bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain-Derived Neurotrophic Factor (BDNF) Epigenomic Modifications and Brain-Related Phenotypes in Humans: A Systematic Review
Authors: Treble-Barna Amery , Heinsberg Lacey W. , Stec Zachary , Breazeale Stephen , Davis Tara S. , Kesbhat Aboli A. , Chattopadhyay Ansuman , VonVille Helena M. , Ketchum Andrea M. , Yeates Keith Owen , Kochanek Patrick M. , Weeks Daniel E. , Conley Yvette P.
Published: September 2022

Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1,701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.

Highlights

153 articles examined BDNF epigenomic modifications and brain-related phenotypes

Novel BDNF DNA Methylation Map allows users to interactively visualize CpGs

BDNF epigenomics lack robust/replicated results due to methodological heterogeneity
Psychotropic drugs in Portugal from 2016 to 2019: a nationwide pharmacoepidemiological profile
Authors: Madeira Luís , Queiroz Guilherme , Henriques Rui
Published: September 2022

Background

The prescription of psychotropic medication is rising in Europe along the last decade. Exploring consumption patterns in pre-pandemic times in Portugal, as well as relevant socio-demographic determinants, can help establish comparisons with worldwide patterns and support public health policies for mental health.

Methods

Descriptive, non-comparative cohort study, comprising full nationwide drug prescription records in Portugal along antidepressant, antipsychotic, and anxiolytic classes. Statistical analysis of prescription and consumption patterns according to reference dosages and guided by several criteria, including active substance, demographics, geography, associated medical specialty, and incurred costs.

Results

An increase of 29.6% and 34.7% in the consumption of antipsychotics and antidepressants between 2016 and 2019 is highlighted, reasonably accompanied by an increase of 37M Eur in total expenditure (>20M Eur in public copay) for these classes of drugs. Disparities in sociodemographic and geographical incidence are identified. Amongst other pivotal results, we further observed that 64% of psychotropic drug prescriptions are undertaken by general practitioners, while only 21% undertaken by neurological and psychiatric specialties.

Conclusion

Nationwide patterns of psychotropic drug prescription in Portugal reveal notable trends and determinants, establishing a reference point for cross-regional studies and being currently assessed at a national level to establish psychosocial initiatives and guidelines for the clinical practice and medical training.

Novelty

To our knowledge, first Portuguese psychopharmacoepidemiological study assessing: 1) economic correlates; 2) prescription patterns by medical specialty; 3) adherence rates and geographical determinants; 4) consumption patterns by active substance; and 5) systematic trends for the pre-pandemic period.
Long-Term Opioid Use and Emotional, Cognitive, and Sensorimotor Function in Chronic Back Pain
Authors: Rached Gaelle , Vigotsky Andrew D. , Branco Paulo , Jabakhanji Rami , Schnitzer Thomas J. , Vania Apkarian A. , Baliki Marwan N.
Published: September 2022

This study examines cognitive, emotional, sensory, and motor function in patients with chronic back pain (CBP) with and without long-term opioid exposure (CBP+O vs. CBP−O) and the influence of race and sex on these outcomes. We recruited 64 CBP+O (mean 7.4 years of opioid use) and 64 matched CBP−O. We collected pain intensity, pain duration, NIH Toolbox outcomes, and measures of opioid use: dosage, duration, blood levels, and withdrawal symptoms. We compared both groups to a normative sample, examined sex and race influences separately, and related CBP+O’s NIH Toolbox outcomes to their opioid use measures.

CBP+O reported greater pain interference and poorer emotional function. Sex moderated opioid exposure’s effects on cognitive performance and social satisfaction, while race moderated motor dexterity and taste outcomes. In CBP+O, 1) opioid dosage was associated with cognitive speed and sensory performance; 2) blood levels of opioids corresponded with poorer attention, motor endurance, and more severe stress and negative affect; 3) opioid use duration was related to improved working memory; while 4) higher withdrawal symptoms were associated with poorer cognitive performance, worsened negative emotions, and decreased grip strength.

The study demonstrates both positive and negative outcomes associated with long-term opioid use in CBP, highlighting the need to consider sex- and race-related factors when assessing function in this population.
Modulation of neural variability: Age-related reduction, GABAergic basis, and behavioral implications
Authors: Lalwani Poortata , Polk Thad A. , Garrett Douglas D.
Published: September 2022

