bluuebunny/crossref_metadata_2025 huggingface dataset:
Alterations in rhythmic and non-rhythmic resting-state EEG activity and their link to cognition in older age
Authors: Cesnaite Elena , Steinfath Paul , Idaji Mina Jamshidi , Stephani Tilman , Kumral Deniz , Haufe Stefan , Sander Christian , Hensch Tilman , Hegerl Ulrich , Riedel-Heller Steffi , Röhr Susanne , Schroeter Matthias L. , Witte A. Veronica , Villringer Arno , Nikulin Vadim V.
Published: August 2021

While many structural and biochemical changes in the brain have been previously associated with aging, the findings concerning electrophysiological signatures, reflecting functional properties of neuronal networks, remain rather controversial. To try resolve this issue, we took advantage of a large population study (N=1703) and comprehensively investigated the association of multiple EEG biomarkers (power of alpha and theta oscillations, individual alpha peak frequency (IAF), the slope of 1/f power spectral decay), aging, and aging and cognitive performance. Cognitive performance was captured with three factors representing processing speed, episodic memory, and interference resolution. Our results show that not only did IAF decline with age but it was also associated with interference resolution over multiple cortical areas. To a weaker extent, 1/f slope of the PSD showed age-related reductions, mostly in frontal brain regions. Finally, alpha power was negatively associated with the speed of processing in the right frontal lobe, despite the absence of age-related alterations. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered when investigating the association between age, neuronal activity, and cognitive performance.
The human-baited host decoy trap (HDT) is an efficient sampling device for exophagic malaria mosquitoes within irrigated lands in southern Malawi
Authors: Zembere Kennedy , Chirombo James , Nasoni Peter , McDermott Daniel P. , Tchongwe-Divala Lizzie , Hawkes Frances M. , Jones Christopher M.
Published: August 2021

Irrigation schemes provide an ideal habitat for Anopheles mosquitoes particularly during the dry season. Reliable estimates of outdoor host-seeking behaviour are needed to assess the impact of vector control options and this is particularly the case for Anopheles arabiensis which displays a wide range of behaviours that circumvent traditional indoor-insecticide based control. In this study we compared the Host Decoy Trap (HDT) with the Human Landing Catch (HLC) and Suna trap in a repeated Latin square design in two villages on an irrigated sugar estate in southern Malawi. Over the course of 18 trapping nights we caught 379 female Anopheles, the majority of which were identified as An. arabiensis. Overall, the HDT and HLC caught a similar number of Anopheles per night with both methods catching significantly higher densities than the Suna trap across both villages. Regardless of the density of Anopheles mosquitoes in each village the HLC and HDT demonstrated broadly similar sampling efficacy. We conclude that the HDT is an effective sampling device for outdoor host seeking An. arabiensis in southern Malawi. The presence of An. arabiensis in irrigated lands during the dry season poses a challenge for ongoing indoor vector control efforts.
Gene regulatory network analysis identifies key genes and regulatory mechanisms involved in acute myocardial infarction using bulk and single cell RNA-seq data
Authors: Luo Jiaxin , Wu Lin , Liu Dinghui , Xiong Zhaojun , Wang Linli , Qian Xiaoxian , Sun Xiaoqiang
Published: August 2021

Cardiovascular and cerebrovascular diseases are leading causes of death worldwide, accounting for more than 40% of all deaths in China. Acute myocardial infarction (AMI) is a common cardiovascular disease and traditionally divided into ST-segment (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), which are known with different prognoses and treatment strategies. However, key regulatory genes and pathways involved in AMI that may be used as potential biomarker for prognosis are unknown. In this study, we constructed weighted gene co-expression networks for differential expressed genes between STEMI and NSTEMI patients based on whole-blood RNA-seq transcriptomics. Network topological attributes (e.g., node degree, betweenness) were analyzed to identify key genes involved in different functional network modules. Furthermore, we used single-cell RNA-seq data to construct multilayer signaling network to infer regulatory mechanisms of the above key genes. PLAUR (receptor for urokinase plasminogen activator) was found to play a vital role in transducing inter-cellular signals from endothelial cells and fibroblast cells to intra-cellular pathways of myocardial cells, leading to gene expression involved in cellular response to hypoxia. Our study sheds lights on identifying molecular biomarkers for diagnosis and prognosis of AMI, and provides candidate key regulatory genes for further experimental validation.
Using Continuous Directed Evolution to Improve Enzymes for Plant Applications
Authors: García-García Jorge D. , Van Gelder Kristen , Joshi Jaya , Bathe Ulschan , Leong Bryan J. , Bruner Steven D. , Liu Chang C. , Hanson Andrew D.
Published: August 2021

Continuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful new way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of theSaccharomyces cerevisiaeOrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (‘plantize’) enzymes from prokaryotes – especially exotic prokaryotes – to function well in mild, plant-like conditions.

