bluuebunny/crossref_metadata_2025 huggingface dataset:
Sleep pressure propels cerebrovascular oscillations while sleep intensity correlates with respiration- and cardiac-driven brain pulsations
Authors: Ulv Larsen Sara Marie , Holst Sebastian Camillo , Olsen Anders Stevnhoved , Ozenne Brice , Zilstorff Dorte Bonde , Brendstrup-Brix Kristoffer , Weikop Pia , Pleinert Simone , Kiviniemi Vesa , Jennum Poul Jørgen , Nedergaard Maiken , Knudsen Gitte Moos
Published: October 2024

The waste-clearing flow of cerebrospinal fluid through the brain is driven by cerebrovascular, respiratory, and cardiac forces and is thought to be regulated by homeostatic sleep mechanisms. In a circadian-controlled sleep and sleep deprivation study, we investigated how heightened sleep pressure and slow-wave-rich sleep affect physiological brain oscillations in humans, as measured with accelerated neuroimaging. Our study also included a randomised, double-blind, placebo-controlled, cross-over administration of the adrenergic antagonist carvedilol, which allowed us to examine the effect of modulating cerebrovascular pulsatility. We report that sleep deprivation increases low frequency brain oscillations (LFOs) more than sleep does, with LFOs during sleep correlating with cognitive measures of sleep pressure. Conversely, slow-wave-rich NREM sleep (stages N2 and N3) enhances respiration- and cardiac-driven brain pulsations – particularly within grey and white matter. The strength of these brain pulsations escalates with sleep depth (N3 > N2) and correlates with EEG delta power. Carvedilol dampens LFOs, supporting that these reflect cerebrovascular oscillations. Altogether, our findings indicate that sleep pressure promotes cerebrovascular oscillations, while sleep slow waves synchronise with respiration- and cardiac-driven brain pulsations.

Graphical Abstract
Factors to Perceived Quality of Community Based Health Insurance Utilization Among Admitted Patients at St. Paul’s Hospital Millennium Medical College and AaBET Hospital, Addis Ababa, Ethiopia
Authors: Guddu Dessalegn Keney , Asres Yared Lasebew , Dullo Abrham Getachew , Shawel Tefaye Getachew
Published: October 2024

Background

Community based health insurance(CBHI) was introduced by the Ethiopian government in 2011 with the aim to improve access and quality of health care to the poor informal workers. But studies show that CBHI scheme based service quality is also reported to be low.On the other hand, there has been scarcity of data on barriers to quality of service utilized particularly at hospital level by the insured patients.

Objective

The aim of this study was to identify the barriers to good quality of community based health insurance utilization among admitted patients at St. Paul’s Hospital Millenium Medical College and AaBET Hospital, Ethiopia.

Methods

Cross sectional mixed design implementing quantitative from chart review as well as qualitative study using phenomenological design using focused group discussion and indepth interview involving the concerned CBHI stake holders was conducted from June1-July15,2023. Opendata kit (ODK) was used for quantitatie data collection and SPSS V25 and NVIVO V12 were used for data analysis.

Results

Total of 396 clients participated in the study. The mean age of study particiapnts was 43.64± 14.3 years. over all, 72.7% of admitted patients have got good quality community-based health insurance services.Factors significantly affecting quality of CBHI utilization were a clean and attractive hospital environment [AOR = 2.77:95% CI (1.24–6.165)], satisfied with community based health insurance [AOR = 2.45:95% CI (1.11–5.39)] at enrollment, good knowledge of the CBHI scheme [AOR = 1.97:95% CI (1.2– 3.23)], adequate availability of information on CBHI services in hospital [AOR = 2.37:95% CI (1.34–4.21)], higher family monthly income between 5251 and 7800 [AOR = 1.97:95% CI (1.2–3.23)], income more than 7801 birr [AOR = 5.3:95% CI (2.32–10.23)] respectively. The barriers to good quality utilization identified with qualitative exploration include difficulty in accessing hospital service areas(inconvenient) and information, limitation on the type of service provided by the scheme, poor knowledge of patients, overcrowding, long waiting times for chart activation, shortage of drugs and inpatient beds

Conclusion and recommendation

This study determined that the magnitude of good quality community-based health insurance services utilization was moderate compared to previous studies.Policymakers and stakeholders should improve monitoring of quality of CBHI services and further multicenter studies are necessary to improve service quality in public hospitals of Addis Ababa.
Parallel Analysis of Pharmaceuticals and Viruses in Wastewater: An Untargeted Approach to Tracking Population-Level Respiratory Illness Burden
Authors: Baumgartner Stephan , Salvisberg Michelle , Schmidhalter Patrick , Julian Timothy R , Ort Christoph , Singer Heinz
Published: October 2024

1

Wastewater-based surveillance is widely used for the detection and tracking of priority respiratory pathogens. In this study, pharmaceuticals are tracked in wastewater as an untargeted indicator of symptoms related to acute respiratory infections and influenza-like illnesses, such as coughing, fever, and pain, coincident to respiratory viral loads.

From January 2021 to June 2024, wastewater samples from ten wastewater treatment plants across Switzerland serving 23% of the population were analyzed. The analysis encompassed 15 pharmaceuticals and priority respiratory viruses SARS-CoV-2, respiratory syncytial virus, influenza A, and influenza B. Pharmaceutical data were further benchmarked against national clinical surveillance data on a broader range of respiratory pathogens.

