bluuebunny/crossref_metadata_2025 huggingface dataset:
Poor Physical Function Trajectory Predicts Impaired Patient Survival in Older Recipients of Deceased Donor Kidneys: A Prospective Cohort Study
Authors: Tsarpali Vasiliki , Midtvedt Karsten , Lønning Kjersti , Bernklev Tomm , Åsberg Anders , von der Lippe Nanna , Reisæter Anna Varberg , Heldal Kristian
Published: October 2022

Background.

Optimized health-related quality of life (HRQOL) at the time of kidney transplantation (KT) is associated with improved survival. In older KT recipients, we aimed to prospectively evaluate if HRQOL evolution during the first posttransplant year was associated with long-term patient survival.

Methods.

Recipients older than 65 y at KT who received an organ from a deceased brain-dead donor and survived >12 mo posttransplant were eligible. HRQOL was assessed pre-KT, at 10 wk, 6 mo, and 12 mo post-KT, using the Kidney Disease Quality of Life Short Form version 1.3 survey. A mixed-effect model was used to explore HRQOL evolution during the first posttransplant year in long-term survivors compared with nonsurvivors. Distinct HRQOL clusters were identified using a group-based trajectory modeling and their association with patient survival was investigated with Cox proportional hazard regression models.

Results.

We included 192 elderly recipients of deceased brain-dead donor kidneys who were transplanted from 2013 to 2020. Eleven died during the first year leaving 181 for evaluation (male, 125; mean age at KT, 72 y [65–84 y]). During a median observation time post-KT of 4.9 y (11.1–8.5 y), 57 recipients died. In survivors, all the generic and kidney-specific HRQOL domains substantially improved during the first year, whereas in nonsurvivors HRQOL deteriorated. Three longitudinal HRQOL trajectories indicating poor, fair, and good HRQOL evolution were identified. Poor physical function trajectory was significantly associated with higher mortality risk independent of covariates, as compared with good physical trajectory (hazard ratio, 2.38; 95% confidence interval, 1.15–5.01).

Conclusions.

In elderly KT recipients, detection of declining posttransplant physical function may imply impaired survival. Systematic HRQOL monitoring following KT provides added value when evaluating mortality and may guide therapeutic decisions.
Cefiderocol to manage chronic, multi-drug-resistant Burkholderia cepacia complex infection in a patient with cystic fibrosis: a case report
Authors: Nye Clemency , Duckers Jamie , Dhillon Rishi
Published: October 2022

In cystic fibrosis (CF) patients, Gram-negative

Burkholderia cepacia

complex (Bcc) infections are associated with recurrent pulmonary exacerbations. Bcc organisms are innately resistant to many antibiotics, and infection with

B. cenocepacia

is a contraindication to lung transplantation. We report a CF patient with severe lung disease, colonized with Bcc, with a history of around nine exacerbations per year for over 10 years, for whom antibiotic regimens (including targeted and broad-spectrum antibiotics) had not cleared infection or extended the interval between exacerbations. After receiving a 2 week cefiderocol-containing regimen, the patient remained stable for more than 5 months without the need for additional antibiotics or hospital admissions for respiratory exacerbations.
Both cell autonomous and non-autonomous processes modulate the association between replication timing and mutation rate
Authors: Vardi-Yaacov Oriya , Yaacov Adar , Rosenberg Shai , Simon Itamar
Published: October 2022

Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Mutation rates (MR) are known to be higher in late replication timing (RT) regions, but different processes can affect this association. Systematic analysis of the mutational landscape of 2,787 tumors from 32 tumor types revealed that the tumors can be divided into two groups with approximately one third of the tumor samples show weak association between replication timing and mutation rate. Analyses of the two groups revealed that both mutational signatures and mutation in genes involved in DNA replication, DNA repair and chromatin structure impact the association between RT and MR. Surprisingly, analysis of differentially expressed genes between the two groups revealed involvement of cell-cell communication and of the interaction with immune cells in modulating the effect of RT on MR. This provides evidence of the recently described association between mutagenic processes and the immune system in patients’ tumor samples.
Limitation of amino acid availability by bacterial populations during enhanced colitis in IBD mouse model
Authors: Richie Tanner G. , Heeren Leah , Kamke Abigail , Pogranichniy Sophia , Monk Kourtney , Summers Trey , Wiechman Hallie , Ran Qinghong , Sarkar Soumyadev , Plattner Brandon L. , Lee Sonny T. M.
Published: October 2022

Members of the Enterobacteriaceae family includingEscherichia coliare associated with persistent gut inflammation during disorders like inflammatory bowel disease. This is due to rapid microbial colonization during dysbiosis combined with pathogenic tendencies. We characterized the dysbiotic gut community, defined potential functional pathways, and investigated crosstalk between host gene expression and microbial detections in an intestinal inflammation murine model. Members of Enterobacteriaceae family and theEnterococcusgenus were highly detected in dysbiotic mice. These metagenome assembled genomes (MAGs) contained several virulence factors and metabolic pathways necessary to drive perpetual inflammation. Two Enterobacteriaceae MAGs with L-cysteine and L-taurine dioxygenases were strongly correlated with upregulation of the host gene CSAD, responsible for cysteine metabolism. Suggesting these bacteria compete with the host to utilize essential amino acids. We observed that bacterial isolates from dysbiotic mice displayed increased growth rates supplemented with L-cysteine, confirming that these microbes can utilize host nutrients to sustain inflammation.