One-sentence summary

Continuous directed evolution using the yeast OrthoRep system is a powerful new way to improve enzymes for use in plant engineering as illustrated by ‘plantizing’ a bacterial thiamin synthesis enzyme..
Retinoschisin deficiency induces persistent aberrant waves of activity affecting neuroglial signaling in the retina
Authors: Eleftheriou Cyril G. , Corona Carlo , Khattak Shireen , Ivanova Elena , Bianchimano Paola , Liu Yang , Sun Duo , Singh Rupesh , Batoki Julia C. , McAnany Jason J. , Peachey Neal S. , Romano Carmelo , Sagdullaev Botir T.
Published: August 2021

Genetic disorders which present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis (XLRS), an early onset inherited condition caused by mutations in the RS1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of mice lacking RS1, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 13. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study highlights a critical role for RS1 in early retinal development with a potential to disrupt circuit formation to central targets. Additionally, it confers a functional role to RS1 beyond the scope of an adhesion molecule and identifies an early onset for dysfunction, a potential temporal target for therapeutic intervention and diagnosis.

Significance Statement/ Highlights

Photoreceptor inner segments express Rs1 at P5, after which RS1 protein is detected in the inner segments by P9 and throughout the retina at later ages, with structural abnormalities observed by optical coherence tomography at P13 in Rs1 mutant mouse models.

Aberrant glutamate-driven wavelets identified by GCaMP6f-based analyses are a novel pathophysiological feature of RS1 deficient mice that emerge after maximal RS1 expression.

Müller glia display abnormal radial glutamate-driven coordinated and sporadic bursts of activity in RS1-deficient mice.

These data identify a novel pathophysiological feature of RS1-deficient mice and define a window where treatments might be most effective.

Graphical Abstract
Mathematical modeling reveals a complex network of signaling and apoptosis pathways in the survival of memory plasma cells
Authors: Burt Philipp , Cornelis Rebecca , Geißler Gustav , Hahne Stefanie , Radbruch Andreas , Chang Hyun-Dong , Thurley Kevin
Published: August 2021

The long-term survival of memory plasma cells is conditional on the signals provided by dedicated survival niches in the bone marrow organized by mesenchymal stromal cells. Recently, we could show that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-kB- and PI3K-dependent signaling pathways to prevent cell death. However, the precise dynamics of the underlying regulatory network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the required survival signals, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant and essential nature of the two plasma cell survival signals APRIL and stromal cell contact, providing resilience to endoplasmic reticulum stress and mitochondrial stress, respectively. Importantly, the modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.
Mapping of single-cell landscape of acral melanoma and analysis of molecular regulatory network of tumor microenvironment
Authors: He Zan , Xin Zijuan , Fang Xiangdong , Zhao Hua
Published: August 2021

Melanoma is a type of skin malignant tumor with high invasiveness, high metastasis, and poor prognosis. The incidence of melanoma continues to increase. Among them, the subtype of acral melanoma (AM) is more common in Asian populations. AM has higher degree, low immunotherapy response rate. With the help of single-cell sequencing technology provides new technical means for tumor microenvironment research, so that we can more easily explore specific tumor types suitable immunotherapy targets. However, no complete single-cell level differentiation map exists for the AM tumor microenvironment (TME). In this study, we used AM related sample and used the 10× Genomics single-cell transcriptome platform to draw a specific single-cell map of AM, understand the cell composition of AM, and analyze the interaction and molecular regulation of AM TME. Nine cell types were identified, of which malignant cells accounted for the largest proportion, followed by fibroblasts. And the cell interaction network shows that malignant cells, macrophages, B, T and fibroblasts play an important role in AM TME. Our research provides systematic theoretical guidance for the diagnosis and treatment of acral melanoma.
Colorectal cancer risk in bowel adenomas based on lifestyle exposures, tissue preconditioning and DNA methylation
Authors: Sutton Jaim , Moorghen Morgan , Wang Lai Mun , Thirlwell Christina , Pipinikas Christodoulos , Lorincz Attila
Published: August 2021

Background

Colorectal cancer (CRC) is associated with patient demographics, lifestyle exposures and molecular alterations. However, it is not possible to determine which adenomas will progress to CRC, as ethically it is unacceptable to leave and follow adenomas. We hypothesised that certain lifestyle exposures at high levels could precondition exposed bowel tissue by changing and aging it, increasing the risks of deleterious DNA methylation and genetic alterations. We used a novel study design comparing adenomas with concurrent CRC (thus more likely exposed to deleterious lifestyle effects) to single adenomas in bowels with no history of CRC; we called these high (HR) and low-risk (LR) adenomas respectively.

