in this case, the horizontal distance between CoP and CoM is a good predictor of horizontal forces in the corresponding direction. This suggests that linear and angular momentum are simultaneously controlled to follow similar quasi-periodic functions and may explain the success of preceding studies that correlated CoM states to CoP or foot locations. We developed feedback models to predict the ground reaction force and its moments along the sagittal and transverse axes from the preceding CoM state and WBAM respectively. These models were fitted to experimental data of participants walking at normal and slow speeds. The consistent, good fit of both models supports that linear and angular momentum are controlled simultaneously in human walking.
The developmental environment mediates adult seminal proteome allocation in maleDrosophila melanogaster
Authors: von Hellfeld Rebecca , Konietzny Rebecca , Charles Philip D. , Fischer Roman , Kessler Benedikt M. , Wigby Stuart , Sepil Irem , Morimoto Juliano
Published: January 2025

Early life conditions can have long-lasting fitness effects on organisms. In insects, crowding during larval stages impose a significant constraint on adult phenotypes due to increased intraspecific competition for resources, which can modulate males’ success in pre- and post-mating competition in adulthood. Evidence for larval crowding effects on male seminal fluid allocation exists but is limited to a small subset of well-known seminal fluid proteins (Sfps), and often overlooks the interactions between male and female phenotypes. We currently lack a comprehensive understanding of how male and female larval crowding interact to affect production, composition, and transfer of the wider seminal proteome. Here, we manipulatedDrosophila melanogasterlarval crowding (lowversushigh) of males and females to generate individuals with large and small body size, respectively. We mated individuals in a fully factorial design, and measured the abundance, composition, and transfer of Sfps. Large males produced Sfps in significantly higher abundances, yet this difference was marginal and not detected when Sfps were analysed individually. Conversely, small males transferred greater quantities of much of their seminal proteome to females than did large males. When analysing proteins individually, 10 Sfps were transferred in significantly higher abundances by small males than large males. Our results suggest that small males invest more on each mating opportunity, potentially as a response of overall fewer mating opportunities due to their reduced size, or due to the larval cues of high population density. This work provides an insight into early life effects on ejaculate allocation inD. melanogasterand sheds light on the physiological and behavioural responses to developmental conditions in insects.
Combined deletion of cytosolic 5’-nucleotidases IA and II lowers glycemia by improving skeletal muscle insulin action and by lowering hepatic glucose production
Authors: Jacobs R. , Herinckx G. , Galland N. , Balty C. , Vertommen D. , Rider M. H. , Johanns M.
Published: January 2025

Obesity and type 2 diabetes (T2D)-linked hyperglycemia, along with their associated complications, have reached pandemic proportions, becoming a major public health issue. Genetic deletion or pharmacological inhibition of purine nucleotide-metabolizing enzymes has emerged as a potential strategy for treating diseases. We previously showed that cytosolic 5’-nucleotidase II (NT5C2)-deficient mice were protected against high-fat diet (HFD)-induced insulin resistance. In the present study, we investigated effects of dual deletion of cytosolic 5’-nucleotidase IA (NT5C1A) and NT5C2 in mice. We found that NT5C1A/NT5C2 double-knockout (NT5C-dKO) mice exhibited a hypoglycemic phenotype, displaying enhanced skeletal muscle insulin action and reduced hepatic glucose production. In addition to potential involvement of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in their phenotype, NT5C-dKO mice displayed liver and skeletal muscle proteomic alterations most significantly linked to amino acid metabolism. Our findings support the development of novel anti-diabetic treatments using small-molecule cytosolic 5’-nucleotidase inhibitors.