In Brief

Inflammatory bowel disease is associated with an increase in Enterobacteriaceae andEnterococcusspecies, however the mechanisms are unclear. Richieet al. show that these bacterial populations use sulfur metabolism and tolerate host-derived immune-response, to drive host inflammation and fuel growth in the dysbiotic colon. Cultured isolates from dysbiotic mice indicated faster growth supplemented with L-cysteine, showing these microbes can utilize these essential host nutrients.

Highlights

Mice receiving native microbial FMT showed lower colon inflammation scores, higher microbial diversity, detections and gene expression similar to control mice.

Dysbiotic mice displayed increased colon inflammation, higher detection of potential pathogenic MAGs, and upregulation of cysteine dioxygenase and other inflammation response genes

MAGs assigned toEnterococcusand Enterobacteriaceae species were more frequently detected in dysbiotic mice, while almost absent in mice receiving FMT or control mice, they also contain several virulence factors and antibiotic resistance genes.

These MAGs also display potential functions of utilizing host products and nutrients including nitrate, cysteine, and taurine to further fuel their growth and metabolism, which results in persistent host intestinal inflammation.

Isolates in the Enterobacteriaceae family from dysbiotic mice utilize L-cysteine for growth, whereas isolates from FMT and control mice show no significant difference, indicating these bacteria can utilize the host derived cysteine.
Human hippocampal ripples signal encoding of episodic memories
Authors: Sakon John J. , Halpern David J. , Schonhaut Daniel R. , Kahana Michael J.
Published: October 2022

Recent human electrophysiology work has uncovered the presence of high frequency oscillatory events, termed ripples, during awake behavior. This prior work focuses on ripples in the medial temporal lobe (MTL) during memory retrieval. Few studies, however, investigate ripples during item encoding. Many studies have found neural activity during encoding that predicts later recall, termed subsequent memory effects (SMEs), but it is unclear if ripples during encoding also predict subsequent recall. Detecting ripples in 116 neurosurgical participants (n = 61 male) performing an episodic memory task, we find insignificant ripple SMEs in any MTL region, even as these regions exhibit robust high frequency activity (HFA) SMEs. Instead, hippocampal ripples increase during encoding of items leading to recall of temporally or semantically associated items, a phenomenon known as clustering. This subsequent clustering effect (SCE) arises specifically when hippocampal ripples occur during both encoding and retrieval, suggesting that ripples mediate the encoding and future reinstatement of episodic memories.
Polycomb Repressive Complex 1 subunit Cbx4 positively regulates effector responses in CD8 T cells
Authors: Melo G.A. , Xu T. , Calôba C. , Schutte A. , Brum G. , Passos T.O. , Higa L. , Gonçalves A. , Tanuri A. , Viola J.P.B. , Werneck M.B.F. , Nakaya H.I. , Pipkin M.E. , Martinez G.J. , Pereira R.M
Published: October 2022

CD8 T cell differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering the different players in regulating this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. Here, we show that Polycomb Repressive Complex (PRC)1 subunit Chromobox (Cbx)4 favors differentiation to effector CD8 T cells. Cbx4 deficiency in CD8 T cells induced transcriptional signature and phenotype of memory cells, increasing the formation of memory population during acute viral infection. It has been previously shown that besides chromodomain-mediated binding to H3K27me3, Cbx4 function as a SUMO E3 ligase in a SUMO interacting motifs (SIM)-dependent way. The overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in a SIM-dependent way and partially through its chromodomain. Our data revealed a novel role of a Polycomb group protein Cbx4 controlling CD8 T lymphocyte differentiation and indicates the SUMOylation process as a key molecular mechanism connected to chromatin modification in this process.

Understanding the epigenetic control of CTL differentiation is critical for the manipulation of these cells in immunotherapy protocols. This article demonstrates a novel role for Cbx4, a Polycomb-group protein, in supporting CD8 T cell commitment to an effector cell phenotype.
Reconstructing Monosynaptic Connectivity fromin vivoSpike Trains Using Deep Domain-Adaptive Matching
Authors: Sheng Kaiwen , Zhang Shanghang , Zhang Shenjian , He Yutao , Beau Maxime , Qu Peng , Liu Xiaofei , Zhang Youhui , Ma Lei , Du Kai
Published: October 2022