Methods

We carried out a discovery and replication epigenome-wide association study (EWAS) on 106 HR and 111 LR adenomas, profiled with MethylationEPIC BeadChips. In order, to identify differentially methylated positions (DMP), regions (DMR), and DNAm (DNAmethylation) lifestyle exposures and risks, with adjustment for confounders, and gene ontology (GO) and pathway enrichment. Then, two open-source gene expression omnibus (GEO) validation datasets (52, 57 and 49, 48 HR and LR normal bowel tissues respectively) were analysed for these DNAm lifestyle exposures and risks, with adjustment for confounders.

Results

Our EWAS found 5 Bonferroni significant DMPs with absolute delta betas ≥ 5%, and 14 significant DMRs with absolute mean DMR delta betas ≥ 5%, replicated in the GPX7, RGS3 and TMEM135 cancer-associated genes. DNAm high alcohol exposures were strongly associated with increased risk of HR adenomas (odds ratio (OR) per standard deviation (SD) = 2.16 (95% confidence interval (CI) 1.55 - 3.09, p-value = 9.7 × 10-6)). In the validation datasets, DNAm high alcohol (ORperSD = 2.12 (95% CI 1.35 - 3.55, p-value = 2.0 × 10-3) and ORperSD = 1.79 (95% CI 1.14 - 2.96, p-value = 1.7 × 10-2)), and high body mass index (BMI) exposures (ORperSD = 1.72 (95% CI 1.13 - 2.73, p-value = 1.5 × 10-2)) were associated with increased risk of HR normal bowel tissues.

Conclusions

High alcohol and BMI exposures may precondition normal bowel tissues and adenomas for increased risk of DNA methylation alterations associated with CRC progression. The DNAm exposure signatures and our newly identified genes may be useful epigenetic biomarkers for CRC prevention.
Methylation at CpG sites in genomes of aphid Acyrtosiphon pisum and its endosymbiont Buchnera
Authors: Clément Mathilde , Rocha Martine Da , Agnel Sandra , Raddatz Guenter , Robichon Alain , Bailly-Bechet Marc
Published: August 2021

Pea aphid Acyrtosiphon pisum, a sap-feeding insect, has established a mutualistic relationship with an endosymbiotic bacteria (Buchnera aphidicola) that constitutes an evolutionary successful symbiosis to synthetize complex chemical compounds from a nutrient deprived diet. In this study, led by the presence of DNMT1 and a putative DNMT3 methylase in the aphid genome, we investigated the distribution of the methyl groups on 5’cytosine in CpG motifs on the whole genomes of host and endosymbiont, and looked into their correlation with gene expression. The DNA methylation turned to be present at low level in aphid (around 3% of total genomic cytosine) compared to mammals and plants, but increased to ∼9% in genes. Interestingly, the reduced genome of the endosymbiont Buchnera also shows global low level of methyl cytosine despite the fact that its genome does not shelter any DNA methylase. This finding argues for the import of DNA methylase from the host to the endosymbiont. The observed differences in methylation patterns between two clonal variants (host plus endosymbiont) are reported along with the differences in their transcriptome profiles. Our data allowed to decipher a dynamic combinatorial DNA methylation and epigenetic cross talk between host and symbiont in a clonality context that might count for the aphid adaptation to environment.
Dissociating the Neural Correlates of Planning and Executing Tasks with Nested Task Sets
Authors: Cookson Savannah L. , Schumacher Eric H.
Published: August 2021

Task processing (e.g., the preparation and execution of responses) and task representation (e.g., the activation and maintenance of stimulus-response and context information) are two facets of cognitive control supported by lateral frontal cortex (LFC). However, the mechanistic overlap (or distinction) between these two facets is unknown. We explored this by combining a complex task mapping with a pre-cueing procedure. Participants made match/non-match judgments on pairs of stimuli during fMRI recording. Pre-cues on each trial gave variable amounts of information to the participant in anticipation of the stimulus. Our results demonstrated that regions throughout LFC were more active at the stimulus (when responses could be executed) than at the cue (when they could only be prepared), indicating that they supported execution of the task agnostic to the specific task representation. A subset of regions in left caudal LFC showed increased activity with more cue information at the cue and the reverse at the stimulus, suggesting their involvement in reducing uncertainty within the task representation. These results suggest that one component of task processing is preparing and executing the task according to the relevant representation, confined to left caudal LFC, while non-representational functions that occur primarily during execution are supported by different regions throughout the rest of LFC. We further conducted an exploratory investigation of connectivity between the two groups of regions in this study and their potential relationship to the fronto-parietal and cingulo-opercular networks. Regions with both patterns of activity appear to be part of the fronto-parietal network.
Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients
Authors: Lecot Pacôme , Ardin Maude , Dussurgey Sébastien , Alcazer Vincent , Moudombi Lyvia , Hubert Margaux , Swalduz Aurélie , Hernandez-Vargas Hector , Viari Alain , Caux Christophe , Michallet Marie-Cécile
Published: August 2021

Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil-platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStream®X (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14− CD36+ ITGA2B+ NPAs in both healthy donors’ (HDs) and cancer patients’ bloods, but we also showed that NPAs result from the binding of platelets preferentially to low-density neutrophils (LDNs) as opposed to normal-density neutrophils (NDNs). By re-analyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients’ derived NPAs possessed a distinct molecular signature compared with the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs-associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans-endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs-associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.