Moment-to-moment neural variability has been shown to scale positively with the complexity of stimulus input. However, the mechanisms underlying the ability to align variability to input complexity are unknown. Using a combination of computational modeling, fMRI, MR spectroscopy, and pharmacological intervention, we investigated the role of aging and GABA in neural variability during visual processing. We found that participants expressed higher variability when viewing more complex stimuli. Such variability modulation was associated with higher baseline visual GABA levels and was reduced in older adults. When pharmacologically increasing GABA activity, we found that participants with lower baseline GABA levels showed higher drug- related increase in variability modulation, consistent with an inverted-U account. Finally, higher baseline GABA and variability modulation were jointly associated with better visual-discrimination performance. These results suggest that GABA plays an important role in how humans utilize neural variability to adapt to the complexity of the visual world.
The autism-associated Meis2 gene is necessary for cardiac baroreflex regulation in mice
Authors: Roussel J , Larcher R , Sicard P , Bideaux P , Richard S , Marmigère F , Thireau J
Published: September 2022

Recent understanding of Autism Spectrum Disorder (ASD) showed that peripheral primary mechanosensitive neurons involved in touch sensation and central neurons affected in ASD share transcriptional regulators. Mutant mice for ASD-associated transcription factors exhibit impaired primary tactile perception, and restoring those genes specifically in primary sensory neurons rescue some of the anxiety-like behavior and social interaction defects.

Interestingly, peripheral mechanosensitive sensory neurons also project to internal organs including the cardio-vascular system, and an imbalance of the cardio-vascular sympatho-vagal regulation is evidenced in ASD and intellectual disability. ASD patients have decreased vagal tone, suggesting dysfunction of sensory neurons involved in cardio-vascular sensing.

In light of our previous finding that the ASD-associated Meis2 gene is necessary for normal touch neurons development and function, we investigated here if its inactivation in mouse peripheral sensory neurons also affects cardio-vascular sympatho-vagal regulation and baroreflex. Combining echocardiography, pharmacological challenge, blood pressure monitoring and heart rate variability analysis, we found that Meis2 mutant mice exhibited a blunted vagal response independently of any apparent cardiac malformation. These results suggest that defects in primary sensory neurons with mechanosensitive identity could participate in the imbalanced cardio-vascular sympatho-vagal tone found in ASD patients, reinforcing current hypotheses on the role of primary sensory neurons in the etiology of ASD.
Machine learning reveals limited contribution of trans-only encoded variants to the HLA-DQ immunopeptidome by accurate and comprehensive HLA-DQ antigen presentation prediction
Authors: Nilsson Jonas Birkelund , Kaabinejadian Saghar , Yari Hooman , Peters Bjoern , Barra Carolina , Gragert Loren , Hildebrand William , Nielsen Morten
Published: September 2022

HLA class II antigen presentation is key for controlling and triggering T cell immune responses. HLA-DQ molecules, which are believed to play a major role in autoimmune diseases, are heterodimers that can be formed as both cis and trans variants depending on whether the α- and β-chains are encoded on the same (cis) or opposite (trans) chromosomes. So far, limited progress has been made for predicting HLA-DQ antigen presentation. In addition, the contribution of trans-only variants (i.e. variants not observed in the population as cis) in shaping the HLA-DQ immunopeptidome remains largely unresolved. Here, we seek to address these issues by integrating state-of-the-art immunoinformatics data mining models with large volumes of high-quality HLA-DQ specific MS-immunopeptidomics data. The analysis demonstrated a highly improved predictive power and molecular coverage for models trained including these novel HLA-DQ data. More importantly, investigating the role of trans-only HLA-DQ variants revealed a limited to no contribution to the overall HLA-DQ immunopeptidome. In conclusion, this study has furthered our understanding of HLA-DQ specificities and has for the first time cast light on the relative role of cis versus trans-only HLA-DQ variants in the HLA class II antigen presentation space. The developed method, NetMHCIIpan-4.2, is available athttps://services.healthtech.dtu.dk/services/NetMHCIIpan-4.2.
The effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and BDNF changes in chronically stressed adolescent rats
Authors: Haghipanah Motahareh , Saadat Maryam , Safarbalou Asal , Budde Thomas , Mohamed Wael , Sadat Afraz Elham , Moradikor Nasrollah
Published: September 2022

Chronic stress during the pre-pubertal period has adverse effects in developing neuropsychiatric disorders such as depression and anxiety. The administration of supplements with antioxidant properties may alleviate depression and anxiety behavior. This study investigated the effects of oral supplementation of Japanese sake yeast on anxiety, depressive-like symptoms, oxidative stress, and changes in brain-derived neurotropic factor (BDNF) in adolescence rats subjected to chronic stress.

In order to assess the effects of chronic stress, adolescent rats were grouped into one non-stressed control group (non-stress) and four different experimental groups. The other animals were subjected to stress and orally received normal saline (Control-stress), 15 mg/kg yeast (Stress-15), 30 mg/kg yeast (Stress-30) and 45 mg/kg yeast (Stress-45). Anxiety and depression-like behavior, BDNF levels, and oxidative stress markers were evaluated.

The rats exposed to stress exhibited anxiogenic and depression-like behavior as well as lower levels of BDNF and higher levels of oxidative markers compared with non-stressed rats (P<0.05). However, the oral supplementation of sake yeast decreased anxiogenic and depression-like behavior and oxidative indices, and also increased BDNF levels compared to stressed rats treated with saline in a dose-dependent manner (P<0.05).