The pharmaceutical compounds dextrorphan (indicative of dextromethorphan), pheniramine, clarithromycin, acetaminophen, and codeine showed a strong correlation with respiratory viral loads. This enabled the estimation of pathogen-specific and cumulative symptom burdens in the population. Additionally, notable increases in pharmaceutical loads without corresponding increases in viral loads in 2021 and 2024 signaled high community symptom burdens linked to unsurveilled pathogens.

The study demonstrates that pharmaceutical surveillance can inform respiratory disease burden and highlights the broader potential of integrated surveillance to assess population-scale symptoms, indicating emerging public health threats beyond those routinely monitored.
Academic stress through salivary biomarkers: A multivariate analysis of cortisol, IL-1β, CRP, and IgA levels and their variations as a function of sex
Authors: Klagges Rodrigo Castillo , Sáez Camila Pezo , Aguila Luis , Pantoja Verónica , Seguel Favián Treulen
Published: October 2024

Introduction

Academic stress can activate physiological changes mediated by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, triggering the release of biomarkers such as cortisol and proinflammatory cytokines. Although physiological stress has been studied in relation to different inducers and diseases, there is still a gap regarding the association of academic stress with biological markers. Thus, this study aimed to associate the levels of academic stress against biological markers isolated from saliva from undergraduates’ students.

Materials and methods

81 students (53 women and 28 men) were recruited and completed the SISCO inventory to determine the level of academic stress. The levels of cortisol, interleukin-1β (IL-1β), C-reactive protein (CRP) and immunoglobulin A (IgA) from saliva samples were determined by ELISA assays, and data were analyzed using ANOVA, Pearson correlation tests. A predictor model was estimated by lineal regression.

Results

Stress categorization following the SISCO inventory showed that 37% of the students grouped in the low stress level (<48%), 35% grouped in the moderate stress level (>49% <60%), and 28% in high stress level (>61% <100%). The levels of salivary markers were similar across stress categories, however the trends identified—such as the decrease in cortisol and the increase in pro-inflammatory markers in male participants categorized in the high stress group—suggest a possible association between these biomarkers with academic stress gender-dependent. The multivariable model including the 4 biomarkers resulted in R2= 0.14 with predictions that were roughly within +/-20% of stress levels.

Conclusion

In conclusion, no significance was found in the association of salivary biomarkers with academic stress levels. However, trends were observed with increasing levels of academic stress in men. The concentration of these biomarkers may be affected by sex. Further research will consider individual factors, longitudinal assessments, and the use of multiple psychometric tools to better define the interaction between academic stress and salivary biomarkers.
Chronic recording of brain activity in awake toads
Authors: Shaykevich Daniel A. , Woods Grace A. , O’Connell Lauren A. , Hong Guosong
Published: October 2024

Background

Amphibians represent an important evolutionary transition from aquatic to terrestrial environments and they display a large variety of complex behaviors despite a relatively simple brain. However, their brain activity is not as well characterized as that of many other vertebrates, partially due to physiological traits that have made electrophysiology recordings difficult to perform in awake and moving animals.

New method

We implanted flexible mesh electronics in the cane toad (Rhinella marina) and performed extracellular recordings in the telencephalon of anesthetized toads and partially restrained, awake toads over multiple days.

Results

We recorded brain activity over five consecutive days in awake toads and over a 15 week period in a toad that was anesthetized during recordings. We were able to perform spike sorting and identified single- and multi-unit activity in all toads.

Comparison with existing methods

To our knowledge, this is the first report of a modern method to perform electrophysiology in non-paralyzed toads over multiple days, though there are historical references to short term recordings in the past.

Conclusions

Implementing flexible mesh electronics in amphibian species will allow for advanced studies of the neural basis of amphibian behaviors.
Methylation Clocks Do Not Predict Age or Alzheimer’s Disease Risk Across Genetically Admixed Individuals
Authors: Cruz-González Sebastián , Gu Esther , Gomez Lissette , Mews Makaela , Vance Jeffery M. , Cuccaro Michael L. , Cornejo-Olivas Mario R. , Feliciano-Astacio Briseida E. , Byrd Goldie S. , Haines Jonathan L. , Pericak-Vance Margaret A. , Griswold Anthony J. , Bush William S. , Capra John A.
Published: October 2024

Epigenetic clocks that quantify rates of aging from DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer’s disease (AD), and environmental and social stressors. However, methylation clocks have not been validated in genetically diverse cohorts. Here we evaluate a set of methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and white co-horts. The clocks are less accurate at predicting age in genetically admixed individuals, especially those with substantial African ancestry, than in the white cohort. The clocks also do not consistently identify age acceleration in admixed AD cases compared to controls. Methylation QTL (meQTL) commonly influence CpGs in clocks, and these meQTL have significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk beyond their training populations and suggest avenues for improving their portability.
Unlocking the role of SH3PXD2B in epithelial-to-mesenchymal transition driving Breast Cancer Lung Metastasis
Authors: Das Subhajit , Khilwani Riya , Singh Shailza
Published: October 2024