Novelty and Impact

Platelets physically interact with peripheral blood neutrophils to form neutrophil-platelet aggregates (NPAs), known to promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. We showed that NPAs-associated neutrophils were a yet-unreported unique subset of circulating neutrophils associated with a worse patient prognosis in several cancer types. NPAs may hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.
Cryo-ET of a human GBP coatomer governing cell-autonomous innate immunity to infection
Authors: Zhu Shiwei , Bradfield Clinton J. , Mamińska Agnieszka , Park Eui-Soon , Kim Bae-Hoon , Kumar Pradeep , Huang Shuai , Zhang Yongdeng , Bewersdorf Joerg , MacMicking John D.
Published: August 2021

All living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, these activities generate large supramolecular complexes that recruit immune proteins for protection. Here, we solve the native structure of a massive antimicrobial complex generated by polymerization of 30,000 human guanylate-binding proteins (GBPs) over the entire surface of virulent bacteria. Construction of this giant nanomachine takes ∼1-3 minutes, remains stable for hours, and acts as a cytokine and cell death signaling platform atop the coated bacterium. Cryo-ET of this “coatomer” revealed thousands of human GBP1 molecules undergo ∼260 Å insertion into the bacterial outer membrane, triggering lipopolysaccharide release that activates co-assembled caspase-4. Together, our results provide a quasi-atomic view of how the GBP coatomer mobilizes cytosolic immunity to combat infection in humans.

One-Sentence Summary

Thousands of GBPs coat cytosolic bacteria to engineer an antimicrobial signaling platform inside human cells.
Kif9 is an active kinesin motor required for ciliary beating and proximodistal patterning of motile axonemes
Authors: Konjikusic Mia J. , Lee Chanjae , Yue Yang , Shrestha Bikram D. , Nguimtsop Ange M. , Horani Amjad , Brody Steven , Prakash Vivek N. , Gray Ryan S. , Verhey Kristen J. , Wallingford John B.
Published: August 2021

Most motile cilia have a stereotyped structure of nine microtubule outer doublets and a single central pair of microtubules. The central pair microtubules are surrounded by a set of proteins, termed the central pair apparatus. A specific kinesin, Klp1 projects from the central pair and contributes to ciliary motility in Chlamydomonas. The vertebrate orthologue, Kif9 is required for beating in mouse sperm flagella, but the mechanism of Kif9/Klp1 function remains poorly defined. Here, using Xenopus epidermal multiciliated cells, we show that Kif9 is necessary for ciliary motility as well as leads to defects in the distal localization of not only central pair proteins, but also radial spokes and dynein arms. In addition, single-molecule assays in vitro revealed that Xenopus Kif9 is a processive motor, though like axonemal dyneins it displays no processivity in ciliary axonemes in vivo. Thus, our data suggest that Kif9 plays both indirect and direct role in ciliary motility.
NORDIC Increases the Sensitivity and Preserves the Spatiotemporal Precision of fMRI Responses
Authors: Dowdle Logan T. , Vizioli Luca , Moeller Steen , Akçakaya Mehmet , Olman Cheryl , Ghose Geoffrey , Yacoub Essa , Uğurbil Kâmil
Published: August 2021

As the neuroimaging field moves towards detecting smaller effects at higher spatial resolutions, and faster sampling rates, there is increased attention given to the deleterious contribution of unstructured, thermal noise. Here, we critically evaluate the performance of a recently developed reconstruction method, termed NORDIC, for suppressing thermal noise using datasets acquired with various field strengths, voxel sizes, sampling rates, and task designs.

Following minimal preprocessing, statistical activation (t-values) of NORDIC processed data was compared to the results obtained with alternative denoising methods. Additionally, we examined the consistency of the estimates of task responses at the single-voxel, single run level, using a finite impulse response (FIR) model. To examine the potential impact on effective image resolution, the overall smoothness of the data processed with different methods was estimated. Finally, to determine if NORDIC alters or removes important temporal information, we employed an exhaustive leave-p-out cross validation approach, using FIR task responses to predict held out timeseries, quantified using R2.

After NORDIC, the t-values are increased, an improvement comparable to what could be achieved by 1.5 voxels smoothing, and task events are clearly visible and have less cross-run error. These advantages are achieved in the absence of large changes in estimates of spatial smoothness. Cross-validated R2s based on the FIR models show that NORDIC is not measurably distorting the temporal structure of the data and is the best predictor of non-denoised time courses. The results demonstrate that analyzing 1 run of data after NORDIC produces results equivalent to using 2 to 3 original runs and that NORDIC performs equally well across a diverse array of functional imaging protocols.