Inferring the monosynaptic connectivity of neural circuits fromin vivoexperimental data is essential for understanding the neural architecture that underpins behavior and cognition. However, advanced machine learning (ML) methods, especially deep learning, face significant challenges becausein vivoobservation is limited and incomplete, making it impractical to obtain ground-truth labeling. As a result, researchers typically rely on synthetic data generated by biophysical neural models for initial training. However, this reliance introduces the well-known “model mismatch” problem, whereby synthetic neural dynamics do not accurately reflect the complexity of real neural activity. To address these challenges, we introduce DeepDAM (Deep Domain Adaptive Matching), a flexible and robust framework that combines cutting-edge ML techniques with biophysical modeling. DeepDAM utilizes both synthetic data and unlabeledin vivorecordings to fine-tune deep neural networks (DNNs), so that the feature space of the DNNs is adaptively aligned with real neural dynamics, thus effectively mitigating the model mismatch problem and dramatically improving inference performance. We validated DeepDAM using extracellular recordings in the hippocampal CA1 region of freely behaving mice. Surprisingly, the framework achieved a Matthews correlation coefficient of 0.97–1.0 for monosynaptic connectivity inference, significantly outperforming existing methods (∼0.6–0.7). Additionally, our framework demonstrates robust adaptability to diverse experimental conditions and a broad range of neural properties and scales, including inference of single-neuron biophysics, synaptic dynamics, and microcircuit dynamics in multipleex vivoscenarios. This work marks a significant step towards the accurate and comprehensive reconstruction of functional mammalian brains by integrating data-driven ML techniques with first-principles insights.
A novel therapeutic approach of ultrasound stimulation to restore forelimb functions following cervical cord injury in rats
Authors: Ahmed Rakib Uddin , Alam Monzurul , Li Shuai , Palanisamy Poornima , Zhong Hui , Zheng Yong-Ping
Published: October 2022

Low-intensity pulsed ultrasound (LIPUS) stimulation has shown promising results in neurorehabilitation following a traumatic injury in brain and peripheral nerves. However, the effects of LIPUS stimulation in the injured neural circuit after spinal cord injury (SCI) are still unknown. We investigated the effects of LIPUS on forelimb functions in chronic cervical cord injured rats with and without a serotonergic agonist drug, Buspirone treatment. Twenty-six rats were trained for forelimb reaching and grasping followed by C4 dorsal funiculi crush injury. To deliver LIPUS, a silicon-coated ultrasound disc was implanted above the cervical cord and EMG electrodes were implanted into forelimb muscles. In two cohorts (LIPUS and LIPUS + Buspirone) rats were tested pre-, with- and post-ultrasound stimulation. In LIPUS group rats, fore-limb reaching and grasping success rates first increased and then dropped after 3 weeks while for combination of drug and LIPUS stimulation the score continued to increase. Furthermore, LIPUS stimulation alone did not result in any significant improvement of grip strength compared to the control and combined groups. The findings of this study indicated the potential of LIPUS in SCI recovery and offer a future research direction of a new neuromodulation method.
Optic radiations representing different eccentricities age differently
Authors: Kruper John , Benson Noah C. , Caffarra Sendy , Owen Julia , Wu Yue , Lee Aaron Y. , Lee Cecilia S. , Yeatman Jason , Rokem Ariel
Published: October 2022

The white matter pathways that carry information from the foveal, macular, and peripheral visual fields have distinct biological properties. The optic radiations (OR) carry foveal and peripheral information from the thalamus to the primary visual cortex (V1) through adjacent but separate pathways in the white matter. Here, we perform white matter tractometry using pyAFQ 1 on a large sample of diffusion MRI (dMRI) data from the UK Biobank dataset (UKBB; N=6021; age 45-81). We use pyAFQ to characterize white matter tissue properties in parts of the OR that transmit information about the foveal, macular, and peripheral visual fields, and to characterize the changes in these tissue properties with age. We find that (1) independent of age there is higher fractional anisotropy, lower mean diffusivity, and higher mean kurtosis in the foveal and macular OR than in peripheral OR, consistent with denser, more organized nerve fiber populations in foveal/parafoveal pathways, and (2) age is associated with increased diffusivity and decreased anisotropy and kurtosis, consistent with decreased density and tissue organization with adulthood aging. However, anisotropy in foveal OR decreases faster with age than in peripheral OR, while diffusivity increases faster in peripheral OR, suggesting foveal/peri-foveal OR and peripheral OR differ in how they age.
The impact of elevated aestivation temperatures on the behaviour of Bogong Moths (Agrotis infusa)
Authors: Lownds Rose M , Turbill Christopher , White Thomas E , Umbers Kate DL
Published: October 2022

Bogong moths are an iconic Australian insect that migrates annually in spring from low elevation locations in southern and eastern Australia to the Australian Alps where they aestivate during summer. As summer ends they make their return journey to the breeding grounds where they mate, lay eggs and die. Given the moth’s extreme behaviour in seeking out cool alpine habitat and with the knowledge that average temperatures at their aestivation sites are rising because of climate change, we assessed whether increased temperatures affect Bogong moth activity during aestivation. Our first hypothesis was that moth activity would be affected by temperature, and we found that moths were more active at higher temperatures, especially during the day, with near-constant activity at 15 °C at all times of day. Our second hypothesis was that moth mass would be different after aestivating at different temperatures for a week due to dehydration or consumption of body energy reserves. We found that moth wet mass loss increased with increasing temperature, but found no difference in dry mass among temperature treatments. Overall, our results suggest that Bogong moth activity will increase with increasing temperatures at their aestivation sites. The impact of warming on the success of individuals to complete their aestivation and journey back to their lowlands to breed should be investigated as a matter of priority to better understand the impact of changes in aestivation behaviour on population dynamics.
Hearing the World Differently: Examining Predictive Coding Accounts of Autism Using MEG
Authors: Rapaport Hannah , Pellieano Elizabeth , Seymour Robert A. , Benikos Nicholas , He Wei , Sun Yanan , Brock Jon , Sowman Paul F.
Published: October 2022