Despite advancements in breast cancer treatment, metastasis remains a significant challenge, contributing to high mortality rates. This study investigates the mechanisms underlying breast cancer lung metastasis, with a particular emphasis on the role of SH3PXD2B in driving epithelial-to-mesenchymal transition. Here, we analyzed RNA sequencing data from CCLE and TCGA databases and characterized that SH3PXD2B expression is elevated in breast cancer (BC) and lung cancer (LC) tissues compared to non-transformed tissues. Bioinformatics analysis revealed that SH3PXD2B regulates several cellular processes and is associated with poor prognosis in breast cancer (BRCA) and lung adenocarcinoma (LUAD) patients. Functional experiments underscore that the upregulation of SH3PXD2B promoted BC and LC cell migration in vitro; however, its knockdown inhibited the effect. Mechanistically, the mass spectrometry analysis was utilized to pull down interacting partners of SH3PXD2B, and the findings were substantiated by immunoblotting. Additionally, our findings on immunofluorescence and gene expression analysis demonstrated the additive role of SH3PXD2B and migratory proteins in promoting breast cancer progression. Further, we performed bioluminescent IVIS imaging analysis to trace the metastatic spread of MDA-MB-468 cells and observed strong signals and a high degree of dissemination to distant organs. Collectively, our results highlight the importance of SH3 domains in aggravating breast transformation, which can therefore serve as a promising therapeutic strategy in counteracting breast-related malignancy.

Abstract Figure
Evolution of Key Factors Influencing Performance Across Phases in Junior Short Sprints
Authors: Oku Kyosuke , Kai Yoshihiro , Koda Hitoshi , Gonno Megumi , Tanaka Maki , Matsui Tomoyuki , Watanabe Yuya , Morihara Toru , Kida Noriyuki
Published: October 2024

Sprint performance plays a crucial role in various sports. Short sprints vary in court size and competitive characteristics but are common in many sports. Although the relationship between age and muscle strength has been explored in short sprints, there is limited understanding of how various physical factors interact, particularly concerning differences in the acceleration phase. This study examined the relationship between sprint times at 0‒2.5 m, 2.5‒5 m, and 5‒10 m intervals and various factors in junior athletes. Results indicated that sprint times increased with age, and is correlated with muscle strength and flexibility. Partial correlation analysis showed that faster times in the 0‒2.5 m interval were associated with higher hip flexibility; in the 2.5‒5 m interval, faster times were associated with higher core flexibility; and in the 5‒10 m interval, a relationship with standing long jump performance was confirmed. Furthermore, lower fat-free body weight translated to higher performance. In the acceleration phase of 10 m, flexibility immediately after the start and the subsequent horizontal propulsive force is important factors that are strongly related to performance change in each interval. The study results illuminate the mechanism behind short sprints in junior athletes and emphasize the importance of daily training, considering the sprint distance required for each sport.
Discovery and Biosynthesis of Sulfenicin and Its New-to-Nature Acylsulfenic Acid Functional Group
Authors: Xue Dan , Zou Hongbin , Lv Wei , Madden Michael D. , Lian Xiaoying , Xu Mingming , Pulliam Conor , Older Ethan A. , Hou Lukuan , Campbell Andrew , de Rond Tristan , Awakawa Takayoshi , Yuan Chunhua , Moore Bradley S. , Li Jie
Published: October 2024

Life’s organic molecules are built with diverse functional groups that enable biology by fine tuning intimate connections through time and space. As such, the discovery of new-to-nature functional groups can expand our understanding of the natural world and motivate new applications in biotechnology and biomedicine. Herein we report the genome-aided discovery of sulfenicin, a novel polyketide-nonribosomal peptide hybrid natural product from a marineStreptomycesbacterium bearing a unique acylsulfenic acid functionality. Through a series of heterologous biosynthesis, functional genetics, and enzymatic reconstitution experiments, we show that this previously described synthetic functional group is biologically assembled by a set of enzymes from both primary and secondary metabolism, including a novel flavin-dependentS-hydroxylase that hydroxylates a thiocarboxylic acid’s sulfur atom. While the sulfenicin biosynthetic gene cluster is presently without parallel in public databases, acylsulfenic acid-encoding enzymes are widely distributed in bacterial genomes, implying that this labile functional group may similarly have a broad distribution among specialized metabolites.
Exogenous selenium supplements reduce cadmium accumulation and restores micronutrient content in rice grains
Authors: Barman Falguni , Guha Titir , Kundu Rita
Published: October 2024

Purpose

Cadmium (Cd) contamination in agricultural soil and accumulation in rice poses serious threat to human health. It is reported that Selenium (Se) can mitigate the toxic effect of Cd in rice. But the underlying mechanism of Se preventing the Cd accumulation and restoring the micronutrient content in rice grains have not been studied before. Therefore, our main aim is to reduce Cd content and restore micronutrient content in rice grain and study the mechanism.

Methods

Two indigenous rice genotypes (Maharaj and Jamini) were exposed to 10 and 50 µM Cd in presence and absence of Se (5µM) with a control set and assessed for plant growth, biomass, Cd content, ROS and antioxidants for Cd induced toxicity and amelioration. Genes for micronutrient transporters were studied by RT-PCR. Grain Cd and micronutrient content and agronomic parameters were also studied.

Results

Se supplementation increased plant growth, biomass, and yield under Cd stress. SEM and EDX analysis revealed that Se-Cd complex formed on root surfaces restricted Cd uptake by the roots preventing root damage. Soil analysis confirmed that Se decreased Cd bioavailability, restricted root to shoot Cd translocation, ultimately reducing Cd accumulation and restoring micronutrients in grain. This was further validated by fluorescent Leadmium dye staining. In (Se+Cd) treated seedlings, up-regulation of S metabolism and nutrient transporter genes also contributed to the mitigation of Cd stress.