Significance Statement

For functional neuroimaging, the increasing availability of higher field strengths and ever higher spatiotemporal resolutions has led to concomitant increase in concerns about the deleterious effects of thermal noise. Historically this noise source was suppressed using methods that reduce spatial precision such as image blurring or averaging over a large number of trials or sessions, which necessitates large data collection efforts. Here, we critically evaluate the performance of a recently developed reconstruction method, termed NORDIC. Across datasets varying in field strength, voxel sizes, sampling rates, and task designs, NORDIC produces substantial gains in data quality. Both conventional t-statistics derived from general linear models and coefficients of determination for predicting unseen data are improved, while avoiding meaningful increases in typical estimates of image smoothness or substantial losses of temporal information.
Redesigning the Eterna100 for the Vienna 2 folding engine
Authors: Koodli Rohan V. , Rudolfs Boris , Wayment-Steele Hannah K. ,   Eterna Structure Designers, Das Rhiju
Published: August 2021

The rational design of RNA is becoming important for rapidly developing technologies in medicine and biochemistry. Recent work has led to the development of several RNA secondary structure design algorithms and corresponding benchmarks to evaluate their performance. However, the performance of these algorithms is linked to the nature of the underlying algorithms for predicting secondary structure from sequences. Here, we show that an online community of RNA design experts is capable of modifying an existing RNA secondary structure design benchmark (Eterna100) with minimal alterations to address changes in the folding engine used (Vienna 1.8 updated to Vienna 2.4). We tested this new Eterna100-V2 benchmark with five RNA design algorithms, and found that neural network-based methods exhibited reduced performance in the folding engine they were evaluated on in their respective papers. We investigated this discrepancy, and determined that structural features, previously classified as difficult, may be dependent on parameters inherent to the RNA energy function itself. These findings suggest that for optimal performance, future algorithms should focus on finding strategies capable of solving RNA secondary structure design benchmarks independently of the free energy benchmark used. Eterna100-V1 and Eterna100-V2 benchmarks and example solutions are freely available at https://github.com/eternagame/eterna100-benchmarking.
Wear and Tear of the Intestinal Visceral Musculature by Intrinsic and Extrinsic Factors
Authors: Kim Ho D. , So Eric , Lee Jiae , Wang Yi , Gill Vikram S. , Gorbacheva Anna , Han Hee Jin , Ng Katelyn G.-L. , Ning Ken , Pranoto Inez K.A. , Cabrera Alejandra J.H. , Eom Dae Seok , Kwon Young V.
Published: August 2021

The gut visceral musculature plays essential roles in not only moving substances through the lumen but also maintaining the function and physiology of the gut. Although the development of the visceral musculature has been studied in multiple model organisms, how it degenerates is poorly understood. Here, we employ the Drosophila midgut as a model to demonstrate that the visceral musculature is disrupted by intrinsic and extrinsic factors, such as aging, feeding, chemical-induced tissue damage, and oncogenic transformation in the epithelium. Notably, we define four prominent visceral musculature disruption phenotypes, which we refer as ‘sprout’, ‘discontinuity’, ‘furcation’, and ‘crossover’ of the longitudinal muscle. Given that the occurrence of these phenotypes is increased during aging and under various stresses, we propose that these phenotypes can be used as quantitative readouts of deterioration of the visceral musculature. Intriguingly, administration of a tissue-damaging chemical dextran sulfate sodium (DSS) induced similar visceral musculature disruption phenotypes in zebrafish larvae, indicating that ingestion of a tissue-damaging chemical can disrupt the visceral musculature in a vertebrate as well. Our study provides insights into the deterioration of the gut visceral musculature and lays a groundwork for investigating the underlying mechanisms in Drosophila as well as other animals.
Comparative analysis of mandible morphology in four ant species with different foraging and nesting habits
Authors: Chowdhury Ritabrata , Rastogi Neelkamal
Published: August 2021