In sum, stress caused anxiety and depression behavior, increased oxidative indices, and reduced BDNF levels while sake yeast alleviated adverse effects of stress on anxiety and depression behaviors, decreased oxidative markers, and increased BDNF levels.
Effects of Oxytocin Receptor Blockade on Dyadic Social Behavior in Monogamous and Non-MonogamousEulemur
Authors: Grebe Nicholas M. , Sheikh Alizeh , Ohannessian Laury , Drea Christine M.
Published: September 2022

A prominent body of research spanning disciplines has been focused on the potential underlying role for oxytocin in the social signatures of monogamous mating bonds. Behavioral differences between monogamous and non-monogamous vole species, putatively mediated by oxytocinergic function, constitute a key source of support for this mechanism, but it is unclear to what extent this hormone–behavior linkage extends to the primate order. In a preregistered experiment, we test if oxytocin receptor blockade affects affiliative behavior in mixed-sex pairs ofEulemur, a genus of strepsirrhine primate containing both monogamous and non-monogamous species. Inconsistent with past studies in monogamous voles or monkeys, we do not find confirmatory evidence inEulemurthat monogamous pairs affiliate more than non-monogamous pairs, nor that oxytocin receptor blockade of one pair member selectively corresponds to reduced affiliative or scent-marking behavior in monogamous species. We do, however, find exploratory evidence of a pattern not previously investigated: simultaneously blocking oxytocin receptors in both members of a monogamous pair predicts lower rates of affiliative behavior relative to controls. Our study demonstrates the value of non-traditional animal models in challenging generalizations based on model organisms, and of methodological reform in providing a potential path forward for behavioral oxytocin research.
Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells
Authors: Klein Fabian , Veiga-Villauriz Clara , Börsch Anastasiya , Maio Stefano , Palmer Sam , Zuklys Saulius , Calvo-Asensio Irene , Musette Lucas , Deadman Mary E. , Dhalla Fatima , White Andrea , Lucas Beth , Anderson Graham , Holländer Georg A.
Published: September 2022

The network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells’ individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.
Hotspot propensity across mutational processes
Authors: Arnedo-Pac Claudia , Muiños Ferran , Gonzalez-Perez Abel , Lopez-Bigas Nuria
Published: September 2022

The ability to study mutation rate variability at nucleotide resolution is impaired by the sparsity of observed mutational events across the genome. To circumvent this problem, here we investigated the propensity of 14 different mutational processes to form recurrently mutated sites across tumour samples (hotspots). We found that mutational signatures 1 (SBS1) and 17 (SBS17a and SBS17b) have the highest propensity to form hotspots, generating 5-78 times more than other common somatic mutational processes. After accounting for trinucleotide mutational probabilities, sequence composition and heterogeneity of mutation rates at 10 Kbp, the majority (89-95%) of SBS17a and b hotspots remain unexplained. This suggests that local genomic features play a significant role in SBS17a and b hotspot propensity, among which we identify CTCF binding as a minor contributor. In the case of SBS1, we demonstrate that including genome-wide distribution of methylated CpGs sites into our models can explain most (80-100%) of its hotspot propensity. We also observe an increased hotspot propensity of SBS1 in normal tissues from mammals, as well as inde novogermline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.
Whole-genome resequencing data support a single introduction of the invasive white pine sawfly, Diprion similis
Authors: Davis Jeremy S. , Sim Sheina , Geib Scott , Sheffler Brian , Linnen Catherine R.
Published: September 2022

Biological introductions are unintended “natural experiments” that provide unique insights into evolutionary processes. Invasive phytophagous insects are of particular interest to evolutionary biologists studying adaptation, as introductions often require rapid adaptation to novel host plants. However, adaptive potential of invasive populations may be limited by reduced genetic diversity—a problem known as the “genetic paradox of invasions”. One potential solution to this paradox is if there are multiple invasive waves that bolster genetic variation in invasive populations. Evaluating this hypothesis requires characterizing genetic variation and population structure in the introduced range. To this end, we assemble a reference genome and describe patterns of genetic variation in the introduced white pine sawfly, Diprion similis. This species was introduced to North America in 1914, where it has undergone a rapid host shift to the thin-needled eastern white pine (Pinus strobus), making it an ideal invasion system for studying adaptation to novel environments. To evaluate evidence of multiple introductions, we generated whole-genome resequencing data for 64 D. similis females sampled across the North American range. Both model-based and model-free clustering analyses supported a single population for North American D. similis. Within this population, we found evidence of isolation-by-distance and a pattern of declining heterozygosity with distance from the hypothesized introduction site. Together, these results support a single-introduction event. We consider implications of these findings for the genetic paradox of invasion and discuss priorities for future research in D. similis, a promising model system for invasion biology.
Sustainable reference points for multispecies coral reef fisheries
Authors: Zamborain-Mason Jessica , Cinner Joshua E. , MacNeil M. Aaron , Graham Nicholas A. J. , Hoey Andrew S. , Beger Maria , Brooks Andrew J. , Booth David J. , Edgar Graham J. , Feary David A. , Ferse Sebastian C. A. , Friedlander Alan M. , Gough Charlotte L. A. , Green Alison L. , Mouillot David , Polunin Nicholas V.C. , Stuart-Smith Rick D. , Wantiez Laurent , Williams Ivor D. , Wilson Shaun K. , Connolly Sean R.
Published: September 2022