Conclusions

So, the Se supplementation can be considered as a cost-effective, ecofriendly and sustainable approach to produce Cd free rice cultivation in Cd polluted soil.
Pre-existing intratumoral stem-like CD8+T-cells drive radiotherapy-induced tumor control
Authors: Köksal Hakan , Herbst Michael , Perreira Paulo , Nater Marc , Regli Nicola , Boudjeniba Cheïma , Borgoni Nese Erdem , Cecconi Virginia , Broek Maries van den
Published: October 2024

CD8+T-cells are essential for spontaneous and therapy-induced restriction of tumor progression. Upon radiotherapy, these pre-existing CD8+T-cells expand rapidly after their initial decline and are essential and sufficient for early tumor control. Stem-like CD8+T-cells proliferate and differentiate into effector CD8+T-cells in response to radiotherapy and are thus key determinants of therapy efficacy. Our findings highlight the critical role of intratumoral stem-like CD8+T-cells in driving radiotherapy-induced anti-tumor immunity. Our study provides deeper insights into the dynamic behavior of CD8+T-cells and their critical involvement in tumor control following radiotherapy.
Investigating theDiuraphis noxia-Triticum aestivuminteraction using transcriptomics
Authors: Swiegers Hendrik W. , Foyer Christine H. , Botha Anna-Maria
Published: October 2024

Aphids often overcome host plant resistance by developing virulence. However, the underlying mechanisms and the precise modifications involved remain poorly understood. Additionally, the molecular response of resistant host plants during compatible (virulent aphid) and incompatible (avirulent aphid) interactions is another area requiring further investigation.

Here,Diuraphis noxia(Russian wheat aphid) biotypes of varying virulence were transferred from susceptibleTriticum aestivumto a near-isogenic line containing theDn7resistance gene. Transcriptomes of theD. noxiabiotypes and the resistant host were sequenced before and after the host shift.

Transcriptomic analysis indicated that theD. noxiabiotypes had unique responses which were involved in detoxification (e.g. L-xylulose reductase), membrane transport (e.g. Tert-1) and epigenetic regulation. In addition, many transposable elements were rapidly differentially regulated between biotypes and because of the host shift. In the host plant, all biotypes induced jasmonic acid signalling and terpenoid biosynthesis. However, the mono- and diterpenoid pathways were only upregulated following feeding by the biotypes avirulent toDn7and not SAMv2.

Rapid differential expression of transposons suggests a mechanism of adaptation for clonally reproducing aphids. Furthermore, SAMv2 may possess mechanisms to modulate the defence response ofDn7-containingT. aestivum.
A deep learning approach to detect and visualise sexual dimorphism in monomorphic species
Authors: Silva Nicolas J. , Ferreira André C. , Silva Liliana R. , Perret Samuel , Tieo Sonia , Renoult Julien P. , Covas Rita , Doutrelant Claire
Published: October 2024

Sex recognition is facilitated by dimorphism in some traits. However, humans often fail to find the traits that allow to distinguish between sexes in other species. Deep learning has the potential to surpass humans in identifying cryptic differences between sexes, but, so far, has rarely been used to assess sexual dimorphism. In this study, we evaluated (i) the ability of a fine-tuned classification neural network, EfficientNet, to find differences between sexes in a species that appears monomorphic to humans, the sociable weaver (Philetairus socius). We then assessed (ii) the benefits of Grad-CAM visualisation techniques to understand which parts of the individuals are used by the network to differentiate the sexes. We trained 10-folds cross-validation models on more than 4,500 pictures of the head from more than 1,300 individuals. Our results show that the network can predict sex of sociable weavers with an accuracy of 76%, which is considerably higher than humans’ performance, and that the model was similarly good at predicting females and males. When interpreting the probability of being classified to one sex, our results further reveal an effect of the interaction of sex with age on the confidence score of the models which shows that younger males are less masculine than older ones, and older females more masculine than younger ones. Finally, using Grad-CAM we found that the model mostly uses the beak region to predict the sex of individuals. Overall, this work shows that artificial intelligence has the potential to be a non-invasive sexing tool, surpassing human capabilities and aiding in pinpointing potential cryptic dimorphic body parts that have yet to be identified. In birds, half of the world’s species appear sexually monomorphic to humans, and re-evaluation of species dimorphism with this type of methods could deepen our understanding of the effect of selection on animal traits.
Citrate synthase improves sepsis-induced lung injury by reconstructing the mitochondrial tricarboxylic acid cycle of macrophages
Authors: Sun Jiaojiao , Jin Sihao , Wang Zhiqiang
Published: October 2024

Background

The destruction of mitochondrial function during sepsis-induced acute lung injury (sepsis-ALI) can lead to tissue cell damage and organ dysfunction. Citrate synthase (CS) may maintain cellular energy metabolism by enhancing the mitochondrial tricarboxylic acid cycle (TCA cycle) in macrophages.

Methods

76 healthy donors and 89 sepsis patients were included. The levels of CS were determined using ELISA. We established a cecal ligation and puncture (CLP) model of sepsis to evaluate the effects of CS on lung injury by lung macrophages-specific CS knockdown or CS inhibitors. Isolated mouse lung macrophages were stimulated with LPS to observe the impact of CS overexpression and knockdown on TCA cycle.