Mandibles of ants can be considered as one of the most vital tools for the survival and success of their colonies since these are extensively utilised for defence, nest maintenance and foraging activities. We hypothesised that mandibular design is strongly dependent on the respective ecological niche and foraging habit of an ant species. In the present study, we compared the external morphology and zinc content in the mandibles of four species of ants by using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). The ant mandible morphology varied significantly in accordance with their species-specific foraging and nesting strategies. The sickle-shaped mandibles of the strongly predaceous,Oecophylla smaragdinaworker ants were characterised by a large number of pointed teeth which would be of immense utility for subduing the prey, while the shovel-shaped, highly sclerotized mandibles ofCataglyphus longipedemants appear to be adaptations for the solitary scavenging habit and nest maintenance in arid habitats. The large-sized mandibles ofCamponotus compressusants and the stout mandibles of the predatory,Tetraponera. rufonigraforager ants, have apparently evolved for collection of sugary secretions by the former and for the solitary foraging and arboreal nesting habit of the latter. The mandibular zinc content was highest inT. rufonigraants and the lowest in the mandibles of the sugar-lovingCm. compressusants. The diversity in the arrangement of bristles and the type of mandibular concavities, have also evolved accordingly. Thus, this study might prove to be instrumental in evaluating the various physical mechanisms involved in the evolution of insect mandibles for their defined function.
MRI-Visible Perivascular Space (PVS) Changes with Long-Duration Spaceflight
Authors: Hupfeld Kathleen E. , Richmond Sutton B. , McGregor Heather R. , Schwartz Daniel L. , Luther Madison , Beltran Nichole E. , Kofman Igor S. , De Dios Yiri E. , Riascos Roy F. , Wood Scott J. , Bloomberg Jacob J. , Mulavara Ajitkumar P. , Silbert Lisa , Iliff Jeffrey J. , Seidler Rachael D. , Piantino Juan
Published: August 2021

Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent sixT1-weighted 3T MRI scans, twice prior to launch and four times following their return to Earth after ∼6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established automated segmentation algorithm. We found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (adjusted for age, sex, and time between landing and first MRI scan). Moreover, experienced astronauts exhibited a significant correlation between more previous flight days and greater PVS median length at baseline, suggesting that experienced astronauts exhibit holdover effects from prior spaceflight(s). There was also a significant positive correlation between pre- to post-flight increases in PVS median length and increases in right lateral ventricular volume. The presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that spaceflight is associated with PVS morphological changes, and specifically that spaceflight experience is an important factor in determining PVS characteristics.
LESSONS FROM THE COVID-19 THIRD WAVE IN CANADA: THE IMPACT OF VARIANTS OF CONCERN AND SHIFTING DEMOGRAPHICS
Authors: McAlister Finlay A. , Nabipoor Majid , Chu Anna , Lee Douglas S. , Saxinger Lynora , Bakal Jeffrey A.
Published: August 2021

Importance

With the emergence of more transmissible SARS-CoV-2 variants of concern (VOC), there is an urgent need for evidence about disease severity and the health care impacts of VOC in North America, particularly since a substantial proportion of the population have declined vaccination thus far.

Objective

To examine 30-day outcomes in Canadians infected with SARS-CoV-2 in the first year of the pandemic and to compare event rates in those with VOC versus wild-type infection.

Design

Retrospective cohort study using linked healthcare administrative datasets.

Setting

Alberta and Ontario, the two Canadian provinces that experienced the largest third wave in the spring of 2021.

Participants

All individuals with a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction swab from March 1, 2020 until March 31, 2021, with genomic confirmation of VOC screen-positive tests during February and March 2021 (wave 3).

Exposure of Interest

VOC versus wild type SARS-CoV-2

Main Outcomes and Measures

All-cause hospitalizations or death within 30 days after a positive SARS-CoV-2 swab.

Results

Compared to the 372,741 individuals with SARS-CoV-2 infection between March 2020 and January 2021 (waves 1 and 2 in Canada), there was a shift in transmission towards younger patients in the 104,232 COVID-19 cases identified in wave 3. As a result, although third wave patients were more likely to be hospitalized (aOR 1.34 [1.29-1.39] in Ontario and aOR 1.53 [95%CI 1.41-1.65] in Alberta), they had shorter lengths of stay (median 5 vs. 7 days, p<0.001) and were less likely to die within 30 days (aOR 0.66 [0.60-0.71] in Ontario and aOR 0.74 [0.62-0.89] in Alberta). However, within the third wave, patients infected with VOC (91% Alpha) exhibited higher risks of death (aOR 1.52 [1.27-1.81] in Ontario and aOR 1.67 [1.13-2.48] in Alberta) and hospitalization (aOR 1.57 [1.47-1.69] in Ontario and aOR 1.88 [1.74-2.02] in Alberta) than those with wild-type SARS-CoV-2 infections during the same timeframe.

Conclusions and Relevance

On a population basis, the shift towards younger age groups as the COVID-19 pandemic has evolved translates into more hospitalizations but shorter lengths of stay and lower mortality risk than seen in the first 10 months of the pandemic in Canada. However, on an individual basis, infection with a VOC is associated with a higher risk of hospitalization or death than the original wild-type SARS-CoV-2 – this is important information to address vaccine hesitancy given the increasing frequency of VOC infections now.
Host lung environment limits Aspergillus fumigatus germination through a SskA-dependent signaling response
Authors: Kirkland Marina E. , Stannard McKenzie , Kowalski Caitlin H. , Mould Dallas , Caffrey-Carr Alayna , Temple Rachel M. , Ross Brandon S. , Lofgren Lotus A. , Stajich Jason E. , Cramer Robert A. , Obar Joshua J.
Published: August 2021