Sustainably managing fisheries requires regular and reliable evaluation of stock status. However, most multispecies reef fisheries around the globe tend to be data-poor and lack research and monitoring capacity (e.g., long-term fishery data), preventing the estimation of sustainable reference points against which stocks can be assessed. Here, combining fish biomass data for more than 2000 coral reefs with catch estimates from 99 jurisdictions, we estimate site-specific sustainable reference points for coral reef fisheries and use these to assess the status of coral reef fish stocks. We reveal that more than half of jurisdictions with available information have stocks of conservation concern, having failed at least one fisheries sustainability benchmark. We quantify the trade-offs between biodiversity, mean fish length, and ecosystem functions relative to key benchmarks and highlight the ecological benefits of increasing sustainability. Our approach yields multispecies sustainable reference points for coral reef fisheries using environmental conditions, a promising means for enhancing the sustainability of the world’s coral reef fisheries.

Teaser

A global assessment of the sustainability of multispecies reef fisheries indicates that more than half of jurisdictions have failed at least one of two key sustainability benchmarks.
Common insecticide affects spatial navigation in bats at environmentally-realistic doses
Authors: Sandoval-Herrera Natalia , Lara-Jacobo Linda , Vargas Soto Juan S. , Faure Paul A. , Simmons Denina , Welch Kenneth
Published: September 2022

Bats are potentially exposed to pesticides via foraging in croplands. Common pesticides like organophosphates are neurotoxic for vertebrates and even low doses can impair essential processes such as locomotion and cognition. These sublethal effects are usually studied using molecular biomarkers with limited ecological relevance. Behavioral studies, in contrast, represent a more informative yet sensitive approach. Spatial navigation, for example, is an ecologically relevant behavior that is modulated by cellular pathways potentially targeted by neurotoxicants. We evaluated whether bats’ ability to memorize and navigate novel spaces was negatively affected by environmental relevant doses of chlorpyrifos, a common organophosphate insecticide. We also tested how the behavioral response correlated with molecular biomarkers. We orally dosed captive big brown bats (Eptesicus fuscus) with chlorpyrifos and studied exploratory behavior in two testing arenas. We evaluated similarity of stereotype flight trajectories in a flight tent, and associative memory in a Y-maze. We quantified brain cholinesterase (ChE) activity as a cellular biomarker and employed non-targeted proteomics as molecular biomarkers. Bats exposed to chlorpyrifos were less explorative and made more incorrect choices in the Y-maze, but the consistency of their flight trajectories was unaffected. Exposed bats had 30% lower ChE activity, showed down-regulation of proteins involved in memory (VP37D), learning and sound perception (NOX3). Other important nervous system processes such as synaptic function, plasticity, oxidative stress, and apoptosis were enriched in chlorpyrifos-exposed bats. These results support the sensitivity of behavior as a biomarker of toxicity and the importance of considering other levels of organization to help explain the mechanisms underlying altered behavior due to human activities.
Melanoma-intrinsic NR2F6 activity regulates anti-tumor immunity
Authors: Kim Hyungsoo , Feng Yongmei , Murad Rabi , Klepsch Victoria , Baier Gottfried , Ronai Ze’ev A
Published: September 2022

Nuclear receptors (NRs) have been implicated in tumor and immune cell regulation, most notably in hormone-dependent cancers. Here we identify a tumor-intrinsic function of the orphan nuclear receptor NR2F6 in regulating anti-tumor immunity. We selected NR2F6 among 48 candidate NRs based on an expression pattern in melanoma patient specimens coinciding with the IFNγ signature, which is associated with positive responses to immunotherapy and favorable patient outcomes. Further delay of melanoma development was achieved upon combination of NR2F6 inhibition with anti-PD1 therapy. NR2F6 loss in B16F10 and YUMM1.7 melanoma cells attenuated tumor development in immune-competent but not -incompetent mice via increased CD8+ T cell infiltration and activation. Inhibition of NACC1 and FKBP10, identified here as NR2F6 effectors, phenocopied NR2F6 loss. Remarkably, inoculation of NR2F6 KD melanoma cells into mice genetically deficient in NR2F6 further enhanced tumor growth inhibition. Identifying a tumor-intrinsic function of NR2F6 which complements its tumor-extrinsic role could be thus exploited to develop novel anti-cancer therapies.
Evaluating the Robustness of Connectivity Methods to Noise for In Silico Drug Repurposing Studies
Authors: Tham Nevin , Langley Sarah R
Published: September 2022