Results

In sepsis patients, CS was expressed at low levels and positively correlates with lung function parameters. In sepsis mice, knockdown CS or inhibiting its expression exacerbated lung injury and oxidative stress. In macrophages, inhibiting CS expression affected TCA cycle and worsened cell apoptosis, while overexpressing CS promoted TCA cycle, alleviating cell apoptosis, enhancing cellular energy production, and reducing oxidative stress levels. The supplementation of citric acid (a downstream metabolite of CS) helped alleviate mitochondrial damage and promotes the TCA cycle.

Conclusions

These results suggest that targeting CS may be a promising therapeutic approach for treating sepsis.
Effects of non-invasive brain stimulation on effective connectivity during working memory task in Neurofibromatosis Type 1 patients
Authors: Litwińczuk Marta Czime , Garg Shruti , Williams Stephen R. , Green Jonathan , Lea-Carnall Caroline , Trujillo-Barreto Nelson J
Published: October 2024

This study examined the effects of anodal transcranial direct current stimulation (atDCS) on effective connectivity during a working memory task. Eighteen adolescents with Neurofibromatosis Type 1 (NF1) completed a single□blind sham□controlled cross□over randomised atDCS trial. Dynamic causal modelling was used to estimate the effective connectivity between regions that showed working memory effects from the fMRI. Group-level inferences for between sessions (pre- and post-stimulation) and stimulation type (atDCS and sham) effects were carried out using the parametric empirical Bayes approach. A correlation analysis was performed to relate the estimated effective connectivity parameters of left dlPFC pre-atDCS and post-atDCS to the concentration of gamma-aminobutyric acid (GABA) measured via magnetic resonance spectroscopy (MRS-GABA). Next, correlation analysis was repeated using all working memory performance and all pre-atDCS and post-atDCS connectivity parameters. It was found that atDCS decreased average excitatory connectivity from left dorsolateral prefrontal cortex (dlPFC) to left superior frontal gyrus and increased average excitatory connectivity to left globus pallidus. Further, reduced average intrinsic (inhibitory) connectivity of left dlPFC was associated with lower MRS-GABA. However, none of the connectivity parameters of dlPFC showed any association with performance on a working memory task. These findings suggest that atDCS reorganised connectivity from frontal to fronto-striatal connectivity. As atDCS-related changes were not specific to the effect of working memory, they may have impacted general cognitive control processes. In addition, by reducing MRS-GABA, atDCS might make dlPFC more sensitive and responsive to external stimulation, such as performance of cognitive tasks.

Highlights

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atDCS was applied to left dlPFC in NF1 patients during working memory

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After atDCS, no effect on modulatory connectivity

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Evidence for increased N-back average connectivity from dlPFC to globus pallidus

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Less dlPFC MRS-GABA was associated with less dlPFC inhibition
Lactate production from lactose-rich wastewater: A comparative study on reactor configurations to maximize conversion rates and efficiencies
Authors: Temovska Monika , Hegner Richard , Ortiz-Ardila Andrés E. , Usack Joseph G. , Angenent Largus T.
Published: October 2024

About 90% of global lactate production is derived from bacterial fermentation of sugarsviapure cultures of homofermentative bacteria in batch mode. Acid whey, which is a wastewater from the yogurt industry with lactose and galactose as the main sugars, can be used as an alternative substrate for the commercial production of lactate. Operating open cultures of microbial consortia (i.e., reactor microbiomes) reduces the costs of lactate production by circumventing sterilization, while continuous operation achieves higher productivity at shorter production times. Homofermentation can be achieved by maintaining acidic and thermophilic conditions, while product formation in continuous systems can be increased with biomass retention strategies. To find the best reactor configuration for lactate production from acid whey, we operated three different reactor configurations:(1)an upflow anaerobic sludge blanket (UASB) reactor;(2)an anaerobic filter reactor (AFR); and(3)an anaerobic continuously stirred tank reactor (CSTR) with a hollow-fiber membrane module. We operated at different hydraulic retention times (HRTs) to find the optimum parameters to maximize the lactose and galactose-into-lactate (LG-into-LA) conversion efficiency. We did not use an inoculum but enriched the endogenous D-lactate-producingLactobacillusspp. that later dominated the reactor microbiomes (> 90% relative abundance). Undissociated lactic acid concentrations of more than 60 mmol C L-1inhibited the microbiomes. We alleviated the inhibition effect by shortening the HRT to 0.6 days and using diluted acid-whey substrate (1.67-fold dilution) to achieve almost complete conversion of the acid-whey sugars to lactate. At the 0.6-day HRT commencement, the AFR and CSTR performed better than the UASB reactor due to their better cell retention abilities. During the period between Day 365-384, we experienced an error in the pH control of the CSTR system during which the pH value dropped to 4.3. After this pH-error period, the LG-into-LA conversion efficiency for the CSTR considerably improved and surpassed the AFR. We achieved the highest lactate conversion rate of 1256 ± 46.3 mmol C L-1d-1(1.57 ± 0.06 g L-1h-1) at a LG-into-LA conversion efficiency of 82.2 ± 3.4% (in mmol C), with a yield of 0.85 ± 0.02 mmol C mmol C-1(product per consumed substrate) for the CSTR.
Computational generation of long-range axonal morphologies
Authors: Berchet Adrien , Petkantchin Remy , Markram Henry , Kanari Lida
Published: October 2024