Aspergillus fumigatus isolates display significant heterogeneity in growth, virulence, pathology, and inflammatory potential in multiple murine models of invasive aspergillosis. Previous studies have linked the initial germination of a fungal isolate in the airways to the inflammatory and pathological potential; but the mechanism(s) regulating A. fumigatus germination in the airways are unresolved. To explore the genetic basis for divergent germination phenotypes, we utilized a serial passaging strategy in which we cultured a slow germinating strain (AF293) in a murine lung based medium for multiple generations. Through this serial passaging approach, a strain emerged with an increased germination rate that induces more inflammation than the parental strain (herein named Lung Homogenate Evolved (LH-EVOL)). We identified a potential loss of function allele of Afu5g08390 (sskA) in the LH-EVOL strain. The LH-EVOL strain had a decreased ability to induce the SakA-dependent stress pathway, similar to AF293 ΔsskA and CEA10. In support of the whole genome variant analyses, sskA, sakA, or mpkC loss of function strains in the AF293 parental strain increased germination both in vitro and in vivo. Since the airway surface liquid of the lungs contains low glucose levels, the relationship of low glucose concentration on germination of these mutant AF293 strains was examined; interestingly, in low glucose conditions the sakA pathway mutants exhibited an enhanced germination rate. In conclusion, A. fumigatus germination in the airways is regulated by SskA through the SakA MAPK pathway and drives enhanced disease initiation and inflammation in the lungs.

IMPORTANCE

Aspergillus fumigatus is an important human fungal pathogen particularly in immunocompromised individuals. Initiation of growth by A. fumigatus in the lung is important for its pathogenicity in murine models. However, our understanding of what regulates fungal germination in the lung environment is lacking. Through a serial passage experiment using lung-based medium, we identified a new strain of A. fumigatus which has increased germination potential and inflammation in the lungs. Using this serially passaged strain we found it had a decreased ability to mediate signaling through the osmotic stress response pathway. This finding was confirmed using genetic null mutants demonstrating that the osmotic stress response pathway is critical for regulating growth in the murine lungs. Our results contribute to the understanding of A. fumigatus adaptation and growth in the host lung environment.
The STAT5-IRF4-BATF pathway drives heightened epigenetic remodeling in naïve CD4+T cell responses of older adults
Authors: Zhang Huimin , Jadhav Rohit R. , Cao Wenqiang , Goronzy Isabel N. , Jin Jun , Greenleaf William J. , Weyand Cornelia M. , Goronzy Jörg J.
Published: August 2021

T cell aging is a complex process combining the emergence of cellular defects with activation of adaptive mechanisms. Generation of T cell memory is impaired, while a low-inflammatory state is induced, in part due to effector T cells. To determine whether age-associated changes in T cell fate decisions occur early after T cell activation, we profiled the longitudinal transcriptional and epigenetic landscape induced by TCR stimulation comparing naïve CD4+T cells from young and older adults. In spite of attenuated TCR signaling, activation-induced remodeling of the epigenome increased with age, culminating in heightened BATF and BLIMP1 activity. Single cell studies, integrating ATAC-seq and RNA-seq data, identified increases in dysfunctional and in effector T cells and a decrease in BACH2-expressing memory cell precursors. STAT5 activation, in part due to a decline in HELIOS and aberrant IL-2 receptor expression, accounted for the induction of transcription factor networks favoring effector cell differentiation.
Advanced Age Has Dissociable Effects on Hippocampal CA1 and CA3 Ripples
Authors: DiCola Nicholas M. , Lacy Alexa L. , Bishr Omar J. , Kimsey Kathryn M. , Whitney Jenna L. , Lovett Sarah D. , Burke Sara N. , Maurer Andrew P.
Published: August 2021

Sharp-wave/ripples are brief, high-frequency events in hippocampal subregions CA3 and CA1 that occur during rest or pauses in behavior. Ripples detected in CA1 have lower frequency in aged compared to young rats. Although CA1 ripples are theorized to manifest from CA3, ripple dynamics in CA3 have not been examined in aged animals. The current study obtained simultaneous recordings between CA1 and CA3 in young and aged rats to examine sharp-wave/ripple characteristics in both regions in relation to age. While CA1 ripple frequency was reduced with age, there were no age differences in CA3 ripples. In aged, but not young, rats there was also a significant increase in the probability of CA3 and CA1 ripples co-occurring between the pre- and post-behavior rest epochs. Moreover, in both age groups, CA1 ripples that co-occurred with a CA3 ripple had increased frequency, power, and duration. These findings suggest age differences in CA1 are not due to altered afferent input from CA3, but instead reflect distinct mechanisms of ripple generation with age.

HIGHLIGHTS

CA1 ripple frequency is reduced with age.

CA3 ripple characteristics do not change with age.

In aged rats only, CA3-CA1 ripple co-occurrence increased following behavior.