Predictive coding accounts of autism suggest that autistic perception is characterised by divergent precision weighting. The precise nature of this divergence, however, is debated. Here, we sought to disentangle competing predictive coding accounts of autism by testing them at a neural level. To this end, we used paediatric magnetoencephalography to record the auditory evoked fields of 10 young autistic children (M = 6.2 years, range = 4.2– 8.6) and 63 neurotypical children (M = 6.1 years, range = 3.0– 9.8) as they listened to a roving auditory oddball paradigm. For each participant, we subtracted the evoked responses to the ‘standard’ from the ‘deviant’ pure tones to calculate the mismatch field ‘MMF’: an electrophysiological component that is widely interpreted as a neural signature of predictive coding. We found no significant differences between the two groups’ MMF amplitudes, p > .05. An exploratory analysis indicated larger MMF amplitudes in most of the autistic children compared to their average-age-matched neurotypical counterparts, p < .05. We interpret these findings as preliminary evidence in support of the ‘inflexibly high prior and sensory precision’ account, and against the ‘inflexibly low prior-relative-to-sensory precision’ accounts of autistic perception.

Highlights

We used paediatric MEG to compare autistic and neurotypical MMFs amplitudes.

Exploratory case-cohort analyses revealed mostly larger MMFs in autistic cases.

Larger MMFs support the notion of precise, inflexible prediction errors in autism.
Sampling bias in large healthcare claims databases
Authors: Dahlen Alex , Charu Vivek
Published: October 2022

Healthcare claims databases that aggregate claims from multiple commercial insurers are increasingly being used to generate real-world evidence. These databases represent a non-random sample of the underlying population, but often little attention is paid to the inherent sampling bias within the data, and how it might affect results. As an illustrative example, we characterize variation in sampling in Optum's de-identified Clinformatics Data Mart Database (CDM) at the zip-code level in 2018, and identify socioeconomic and demographic factors associated with inclusion.
Digital nanoreactors for control over absolute stoichiometry and spatiotemporal behavior of receptors within lipid bilayers
Authors: Maingi Vishal , Zhang Zhao , Thachuk Chris , Sarraf Namita , Chapman Edwin R. , Rothemund Paul W.K.
Published: October 2022

Interactions between membrane proteins are essential for cell survival and proper function, but the structural and mechanistic details of these interactions are often poorly understood. Even the biologically functional ratio of protein components within a multi-subunit membrane complex—the native stoichiometry—is difficult to establish. We have demonstrated digital nanoreactors that can control interactions between lipid-bound molecular receptors along three key dimensions: stoichiometric, spatial, and temporal. Each nanoreactor is based on a DNA origami ring, which both templates the synthesis of a liposome and provides tethering sites for DNA-based receptors. Receptors are released into the liposomal membrane using strand displacement and a DNA logic gate measures receptor heterodimer formation. High-efficiency tethering of receptors enables the kinetics of receptors in 1:1 and 2:2 absolute stoichiometries to be observed by bulk fluorescence in a plate reader which in principle is generalizable to any ratio. Similar ‘single molecule in bulk’ experiments using DNA-linked membrane proteins could determine native stoichiometry and the kinetics of membrane protein interactions for applications ranging from signalling research to drug discovery.
Simple scaling laws control the genetic architectures of human complex traits
Authors: Simons Yuval B. , Mostafavi Hakhamanesh , Smith Courtney J. , Pritchard Jonathan K. , Sella Guy
Published: October 2022

Genome-wide association studies have revealed that the genetic architectures of complex traits vary widely, including in terms of the numbers, effect sizes, and allele frequencies of significant hits. However, at present we lack a principled way of understanding the similarities and differences among traits. Here, we describe a probabilistic model that combines mutation, drift, and stabilizing selection at individual sites with a genome-scale model of phenotypic variation. In this model, the architecture of a trait arises from the distribution of selection coefficients of mutations and from two scaling parameters. We fit this model for 95 diverse, highly polygenic quantitative traits from the UK Biobank. Notably, we infer similar distributions of selection coefficients across all these traits. This shared distribution implies that differences in architectures of highly polygenic traits arise mainly from the two scaling parameters: the mutational target size and heritability per site, which vary by orders of magnitude across traits. When these two scale factors are accounted for, the architectures of all 95 traits are nearly identical.
Anesthesia-related brain microstructure modulations detected by diffusion MRI
Authors: Lindhardt Thomas Beck , Østergaard Leif , Liang Zhifeng , Hansen Brian
Published: October 2022