Drug repurposing is an approach to identify new therapeutic applications for existing drugs and small molecules. It is a field of growing research interest due to its time and cost effectiveness as compared withde novodrug discovery. One method for drug repurposing is to adopt a systems biology approach to associate molecular ‘signatures’ of drug and disease. Drugs which have an inverse relationship with the disease signature may be able to reverse the molecular effects of the disease and thus be candidates for repurposing. Conversely, drugs which mimic the disease signatures can inform on potential molecular mechanisms of disease. The relationship between these disease and drug signatures are quantified through connectivity scores. Identifying a suitable drug-disease scoring method is key for in silico drug repurposing, so as to obtain an accurate representation of the true drug-disease relationship. There are several methods to calculate these connectivity scores, notably the Kolmogorov-Smirnov (KS), Zhang and eXtreme Sum (XSum). However, these methods can provide discordant estimations of the drug-disease relationship and this discordance can affect the drug-disease indication. Using the gene expression profiles from the Library of Integrated Network-Based Cellular Signatures (LINCS) database, we evaluated the methods based on their drug-disease connectivity scoring performance. In this first-of-its-kind analysis, we varied the quality of disease signatures by using only highly differential genes or by the inclusion of non-differential genes. Further, we simulated noisy disease signatures by introducing varying levels of noise into the gene expression signatures. Overall, we found that there was not one method that outperformed the others in all instances, but the Zhang method performs well in a majority of our analyses. Our results provide a framework to evaluate connectivity scoring methods, and considerations for deciding which scoring method to apply in future systems biology studies for drug repurposing.
Real Time Breast Histology Image Classification with a Mobile Phone
Authors: Ikemura Kenji
Published: September 2022

Background

Deep learning, specifically convolutional neural network, has made a breakthrough in the complex task of computer image recognition. In this study, depthwise separable convolutional neural network (DS-CNN), MobileNets v1, was used in classifying breast cancer histology images on the computer and then on a mobile/smart phone, in real time. This study propose that DS-CNN can be applied for histological image analysis and its network can be transferred to a commercially available mobile phone for real-time histological image analysis captured through the mobile phone camera.

Method

This study utilizes the DS-CNN on breast cancer histology images downloaded from publicly available repository: https://rdm.inesctec.pt/dataset/nis-2017-003. Training set images are augmented by rotation and mirroring the images. DS-CNN is trained to classify breast tissue images between 4 categories: i) normal, ii) benign, iii) carcinoma in-situ, and iv) invasive carcinoma. Finally, the trained DS-CNN is deployed on to a mobile phone to classify the images captured through the mobile phone camera in real-time. The output on the mobile phone screen is the real-time image from the camera and its probability of it being one of the 4 categories (from high to low confidence). Accuracy of DS-CNN is assessed, both on the computer and on mobile phone, by whether its prediction with highest confidence matches the true class in the test dataset. Secondary results of sensitivity and specificities were calculated.

Results

The trained DS-CNN accuracy on the computer reached as high as 86% in 4 class classification. On the mobile phone, accuracy reached 67% in 4 class classification and 78% in 2 class classification (normal or benign vs. in situ or invasive). Training time took less than 30 min on 1.4 GHz Intel Core i5 dual-core CPU. Latency for evaluation on mobile phone was less than 1 second. Demo video of real time histology image analysis with mobile phone can be found here: https://www.youtube.com/watch?v=qx2CdrSuazg

Conclusion

DS-CNN is a fast and efficient neural network architecture that can learn to distinguish histological images even with limited sample size and computational power. The architecture can be deployed onto a mobile phone and maintain relatively good accuracy through the phone camera. It is likely that the accuracy can be increased by expanding the dataset and with updated CNN that are optimized for mobile phones.
Stratification of COVID-19 severity using SeptiCyte RAPID, a novel host immune response test
Authors: Gravrand Victor , Mellot François , Ackermann Felix , Ballester Marie-Christine , Zuber Benjamin , Kirk James T. , Navalkar Krupa , Yager Thomas D. , Petit Fabien , Pascreau Tiffany , Farfour Eric , Vasse Marc
Published: September 2022