Long-range axons are fundamental to brain connectivity and functional organization, enabling communication between different regions of the brain. Recent advances in experimental techniques have yielded a substantial number of whole-brain axonal reconstructions. While most previous computational generative models of neurons have predominantly focused on dendrites, generating realistic axonal morphologies is challenging due to their distinct targeting. In this study, we present a novel algorithm for axon synthesis that combines algebraic topology with the Steiner tree algorithm, an extension of the minimum spanning tree, to generate both the local and long-range compartments of axons. We demonstrate that our computationally generated axons closely replicate experimental data in terms of their morphological properties. This approach enables the generation of biologically accurate long-range axons that span large distances and connect multiple brain regions, advancing the digital reconstruction of the brain. Ultimately, our approach opens up new possibilities for large-scale in-silico simulations, advancing research into brain function and disorders.
Plasticity in cryoprotectant synthesis involves coordinated shunting away from pyruvate production
Authors: van der Burg Karin R. L. , Bozorgi Yasmin , Gyte Katie , Roe Amanda D. , Marshall Katie E.
Published: October 2024

Insects living in temperate regions often accumulate a large amount of glycerol during winter to avoid freezing. This seasonal accrual of glycerol is generally produced from glycogen reserves through the pentose phosphate pathway. An alternative pathway to produce glycerol is through glycolysis, normally used for pyruvate production for eventual ATP synthesis. Aside from seasonal accumulation, some insects will also rapidly increase glycerol production as a short-term response to a sudden cold event, thereby increasing cold hardiness when necessary. In the eastern spruce budwormChoristoneura fumiferana, this plasticity in cold hardiness is locally adapted, where northern populations produce more glycerol upon cold shock. Here we investigate how glycerol is produced during the rapid plastic response to fluctuating cold conditions, and whether this pathway could be a target of local adaptation. After a period of repeated cold exposure, we found evidence of increased enzyme activity and increased mRNA abundance of several proteins associated with glycolysis, and a downregulation in expression of glucose-6-phosphate dehydrogenase, associated with pentose phosphate. Pyruvate production is prevented through downregulation of glyceraldehyde-3-phosphate dehydrogenase. We found higher overall enzyme activity and glycerol accumulation in a northern population from Alberta, although there was no evidence of an interaction effect between population and cold shock treatment. This is one the first studies to show a mechanistic basis of such plasticity in cold hardiness.
Genetic and functional diversity of allorecognition receptors in the urochordate,Botryllus schlosseri
Authors: Rodriguez-Valbuena Henry , Salcedo Jorge , De Their Olivier , Flot Jean Francois , Tiozzo Stefano , De Tomaso Anthony W
Published: October 2024

Allorecognition inBotryllus schlosseriis controlled by a highly polymorphic locus (thefuhc), and functionally similar to missing-self recognition utilized by Natural Killer cells-compatibility is determined by sharing a self-allele, and integration of activating and inhibitory signals determines outcome. We had found these signals were generated by twofuhc-encoded receptors, calledfesteranduncle fester. Here we show thatfestergenes are members of an extended family consisting of >37 loci, and co-expressed with an even more diverse gene family-thefester co-receptors(FcoR). TheFcoRsare membrane proteins related tofester, but include conserved tyrosine motifs, including ITIMs and hemITAMs. Both genes are encoded in highly polymorphic haplotypes on multiple chromosomes, revealing an unparalleled level of diversity of innate receptors. Our results also suggest that ITAM/ITIM signal integration is a deeply conserved mechanism that has allowed convergent evolution of innate and adaptive cell-based recognition systems.
Identification and characterization of a wet adhesive protein extracted fromDreissena bugensis, the freshwater quagga mussel
Authors: Obille Angelico R. , Hasan Rida , Rees David J. , Ng Judith , Carneiro Karina M. M. , Sone Eli D.
Published: October 2024

Mechanisms of wet adhesion have been developed by several aquatic organisms over millions of years of evolutionary processes. Yet, the repertoire of synthetic biocompatible wet adhesive materials is still limited. In most marine bioadhesive proteins, 3,4-dihydroxyphenylalanine (DOPA) plays a significant role in strong interfacial interactions. The bioadhesive proteins in freshwater organisms are less well understood. The quagga mussel (Dreissena bugensis) is a notorious freshwater invasive species in the Great Lakes that attaches to a plethora of surfaces via a byssus. To determine the adhesive proteins in the quagga mussel byssus, we utilized quantitative proteomics to identify the proteins enriched at the byssus-substrate interface. Among the identified proteins was the Dbfp7 protein family. Dbfp7 is a small, polymorphic, and mostly disordered protein that lacks significant amounts of DOPA. Atomic force microscopy measurements of Dbfp7 confirm that this protein has similar adhesion energy to marine mussel adhesive proteins in aqueous conditions despite lacking DOPA. These results suggest that freshwater mussels may employ different mechanisms of adhesion compared to marine byssates. The inclusion of Dbfp7 to the library of known wet bioadhesive proteins – the first functionally characterized freshwater bioadhesive protein to our knowledge – will allow for a better understanding of the fundamental properties required to achieve biocompatible wet adhesion, a crucial step for the development of bio-inspired wet adhesive materials, such as improved medical adhesives.