Brain clearance has been found to be greatly enhanced during sleep and anesthesia. Studies using optical microscopy have attributed this to an anesthesia-related expansion of the brain’s extra-cellular space. These results, however, have been based on invasive experiments with a limited field of view. Here, we employ diffusion kurtosis magnetic resonance imaging to assess brain microstructure in the awake and anesthetized mouse brain. We find both mean diffusivity and mean kurtosis to be significantly decreased in the anesthetized mouse brain compared to the awake state. This effect is observed in both gray matter and white matter. Our findings are consistent with the reports of brain ECS volume increase in sleep and anesthesia. Based on simple simulations, we discuss how an ECS volume increase (cell shrinkage) during sleep and anesthesia can coexist with other aspects of brain physiology. Our study demonstrates that diffusion kurtosis MRI can be used in the study of the glymphatic system. Importantly, our study shows an overlooked effect of anesthesia on brain microstructure which is relevant to preclinical MRI as a whole.
From Genomics to Integrative Taxonomy? The Case Study of Pocillopora Corals
Authors: Oury Nicolas , Noël Cyril , Mona Stefano , Aurelle Didier , Magalon Helene
Published: October 2022

With the advent of genomics, sequencing thousands of loci from hundreds of individuals now appears feasible at reasonable costs, allowing complex phylogenies to be resolved. This is particularly relevant for cnidarians, for which insufficient data due to the small number of currently available markers, coupled with difficulties in inferring gene trees and morphological incongruences, encrypts species boundaries, thereby blurring the study and conservation of these organisms. Yet, can genomics alone be used to delimit species in an integrative taxonomic context? Here, focusing on the coral genus Pocillopora, which plays key roles in Indo-Pacific reef ecosystems but has challenged taxonomists for decades, we explored and discussed the usefulness of multiple criteria (genetics, morphology, biogeography and symbiosis ecology) to delimit species of this genus. Phylogenetic inferences, clustering approaches and species delimitation methods based on genome-wide single-nucleotide polymorphisms (SNPs) were first used to resolve Pocillopora phylogeny and propose genomic species hypotheses from 356 colonies sampled across the Indo-Pacific (western Indian Ocean, tropical southwestern Pacific and south-east Polynesia). These species hypotheses were then compared to previous genetic evidences, as well as to evidences based on morphology, biogeography and symbiosis. Genomics allowed to delimit 21 species hypotheses where only seven are currently recognised based on current taxonomy. Moreover, 13 species were strongly supported by all approaches, either confirming their currently recognised species status, or supporting the presence of new species that need to be formally described. Some of the other genomic species hypotheses were supported by biogeographic or symbiosis evidences, but additional investigations are needed to state on their species status. Altogether, our results support (1) the obsolescence of macromorphology (i.e., overall colony and branches shape) but the relevance of micromorphology (i.e., corallite structures) to refine Pocillopora species limits, (2) the need to identify molecularly species prior to their study, as morphology can blur species identification on the field, (3) the relevance of the mtORF (coupled with other markers in some cases) as a diagnostic marker of most species, and (4) the need for a taxonomical revision in the Pocillopora genus. These results give new insights into the usefulness of multiple criteria for resolving Pocillopora species limits and will ultimately provide helpful insights for the conservation of the species from this scleractinian genus. [biogeography; cryptic species delimitation; Indo-Pacific; microsatellites; morphology; phylogenetics; single-nucleotide polymorphism (SNP); Symbiodiniaceae]
Predicting the temperature-driven development of stage-structured insect populations with a Bayesian hierarchical model
Authors: Studens Kala , Bolker Ben , Candau Jean-Noel
Published: October 2022

The management of forest pests relies on an accurate understanding of the species’ phenology. Thermal performance curves (TPCs) have traditionally been used to model insect phenology; many such models have been proposed and fitted to data from both wild and laboratory-reared populations, most of which have used maximum likelihood estimation (MLE). Analyses typically present point estimates of parameters with confidence intervals, but estimates of the correlations among TPC parameters are rarely provided. Neglecting aspects of model uncertainty such as correlation among parameters may lead to incorrect confidence intervals of predictions. This paper implements a Bayesian hierarchical model of insect phenology incorporating individual variation, quadratic variation in development rates across insects’ larval stages, and non-parametric adjustment terms that allow for deviations from a parametric TPC. We use Hamiltonian Monte Carlo (HMC) for estimation; the model is fitted to a laboratory-reared spruce budworm population as a case study. We assessed the accuracy of the model using stratified, 10-fold cross-validation. Using the posterior samples, we found prediction intervals for spruce budworm development for a given year.
Epigenetics of post-operative delirium: A genome-wide DNA methylation study of neurosurgery patients
Authors: Yamanashi Takehiko , Crutchley Kaitlyn J. , Wahba Nadia E. , Nagao Takaaki , Marra Pedro S. , Akers Cade C. , Sullivan Eleanor J. , Iwata Masaaki , Howard Mathew A , Cho Hyunkeun R. , Kawasaki Hiroto , Hughes Christopher G. , Pandharipande Pratik P. , Hefti Marco M. , Shinozaki Gen
Published: October 2022

Aims

There is no previous study demonstrating the differences of genome-wide DNA methylation (DNAm) profiles between patients with and without postoperative delirium (POD). We aimed to discover epigenetic (DNAm) markers that are associated with POD in blood obtained from patients before and after neurosurgery.