SeptiCyte® RAPID is a gene expression assay measuring the relative expression levels of host response genes PLA2G7 and PLAC8, indicative of a dysregulated immune response during sepsis. As severe forms of COVID-19 may be considered viral sepsis, we evaluated SeptiCyte RAPID in a series of 94 patients admitted to Foch Hospital (Suresnes, France) with proven SARS-CoV-2 infection. EDTA blood was collected prospectively in the emergency department (ED) in 67 cases, in the intensive care unit (ICU) in 23 cases and in conventional units in 4 cases. SeptiScore (0-15 scale) increased with COVID-19 severity. Patients in ICU had the highest SeptiScores, producing values comparable to 8 patients with culture-confirmed bacterial sepsis. Receiver operating characteristic (ROC) curve analysis had an area under the curve (AUC) of 0.81 for discriminating patients requiring ICU admission from patients who were immediately discharged or from patients requiring hospitalization in conventional units. SeptiScores increased with the extent of the lung injury. For 68 patients, a chest computed tomography (CT) scan was performed within 24 hours of COVID-19 diagnosis. SeptiScore > 7 suggested lung injury ≥ 50 % (AUC = 0.86). SeptiCyte RAPID was compared to other biomarkers for discriminating Critical + Severe COVID-19 in ICU, versus Moderate + Mild COVID-19 not in ICU. The mean AUC for SeptiCyte RAPID was superior to that of any individual biomarker or combination thereof. In contrast to C-reactive protein (CRP), correlation of SeptiScore with lung injury was not impacted by treatment with anti-inflammatory agents. SeptiCyte RAPID can be a useful tool to identify patients with severe forms of COVID-19 in ED, as well as during follow-up.
Spinal cord stimulation restores sensation, improves function, and reduces phantom pain after transtibial amputation
Authors: Nanivadekar Ameya C. , Bose Rohit , Petersen Bailey A. , Okorokova Elizaveta V. , Sarma Devapratim , Farooqui Juhi , Dalrymple Ashley N. , Levy Isaiah , Helm Eric R. , Miele Vincent J. , Boninger Michael L. , Capogrosso Marco , Bensmaia Sliman J. , Weber Douglas J. , Fisher Lee E.
Published: September 2022

In the United States, over 1.5 million people live with lower-limb amputation. Existing prosthetic limbs do not restore somatosensory feedback from the limb, resulting in functional impairments including balance deficits and an increased risk of falls. Further, these prostheses do not alleviate the severe phantom limb pain that often follows amputation. Leveraging clinically available spinal cord stimulation electrodes, we designed a system that restores somatosensation in the missing limb, thereby improving balance and gait and reducing phantom limb pain. We show that spinal cord stimulation can evoke sensations in the missing foot and that we can control the location and intensity of those sensations. Further, by modulating stimulation intensity in real time based on signals from a wireless pressure-sensitive shoe insole, subjects exhibit improvements in functional measures of balance and gait stability. Finally, over the duration of the implant period, subjects experienced a clinically meaningful decrease in phantom limb pain. These combined results demonstrate that, with an electrode technology that is currently in widespread clinical use, our approach has the potential to become an important intervention for lower-limb amputation.
Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation
Authors: Theobald H. , Bejarano D.A. , Katzmarski N. , Haub J. , Schulte-Schrepping J. , Yu J. , Bassler K , Ćirović B. , Osei-Sarpong C. , Piattini F. , Vornholz L , Yu X. , Sheoran S. , Al Jawazneh A. , Chakarov S. , Haendler K , Brown G.D. , Williams D.L. , Bosurgi L. , Ginhoux F. , Ruland J. , Beyer M. , Greter M. , Kopf M. , Schultze J.L. , Schlitzer A.
Published: September 2022

The lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms which lead to the functional and developmental adaptation of lung-associated macrophages remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonal macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging and flow cytometric characterization paired to in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Dectin-1 - Card9 signaling-dependent monocyte-derived macrophages (MoAM). MoAMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic and produced large amounts of interleukin 6 upon restimulation. Myeloid cell specific ApoE ablation inhibited monocyte to MoAM differentiation dependent on M-CSF secretion, promoting MoAM cell death thus impeding MoAM maintenance. In vivo, β-glucan-elicited MoAMs limited the bacterial burden of Legionella pneumophilia post infection and ameliorated fibrosis severity in a murine fibrosis model. Collectively these data identify MoAMs that are generated upon environmental cues and ApoE as an important determinant for lung immune resilience.
Thalamic spindles and upstates, but not ripples, coordinate cortico-cortical and hippocampo-cortical co-ripples in humans
Authors: Dickey Charles W. , Verzhbinsky Ilya A. , Kajfez Sophie , Rosen Burke Q. , Gonzalez Christopher E. , Chauvel Patrick Y. , Cash Sydney S. , Pati Sandipan , Halgren Eric
Published: September 2022