Significance Statement

While many aquatic organisms evolved strategies to adhere to surfaces underwater, current synthetic biocompatible adhesives lack reliable adhesive strength in varying aqueous conditions. Investigating freshwater mussel adhesive proteins expands the current understanding of aquatic bioadhesion and offers potential advancements in wet adhesive technology. The discovery of a DOPA-deficient wet adhesive protein derived from the invasive quagga mussels presents a paradigm shift to the currently known mechanisms of byssal bioadhesion, thereby expanding the repertoire of wet adhesive strategies. Further, understanding the mechanism of adhesion employed by this biofouling species can help with the design of anti-fouling strategies to mitigate the impacts of these animals on the infrastructure and ecosystems in the Great Lakes and connected freshwater systems in North America.
Prolonged Hyperactivity Elicits Massive and Persistent Chloride Ion Redistribution in Subsets of Cultured Hippocampal Dentate Granule Cells
Authors: Takano Hajime , Hsu Fu-Chun , Coulter Douglas A.
Published: October 2024

Chloride ions play a critical role in neuronal inhibition through the activity of chloride-permeable GABAAreceptor channels. Ion transporters, chloride channels, and immobile ion species tightly regulate intracellular chloride concentrations. Several studies related to epilepsy suggest that chloride extrusion function may decrease in an activity-dependent manner. Consequently, it is crucial to investigate whether intense neuronal activity, as observed during status epilepticus, could lead to sustained increases in intracellular chloride levels in neurons, which in turn could contribute to epilepsy-associated hyperexcitability. This study utilized the chloride sensitive indicator (6-Methoxyquinolinio) acetic acid ethyl ester bromide (MQAE) combined with fluorescence lifetime imaging (FLIM) to examine whether application of the convulsant, pilocarpine, a muscarinic acetylcholine receptor agonist, could induce synchronous epileptiform activity and elevate intracellular chloride concentrations in hippocampal slice cultures. Using a Gaussian mixture model, we identified a multimodal distribution of intracellular chloride levels among neurons, with a significant subset of these cells exhibiting massive and prolonged (days) chloride accumulation. The combination of multicellular imaging and statistical analysis served as a powerful tool for studying the emergence of multiple, distinct populations of neurons in pathological conditions, in contrast to homogeneous populations evident under control conditions.

Highlights

Maintaining low [Cl−]inis important for inhibitory function, however, hyperactivity, such as that seen in epilepsy, may lead to elevated [Cl−]in.

Pilocarpine induces hyperactivity in dentate granule cells (DGCs) in hippocampal organotypic slice cultures.

Multicellular imaging using a chloride sensing dye with a fluorescence lifetime imaging approach revealed that [Cl−]inis elevated in a subpopulation of DGCs.

Gaussian mixture model analysis is a powerful tool for studying the emergence of cellular heterogeneity in a pathological condition.

Graphic Abstract
An AI-Driven Model of Consciousness, Its Disorders, and Their Treatment
Authors: Toker Daniel , Thum Jasmine A. , Guang Jing , Miyamoto Hiroyuki , Yamakawa Kazuhiro , Vespa Paul M. , Schnakers Caroline , Bari Ausaf A. , Hudson Andrew , Pouratian Nader , Monti Martin M.
Published: October 2024

Understanding the neural signatures of consciousness and the mechanisms underlying its disorders, such as coma and unresponsive wakefulness syndrome, remains a critical challenge in neuroscience. In this study, we present a novel computational approach for the in silico discovery of neural correlates of consciousness, the mechanisms driving its disorders, and potential treatment strategies. Inspired by generative adversarial networks, which have driven recent advancements in generative artificial intelligence (AI), we trained deep neural networks to detect consciousness across multiple brain areas and species, including humans. These networks were then integrated with a genetic algorithm to optimize a brain-wide mean-field model of neural electrodynamics. The result is a realistic simulation of conscious brain states and disorders of consciousness (DOC), which not only recapitulates known mechanisms of unconsciousness but also predicts novel causes expected to lead to these conditions. Beyond simulating DOC, our model provides a platform for exploring therapeutic interventions, specifically deep brain stimulation (DBS), which has shown promise in improving levels of awareness in DOC in over five decades of study. We systematically applied simulated DBS to various brain regions at a wide range of frequencies to identify an optimal paradigm for reigniting consciousness in this cohort. Our findings suggest that in addition to previously studied thalamic and pallidal stimulation, high-frequency stimulation of the subthalamic nucleus, a relatively underexplored target in DOC, may hold significant promise for restoring consciousness in this set of disorders.
SSTR2-targeted theranostics in hepatocellular carcinoma
Authors: Momeny Majid , AghaAmiri Solmaz , Vargas Servando Hernandez , Acidi Belkacem , Ghosh Sukhen C. , Bateman Tyler , Adams Jack , Khalaj Vahid , Kaseb Ahmed O. , Cao Hop S. Tran , Azhdarinia Ali
Published: October 2024

(1)

Background

While the clinical use of radiolabeled somatostatin analogs is established in neuroendocrine tumors, there is significant interest in expanding their use for other somatostatin receptor 2 (SSTR2)-expressing cancers. This study investigates the utility of SSTR2-targeted theranostics in hepatocellular carcinoma (HCC);

(2)

Methods

We measured SSTR2 expression in HCC cell lines and clinical samples using qRT-PCR, Western blot, and a public dataset. We evaluated [67Gallium]Ga-DOTATATE uptake, tested [177Lutetium]Lu-DOTATATE cytotoxicity, and assessed [68Gallium]Ga-DOTATATE tumor targeting in HCC animal models and a patient via PET/CT;

(3)

Results

SSTR2 expression was confirmed in HCC cell lines and clinical samples. Radioligand uptake studies validated SSTR2-mediated [67Gallium]Ga-DOTATATE uptake, and [177Lutetium]Lu-DOTATATE treatment reduced cell proliferation. [68Gallium]Ga-DOTATATE PET/CT scans detected tumors in animal models and spinal metastases in a patient with HCC;

(4)

Conclusion

These findings suggest for the first time that SSTR2-based theranostics could have strong implications for detection and treatment of HCC.