Methods

Pre- and post-surgical blood DNA samples from 37 patients, including 10 POD cases, were analyzed using the Illumina EPIC array genome-wide platform. We examined DNAm differences in blood from patients with and without POD. Enrichment analysis with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes terms were also conducted.

Results

When POD cases were tested for DNAm change before and after surgery, enrichment analyses showed many relevant signals with statistical significance in immune response related-pathways and inflammatory cytokine related-pathways such as “cellular response to cytokine stimulus”, “regulation of immune system process”, “regulation of cell activation”, and “regulation of cytokine production”. Furthermore, after excluding the potential effect of common factors related to surgery and anesthesia between POD cases and non-POD controls, the enrichment analyses showed significant signals such as “immune response” and “T cell activation”, which are same pathways previously identified from an independent non-surgical inpatient cohort. Conclusions: Our first genome-wide DNAm investigation of POD showed promising signals related to immune response, inflammatory response and other relevant signals considered to be associated with delirium pathophysiology. Our data supports the hypothesis that epigenetics are playing an important role in pathophysiological mechanism of delirium and suggest the potential usefulness of epigenetics based biomarker of POD.
Chromosome assembly for the meagre, Argyrosomus regius, reveals species adaptations and sciaenid sex-related locus evolution
Authors: Papadogiannis Vasileios , Manousaki Tereza , Nousias Orestis , Tsakogiannis Alexandros , Kristoffersen Jon B. , Mylonas Constantinos C. , Batargias Constantinos , Chatziplis Dimitrios , Tsigenopoulos Costas S.
Published: October 2022

The meagre, Argyrosomus regius, has recently become a species of increasing economic interest for the Mediterranean aquaculture and there is ongoing work to boost production efficiency through selective breeding. Access to the complete genomic sequence will provide an essential resource for studying quantitative trait-associated loci and exploring the genetic diversity of different wild populations and aquaculture stocks in more detail. Here, we present the first complete genome for A. regius, produced through a combination of long and short read technologies and an efficient in-house developed pipeline for assembly and polishing. Scaffolding using previous linkage map data allowed us to reconstruct a chromosome level assembly with high completeness, complemented with gene annotation and repeat masking. We use this new resource to study the evolution of the meagre genome and other Sciaenids, via a comparative analysis of 25 high-quality teleost genomes. Combining a rigorous investigation of gene duplications with base-wise conservation analysis, we identify candidate loci related to immune, fat metabolism and growth adaptations in the meagre. Following phylogenomic reconstruction, we show highly conserved synteny within Sciaenidae. In contrast, we report rapidly evolving syntenic rearrangements and gene copy changes in the sex-related dmrt1 neighbourhood in meagre and other members of the family. These novel genomic datasets and findings will add important new tools for aquaculture studies and greatly facilitate husbandry and breeding work in the species.
Does prefrontal connectivity during task switching help or hinder children’s performance?
Authors: Schwarze Sina A. , Laube Corinna , Khosravani Neda , Lindenberger Ulman , Bunge Silvia A. , Fandakova Yana
Published: October 2022

The ability to flexibly switch between tasks is key for goal-directed behavior and continues to improve across childhood. Children’s task switching difficulties are thought to reflect less efficient engagement of sustained and transient control processes, resulting in lower performance on blocks that intermix tasks (sustained demand) and trials that require a task switch (transient demand). Sustained and transient control processes are associated with frontoparietal regions, which develop throughout childhood and may contribute to task switching development. We examined age differences in the modulation of frontoparietal regions by sustained and transient control demands in children (8–11 years) and adults. Children showed greater performance costs than adults, especially under sustained demand, along with less upregulation of sustained and transient control activation in frontoparietal regions. Compared to adults, children showed increased connectivity between the inferior frontal junction (IFJ) and lateral prefrontal cortex (lPFC) from single to mixed blocks. For children whose sustained activation was less adult-like, increased IFJ-lPFC connectivity was associated with better performance. Children with more adult-like sustained activation showed the inverse effect. These results suggest that individual differences in task switching in later childhood at least partly depend on the recruitment of frontoparietal regions in an adult-like manner.
Loss of motor cortical inputs to the red nucleus after central nervous system disorders in non-human primates
Authors: Borgognon Simon , Rouiller Eric M.
Published: October 2022

The premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal pathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of M1 and PM to corticorubral projections as well as its plasticity following motor disorders or injuries are not known in non-human primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in intact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson’s disease (PD)-like symptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys were injected with the biotinylated dextran amine (BDA) anterograde tracer either in PM or in M1. We developed a semi-automated algorithm to reliably detect and count axonal boutons within the magnocellular (mRN) and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and M1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. PM’s projection to the ipsilateral pRN is denser than M1’s, matching previous observations for the corticotectal, corticoreticular, and corticosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to functional recovery after SCI, PD and MCI, by reducing direct cortical influence. This reduction possibly privileges direct access to the final output motor system, via emphasis on the direct corticospinal projection.
Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation
Authors: van Tartwijk Francesca W. , Wunderlich Lucia C.S. , Mela Ioanna , Makarchuk Stanislaw , Jakobs Maximilian A.H , Qamar Seema , Franze Kristian , Schierle Gabriele S. Kaminski , St George-Hyslop Peter H. , Lin Julie Qiaojin , Holt Christine E. , Kaminski Clemens F.
Published: October 2022

Aberrant condensation and localisation of the RNA-binding protein fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is also associated with cytoskeletal defects, genetically and through observations of compromised axonal transport. Here, we asked whether compromised axonal cytoskeletal organisation is an early feature of FUS-associated ALS/FTD. We used an ALS-associated mutant FUS(P525L) and the FTD-mimic hypomethylated FUS, FUS(16R), to investigate the common and distinct cytoskeletal changes found in these two reportedXenopusmodels. Combining a novel atomic force microscopy (AFM)-based approach forin vitrocytoskeletal characterisation andin vivoaxonal branching analysis, we found that mutant FUS reduced actin density in the dynamically remodelling growth cone, and reduced axonal branch complexity. We furthermore found evidence of an axon looping defect for FUS(P525L). Therefore, we show that compromised actin remodelling is potentially an important early event in FUS-associated pathogenesis.

Abstract Figure
EMPIAR: The Electron Microscopy Public Image Archive
Authors: Iudin Andrii , Korir Paul K. , Somasundharam Sriram , Weyand Simone , Cattavitello Cesare , Fonseca Neli , Salih Osman , Kleywegt Gerard J. , Patwardhan Ardan
Published: October 2022

Public archiving in structural biology is well established with the Protein Data Bank (PDB; wwPDB.org) catering for atomic models and the Electron Microscopy Data Bank (EMDB; emdb-empiar.org) for 3D reconstructions from cryo-EM experiments. Even before the recent rapid growth in cryo-EM, there was an expressed community need for a public archive of image data from cryo-EM experiments for validation, software development, testing and training. Concomitantly, the proliferation of 3D imaging techniques for cells, tissues and organisms using volume EM (vEM) and X-ray tomography (XT) led to calls from these communities to publicly archive such data as well. EMPIAR (empiar.org) was developed as a public archive for raw cryo-EM image data and for 3D reconstructions from vEM and XT experiments and now comprises over a thousand entries totalling over 2 petabytes of data. EMPIAR resources include a deposition system, entry pages, facilities to search, visualise and download datasets, and a REST API for programmatic access to entry metadata. The success of EMPIAR also poses significant challenges for the future in dealing with the very fast growth in the volume of data and in enhancing its reusability.
Palaeontological evidence for community-level decrease in mesopelagic fish size during Pleistocene climate warming in the eastern Mediterranean
Authors: Agiadi Konstantina , Quillévéré Frédéric , Nawrot Rafał , Sommeville Theo , Coll Marta , Koskeridou Efterpi , Fietzke Jan , Zuschin Martin
Published: October 2022

Mesopelagic fishes are an important element of marine food webs, a huge, still mostly untapped food resource, and great contributors to the biological carbon pump, whose future under climate change scenarios are unknown. The shrinking of commercial fishes within decades has been an alarming observation, but its causes remain contended. Here, we investigate the effect of warming climate on mesopelagic fish size in the eastern Mediterranean Sea during a glacial–interglacial–glacial transition of the Middle Pleistocene (marine isotope stages 20–18; 814–712 Kyr B.P.), which included a 4 °C increase of global seawater temperature. Our results based on fossil otoliths show that the median size of lanternfishes, one of the most abundant groups of mesopelagic fishes in fossil and modern assemblages, declined by ~35% with climate warming at the community level. However, individual mesopelagic species showed different and often opposing trends in size across the studied time interval, suggesting that climate warming in the interglacial resulted in an ecological shift toward increased relative abundance of smaller-sized mesopelagic fishes due to geographic and/or bathymetric distribution range shifts, and the size-dependent effects of warming.
Alignment, calibration, and validation of an adaptive optics scanning laser ophthalmoscope for high-resolution human foveal imaging
Authors: Moon Benjamin , Poletti Martina , Roorda Austin , Tiruveedhula Pavan , Liu Soh Hang , Linebach Glory , Rucci Michele , Rolland Jannick P.
Published: October 2022