The co-occurrence of brief ∼90Hz oscillations (co-ripples) may be important for integrating information across the neocortex and hippocampus and, therefore, essential for sleep consolidation, and cognition in general. However, how such co-ripples are synchronized is unknown. We tested if cortico-cortical and hippocampal-cortical ripple co-occurrences are due to the simultaneous direct propagation of thalamic ripples, and/or if they are coordinated by lower frequency thalamic waves. Using human intracranial recordings, we found that ripples are generated in the anterior and posterior thalamus during local spindles on the down-to-upstate transition in non-rapid eye movement sleep, with similar characteristics as cortical and hippocampal ripples. However, thalamic ripples only infrequently co-occur or phase-lock, with cortical and hippocampal ripples. In contrast, thalamo-cortical spindles and upstates were strongly coordinated with cortico-cortical and hippocampo-cortical co-rippling. Thus, while thalamic ripples may not directly drive multiple cortical or hippocampal sites at ripple frequency, thalamo-cortical spindles and upstates may provide the input necessary for spatially distributed co-rippling to integrate information in the cortex.

Significance Statement

Widespread networks of ∼90 Hz oscillations, called “ripples,” have recently been identified in humans and may help to bind information in the cortex and hippocampus for memory. However, it is not known whether the thalamus generates ripples, and if so whether they, or other thalamic waves, coordinate networks of co-occurring cortical and hippocampal ripples. Here, we show that the human thalamus generates ∼90 Hz ripples during NREM sleep. While thalamic ripples do not appear to directly synchronize ripple co-occurrence in the cortex and hippocampus, our data provide evidence that propagating thalamo-cortical spindles and upstates organize these networks. Thus, the thalamus projects slower frequency waves that modulate higher frequency hippocampo-cortical oscillatory networks for memory in humans.
Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes
Authors: Leblanc F. JA , Lettre G.
Published: September 2022

Most variants identified by genome-wide association studies (GWAS) are located in non-coding regions of the genome. While largely untested functionally, it is assumed that most of these GWAS variants modulate the activity of enhancers. Epigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues that include multiple cell-types. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities. Current best practices to infer the regulatory effect of candidate cis-regulatory elements (cCREs) in multiomic data involve removing biases associated with peak coverage and GC content by generating null distributions of matched ATACseq peaks drawn from different chromosomes. This is done under the assumption that the tested cis- and the matched trans-ATACseq peaks are uncorrelated. This strategy has been broadly adopted by popular single-nucleus multiomic workflows such as Signac. Here, we uncovered limitations and confounders of this approach. We found a strong loss of power to detect a regulatory effect for cCREs with high read counts in the dominant cell-type. We showed that this is largely due to cell-type-specific trans-ATACseq peak correlations creating bimodal null distributions. We tested alternative models and concluded that physical distance and/or the raw Pearson correlation coefficients are the best predictors for peak-gene links when compared to predictions from Epimap (e.g. CD14 area under the curve [AUC] = 0.51 with the method implemented in Signac vs 0.71 with the Pearson correlation coefficients) or validation by CRISPR perturbations (AUC = 0.63 vs 0.73).
Brain glucose metabolism and ageing: A 5-year longitudinal study in a large PET cohort
Authors: Pak Kyoungjune , Malén Tuulia , Santavirta Severi , Shin Seunghyeon , Nam Hyun-Yeol , De Maeyer Sven , Nummenmaa Lauri
Published: September 2022

Background

Ageing and clinical factors impact brain glucose metabolism. However, there is a substantial variation of the reported effects on brain glucose metabolism across studies due to the limited statistical power and cross-sectional study designs.

Methods

We retrospectively analyzed data from 441 healthy males (mean 42.8, range 38-50 years) who underwent health check-up program twice at baseline and 5-year follow-up. Health check-up program included 1) brain 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET), 2) anthropometric and body composition measurements, 3) blood samples, and 4) questionnaires for stress and depression. After spatial normalization of brain FDG PET scans, standardized uptake value ratio (SUVR) was measured from 12 region-of-interests. We used hierarchical clustering analysis to reduce their dimensionality before the Bayesian hierarchical modelling. Five clusters were established for predicting regional SUVR; 1) metabolic cluster (body mass index, waist-to-hip ratio, fat percentage, muscle percentage, homeostatic model assessment index-insulin resistance), 2) blood pressure (systolic, diastolic), 3) glucose (fasting plasma glucose level, HbA1c), 4): psychological cluster (stress, depression), and 5) heart rate. The effects of clinical variable clusters on regional SUVR were investigated using Bayesian hierarchical modelling with brms that applies the Markov-Chain Monte Carlo sampling tools.

Results

All the clinical variables except depression changed during the 5-year follow-up. SUVR decreased in caudate, cingulate, frontal lobe and parietal lobe and increased in cerebellum, hippocampus, occipital lobe, pallidum, putamen, temporal lobe and thalamus. SUVRs of thalamus, pallidum, hippocampus, putamen and parietal lobe were negatively associated with metabolic cluster and the effects of glucose on SUVRs varied across regions. SUVRs of thalamus, hippocampus, cingulate, cerebellum increased and those with occipital lobe decreased with heart rate. The effects of blood pressure and psychological cluster markedly overlapped with zero across regions.