CA1 ripples that co-occurred with CA3 had greater frequency, power, and duration.
Data-driven, participatory characterization of farmer varieties discloses teff breeding potential under current and future climates
Authors: Woldeyohannes Aemiro B. , Iohannes Sessen D. , Miculan Mara , Caproni Leonardo , Ahmed Jemal S. , de Sousa Kauê , Desta Ermias A. , Fadda Carlo , Pè Mario E. , Dell’Acqua Matteo
Published: August 2021

In smallholder farming systems, traditional farmer varieties of neglected and underutilized species (NUS) support the livelihoods of millions of growers and consumers. NUS combine cultural and agronomic value with local adaptation and transdisciplinary methods are needed to fully evaluate their breeding potential. Here, we assembled and characterized the genetic diversity of a representative collection of 366 Ethiopian teff (Eragrostis tef) farmer varieties and breeding materials, describing their phylogenetic relation and local adaptation on the Ethiopian landscape. We phenotyped the collection for its agronomic performance, involving local farmers expert teff growers in a participatory variety evaluation. Our analyses revealed environmental patterns of teff genetic diversity and allowed us to identify ten genetic clusters associated with climate variation and with uneven spatial distribution. A genome wide association study (GWAS) was used to identify loci and candidate genes related to phenology, yield, local adaptation, and farmers’ appreciation. The estimated teff genomic offset under climate change scenarios highlighted an area around lake Tana where teff cropping may be most vulnerable to climate change. Our results show that transdisciplinary approaches may efficiently propel untapped NUS farmer varieties into modern breeding to foster more resilient and sustainable cropping systems.
Benchmarking Computational Integration Methods for Spatial Transcriptomics Data
Authors: Li Yijun , Stanojevic Stefan , He Bing , Jing Zheng , Huang Qianhui , Kang Jian , Garmire Lana X.
Published: August 2021

The increasing popularity of spatial transcriptomics has allowed researchers to analyze transcriptome data in its tissue sample’s spatial context. Various methods have been developed for detecting SV (spatially variable) genes, with distinct spatial expression patterns. However, the accuracy of using these SV genes in clustering has not been thoroughly studied. On the other hand, in single cell resolution sequencing data without spatial context, clustering analysis is usually done on highly variable (HV) genes. Here we investigate if integrating SV genes and HV genes from spatial transcriptomics data can improve clustering performance beyond using SV genes alone. We examined three methods that detect SV genes, including Giotto, spatialDE, and SPARK, and evaluated six methods that integrate different features measured from the same samples including MOFA+, scVI, Seurat v4, CIMLR, SNF, and the straightforward concatenation approach. We applied these methods on 19 real datasets from three different spatial transcriptomics technologies (merFISH, SeqFISH+, and Visium) as well as 20 simulated datasets of varying spatial expression conditions. Our evaluations show that MOFA+ and simple concatenation have good performances in general, despite the variations among datasets and spatial transcriptomics platforms. This work shows that integrating highly variable and spatially variable genes in the spatial transcriptomics data can improve clustering beyond using spatially variable genes only. It also provides practical guides on the choices of computational methods to accomplish this goal.
Intervene or wait? Modelling the timing of intervention in conservation conflicts adaptive management under uncertainty
Authors: Bach Adrian , Minderman Jeroen , Bunnefeld Nils , Mill Aileen , Duthie Alexander B.
Published: August 2021

The timing of biodiversity managers’ interventions can be critical to the success of conservation, especially in situations of conflict between conservation objectives and human livelihood, i.e., conservation conflicts. Given the uncertainty associated with complex social-ecological systems and the potentially irreversible consequences of delayed action for biodiversity and livelihoods, managers tend to simply intervene as soon as possible by precaution. However, refraining from intervening when the situation allows it can be beneficial, notably by saving critical management resources. Here, we introduce a strategy for managers to decide, based on monitoring, whether intervention is required or if waiting is possible. This study evaluates the performance of this waiting strategy compared to a strategy of unconditional intervention at every opportunity. We built an individual-based model of conservation conflict between a manager aiming to conserve an animal population and farmers aiming to maximize yield by protecting their crop from wildlife damage. We then simulated a budget-constrained adaptive management over time applying each strategy, while accounting for uncertainty around population dynamics and around decision-making of managers and farmers. Our results showed that when the decision for the manager to intervene was based on a prediction of population size trajectory, the waiting strategy performed at least as well as unconditional intervention while also allowing managers to save resources by avoiding unnecessary interventions. Under difficult budgetary constraints on managers, this waiting strategy ensured as high yields as unconditional intervention while significantly improving conservation outcomes by compensating managers’ lack of resources with the benefits accrued over waiting periods. This suggests that waiting strategies are worth considering in conservation conflicts, as they can facilitate equitable management with a more efficient use of management resources, which are often limiting in biodiversity conservation.