Advances in adaptive optics scanning laser ophthalmoscope (AOSLO) technology have enabled cones in the human fovea to be reliably resolved, providing new insight into human foveal anatomy, visual perception, and retinal degenerative diseases. These high-resolution ophthalmoscopes require careful alignment of each optical subsystem to ensure diffraction-limited imaging performance, which is necessary for resolving the smallest foveal cones. This paper presents a systematic and rigorous methodology for building, aligning, calibrating, and testing an AOSLO designed for imaging the cone mosaic of the central fovea in humans with cellular resolution. This methodology uses a two-stage alignment procedure and thorough system testing to achieve diffraction-limited performance. Results from retinal imaging of healthy human subjects show that the system can resolve cones at the very center of the fovea, the region where the cones are smallest and most densely packed.
A Suite of Advanced Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v0.1]
Authors: Bogetti Anthony T. , Leung Jeremy M. G. , Russo John D. , Zhang She , Thompson Jeff P. , Saglam Ali S. , Ray Dhiman , Abraham Rhea C. , Faeder James R. , Andricioaei Ioan , Adelman Joshua L. , Zwier Matthew C. , LeBard David N. , Zuckerman Daniel M. , Chong Lillian T.
Published: October 2022

We present six advanced tutorials instructing users in the best practices of using key new features and plugins/extensions of the WESTPA 2.0 software package, which consists of major upgrades for enabling applications of the weighted ensemble (WE) path sampling strategy to even larger systems and/or slower processes. The tutorials demonstrate the use of the following key features: (i) a generalized resampler module for the creation of “binless” schemes, (ii) a minimal adaptive binning scheme for more efficient surmounting of free energy barriers, (iii) streamlined handling of large simulation datasets using an HDF5 framework, (iv) two different schemes for more efficient rate-constant estimation, (v) a Python API for simplified analysis of WE simulations, and (vi) plugins/extensions for Markovian Weighted Ensemble Milestoning and WE rule-based modeling at the system biology level. Applications of the tutorials range from atomistic to residue-level to non-spatial models, and include complex processes such as protein folding and the membrane permeability of a drug-like molecule. Users are expected to already have significant experience with running conventional molecular dynamics simulations and completed the previous suite of WESTPA tutorials.
Direct comparison of epifluorescence and immunostaining for assessing viral mediated gene expression in the primate brain
Authors: Daw Tierney B. , El-Nahal Hala G. , Basso Michele A. , Jun Elizabeth J. , Bautista Alex R. , Samulski R. Jude , Sommer Marc A. , Bohlen Martin O.
Published: October 2022

Viral vector technologies are commonly used in neuroscience research to understand and manipulate neural circuits, but successful applications of these technologies in non-human primate models have been inconsistent. An essential component to improve these technologies is an impartial and accurate assessment of the effectiveness of different viral constructs in the primate brain. We tested a diverse array of viral vectors delivered to the brain and extraocular muscles of macaques and compared three methods for histological assessment of viral-mediated fluorescent transgene expression: epifluorescence (Epi), immunofluorescence (IF), and immunohistochemistry (IHC). Importantly, IF and IHC identified a greater number of transduced neurons compared to Epi. Furthermore, IF and IHC reliably provided enhanced visualization of transgene in most cellular compartments (i.e., dendritic, axonal, and terminal fields), whereas the degree of labeling provided by Epi was inconsistent and predominantly restricted to somas and apical dendrites. Because Epi signals are unamplified (in contrast to IF and IHC), Epi likely provides a more veridical assessment for the amount of accumulated transgene and, thus, the potential to chemo- or optogenetically manipulate neuronal activity. The comparatively weak Epi signals suggest that the current generations of viral constructs, regardless of delivered transgene, are not optimized for primates. This reinforces an emerging viewpoint that viral vectors tailored for the primate brain are necessary for basic research and human gene therapy.
The influence of visual pollution on navigation mechanisms in the damselfish (Chrysiptera cyanea)
Authors: Lunt William Michael , Burt de Perera Theresa , Newport Cait
Published: October 2022

Here, we investigate whether visual pollution has an effect on navigation in coral reef damselfish (Chrysiptera cyanea). Turbidity had no significant influence on the individual fish’s preference between egocentric and visual cues in a simple navigation task, with all individuals exhibiting a striking egocentric preference across all turbidity levels under testing. However, an alteration of cue preference may have occurred on a fine scale. Turbidity had profound effects on fish movement and decision-making behaviour, which has substantial implications for the behaviour of fishes on the ecological scale of a coral reef.
Combining molecular and cell painting image data for mechanism of action prediction
Authors: Tian Guangyan , Harrison Philip J , Sreenivasan Akshai P , Puigvert Jordi Carreras , Spjuth Ola
Published: October 2022

The mechanism of action (MoA) of a compound describes the biological interaction through which it produces a pharmacological effect. Multiple data sources can be used for the purpose of predicting MoA, including compound structural information, and various assays, such as those based on cell morphology, transcriptomics and metabolomics. In the present study we explored the benefits and potential additive/synergistic effects of combining structural information, in the form of Morgan fingerprints, and morphological information, in the form of five-channel Cell Painting image data. For a set of 10 well represented MoA classes, we compared the performance of deep learning models trained on the two datasets separately versus a model trained on both datasets simultaneously. On a held-out test set we obtained a macro-averaged F1 score of 0.58 when training on only the structural data, 0.81 when training on only the image data, and 0.92 when training on both together. Thus indicating clear additive/synergistic effects and highlighting the benefit of integrating multiple data sources for MoA prediction.