Simple Summary

This study investigates the use of SSTR2-targeted theranostics, combining diagnostic and therapeutic approaches, in hepatocellular carcinoma (HCC). We confirmed significant SSTR2 expression in HCC cells and patient samples, showing that radiolabeled compounds such as [67Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE, commonly used in neuroendocrine tumors, could also target HCC. In preclinical models and a patient case, PET/CT imaging and treatments demonstrated effective tumor detection and shrinkage. These findings suggest that SSTR2-targeted theranostics could offer a novel, targeted method for diagnosing and treating HCC, potentially improving outcomes for patients with this challenging cancer.
Art’s Hidden Topology: A window into human perception
Authors: Dmitruk Emil , Bajno Beata , Dreszer Joanna , Bałaj Bibianna , Ratajczak Ewa , Hajnowski Marcin , Janik Romuald A. , Kuś Marek , Kadir Shabnam N. , Rogala Jacek
Published: October 2024

Generations of researchers have sought a link between features of an artistic image and the audience’s experience. However, a direct link between the properties of an image and the responses evoked has still not been established. Given the importance of shape to human perception and artistic creation, it can be assumed that one of the most important aspects of an artistic image is the use of different visual structures. We show that a method from the field of computational topology, persistent homology, can be used to analyse properties of image structures and composition at multiple scales. In order to determine the reliability of this method as a tool for analysing visual artworks, we analysed two different sets of abstract paintings that revealed significant discrepancies in the eye tracking and electroencephalography (EEG) activity of viewers. Our research showed that our newly developed method using persistent homology, not only clearly distinguished between two sets of images, which was not possible with common statistical image properties, but also allowed us to map topological features onto gaze fixation heat maps.
Rigor and Reproducibility of Digital Spatial Profiling on Clinically Sourced Human Tissues
Authors: Smith Kelly D. , MacDonald James W. , Li Xianwu , Beirne Emily , Stewart Galen , Bammler Theo K. , Akilesh Shreeram
Published: October 2024

Spatial transcriptomic profiling enables precise quantification of gene expression with simultaneous localization of expression profiles onto tissue structures. This new technology promises to improve our understanding of the disease mechanisms. Therefore, there is intense interest in applying these methods in clinical trials or as laboratory developed tests to aid in diagnosis of disease. Before these technologies can be more broadly deployed in clinical research and diagnostics, it is necessary to thoroughly understand their performance in real world conditions. In this study, we vet technical reproducibility, data normalization methods and assay sensitivity focusing predominantly on one widely used spatial transcriptomic methodology, digital spatial profiling. Using clinically sourced human tissue specimens, we find that digital spatial profiling exhibits high rigor and reproducibility. Our approach lays the foundation for incorporation of digital spatial profiling methods into clinical workflows.
WNT and TGF-Beta Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Populations
Authors: Monge Cecilia , Waldrup Brigette , Carranza Francisco , Velazquez-Villarreal Enrique
Published: October 2024

One of the fastest-growing minority groups in the U.S. is the Hispanic/Latino population. Recent studies have shown how this population is being disproportionately affected by early-onset colorectal cancer (CRC). Compared to corresponding non-Hispanic White (NHW) patients, Hispanic/Latino patients have both higher incidence of disease and rates of mortality. Two well-established drivers of early-onset CRC in the general population are alterations in the WNT and TGF-Beta signaling pathways; however, the specific roles of these pathways in Hispanic/Latino are poorly understood. Here, we assessed CRC mutations in the WNT and TGF-Beta pathways by conducting a bioinformatics analysis using cBioPortal. Cases of CRC were stratified both by age and ethnicity: 1) early-onset was defined as <50 years vs. late-onset as ≥50 years; 2) we compared early-onset in Hispanics/Latinos to early-onset in NHWs. No significant differences were evident when we compared early-onset and late-onset CRC cases within the Hispanic/Latino cohort. These results are consistent with findings from large cohorts that do not specify ethnicity. However, we found significant differences when we compared early-onset CRC in Hispanic/Latino patients to early-onset CRC in NHW patients: specifically, alterations in the gene bone morphogenetic protein-7 (BMP7) were more frequent in early-onset CRC for the Hispanic/Latino patients. In addition to these findings, we observed that both NHW patients and Hispanic/Latino patients with early-onset disease had better clinical outcomes when there was evidence of WNT pathway alterations. Conversely, only the early-onset Hispanic/Latino population had improved outcomes when there was no evidence of TGF-Beta pathway alterations.In toto, these findings underscore how the WNT and TGF-Beta pathways may act differently in different ethnic groups who have early-onset CRC. These findings may set a stage for developing new therapies tailored for reducing cancer health disparities.