Conclusion

Regionally selective decline in brain glucose utilization begins already in the middle age, while individual differences in brain glucose metabolism remain stable. In addition to ageing, brain glucose utilization is also associated with metabolic cluster, blood glucose levels and heart rate. These effects are also consistent over the studied period of 5 years in the middle adulthood.
A Scalable 3D High-Content Imaging Protocol for Measuring a Drug Induced DNA Damage Response Using Immunofluorescent Sub-nuclear γH2AX Spots in Patient Derived Ovarian Cancer Organoids
Authors: Keles Hakan , Schofield Christopher A. , Rannikmae Helena , Edwards Erin Elizabeth , Mohamet Lisa
Published: September 2022

The high morbidity rate of ovarian cancer has remained unchanged during the past four decades, partly due to lack of understanding of disease mechanisms and difficulties in developing new targeted therapies. Defective DNA damage detection and repair is one of the hallmarks of cancer cells and is a defining characteristic of ovarian cancer. Most in vitro studies to date, involve viability measurements at scale using relevant cancer cell lines, however, the translation to clinic is often lacking. The use of patient derived organoids is closing that translational gap yet the 3D nature of organoid cultures present challenges for assay measurements beyond viability measurements. In particular, high-content imaging has the potential for screening at scale providing a better understanding of mechanism of action of drugs or genetic perturbagens. In this study we report a semi-automated and scalable immunofluorescence imaging assay utilising the development of a 384-well plate based subnuclear staining and clearing protocol and optimisation of 3D confocal image analysis for studying DNA damage dose response in human ovarian cancer organoids. The assay was validated in four organoid models and demonstrated a predictable response to Etoposide drug treatment with lowest efficacy observed in the clinically most resistant model. This imaging and analysis method can be applied to other 3D organoid and spheroid models for use in high content screening.
A dialysis medium refreshment cell culture set-up for an osteoblast-osteoclast coculture
Authors: Vis M.A.M. , de Wildt B.W.M. , Ito K. , Hofmann S.
Published: September 2022

Culture medium exchange leads to loss of valuable auto- and paracrine factors produced by the cells. However, frequent renewal of culture medium is necessary for nutrient supply and to prevent waste product accumulation. Thus it remains the gold standard in cell culture applications. The use of dialysis as a medium refreshment method could provide a solution as low molecular weight molecules such as nutrients and waste products could easily be exchanged, while high molecular weight components such as growth factors, used in cell interactions, could be maintained in the cell culture compartment. This study investigates a dialysis culture approach for an in vitro bone remodeling model. In this model, both the differentiation of human mesenchymal stromal cells (MSCs) into osteoblasts and monocytes (MCs) into osteoclasts is studied. A custom-made simple dialysis culture system with a commercially available cellulose dialysis insert was developed. The data reported here revealed increased osteoblastic and osteoclastic activity in the dialysis groups compared to the standard non-dialysis groups, mainly shown by significantly higher alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activity, respectively. This simple culture system has the potential to create a more efficient microenvironment allowing for cell interactions via secreted factors in mono- and cocultures and could be applied for many other tissues.
The local tumor microbiome is associated with survival in late-stage colorectal cancer patients
Authors: Debelius Justine W. , Engstrand Lars , Matussek Andreas , Brusselaers Nele , Morton James T. , Stenmarker Margaretha , Olsen Renate S.
Published: September 2022

Objective

Colorectal cancer survival has been linked to the microbiome. Single organism analyses suggest Fusobacterium nucleatum as a marker of poor prognosis. However, in situ imaging of tumors demonstrate a polymicrobial tumor-associated community. To understand the role of these polymicrobial communities in survival, we performed an untargeted study of the microbiome in late-stage colorectal cancer patients.

Design

We conducted a nested case-control study in late-stage cancer patients undergoing resection for primary adenocarcinoma. The microbiome of paired colorectal tumor and adjacent tissue samples was profiled using 16S rRNA sequencing; we used compositionally aware ordination and differential ranking to profile the microbial community.

Results

We found a consistent difference in the microbiome between paired tumor and adjacent tissue, despite strong individual microbial identities. Tumors had higher relative abundance of genus Fusobacteria and Campylobacter at the expense of members of families Lachnospriaceae and Rumminococeae. Furthermore, a larger difference between normal and tumor tissue was associated with prognosis: patients with shorter survival had a larger difference between normal and tumor tissue. We found the difference was specifically related to taxa previously associated with cancer. Within the tumor tissue, we identified a 39 member community statistic associated with survival; for every log2 fold increase in this value, an individual’s odds of survival increased by 20% (OR survival 1.20; 95% CI 1.04, 1.33).

Conclusion

Our results suggest that a polymicrobial tumor-specific microbiome is associated with survival in late-stage colorectal cancer patients.