bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Post-operative Pain in Lung Cancer Patients using Pre-operative Peak Alpha Frequency
Authors: Millard Samantha K. , Furman Andrew J. , Kerr Amy , Seminowicz David A. , Gao-Smith Fang , Naidu Babu V. , Mazaheri Ali
Published: November 2021

Aims and Objectives

Experimental models of neuropathic pain suggest that individual peak alpha frequency (PAF), measured using electroencephalography (EEG), can predict future pain sensitivity in experimental settings. Here, we tested whether PAF could predict future pain severity in a clinical setting in patients undergoing thoracotomy.

Methods

Recorded using wearable around the ear electrodes (cEEGrids), the feasibility and efficacy of pre-operative PAF as a neuro-marker for post-operative pain was assessed in 16 patients undergoing thoracic surgery for lung cancer (age = 67.53 ± 4.38 [SD]). Patients also provided numerical ratings (0-10) of current, average, and worst pain pre-operatively as well as within three days post-operatively

Results and Significance

Pre-operative PAF of less than 9 Hz was highly sensitive (1.0) and specific (0.86) in identifying patients who would go on to experience severe (>7/10) worst pain. Moreover, PAF was negatively correlated with patients’ current, average, and worst post-operative pain. PAF was significantly higher for those reporting lower pain severity compared to those reporting higher pain severity in the immediate post-operative period. This suggests that PAF is a promising neuro-marker to pre-operatively assess individual susceptibility to severe pain in the immediate post-operative period, possibly enabling more informed assessment of an individual’s suitability for surgery.
Population-level changes in the mental health of UK workers during the COVID-19 pandemic: A longitudinal study using Understanding Society
Authors: Kromydas Theocharis , Green Michael J , Craig Peter , Katikireddi Srinivasa Vittal , Leyland Alastair H , Niedzwiedz Claire L , Pearce Anna , Thomson Rachel M , Demou Evangelia L
Published: November 2021

Objectives The COVID−19 pandemic has substantially affected workers mental health. We investigated changes in UK workers mental health by industry, social class, and occupation and differential effects by UK country of residence, gender and age.

Methods We used representative Understanding Society data from 6,474 adults (41,207 observations) in paid employment who participated in pre−pandemic (2017−2020) and at least one COVID-19 survey. The outcome was psychological distress (General Health Questionnaire-12; score≥4). Exposures were industry, social class and occupation and are examined separately. Mixed−effects logistic regression was used to estimate relative (OR) and absolute (%) increases in distress before and during pandemic. Differential effects were investigated for UK countries of residence (Non−England/England), gender (Male/female), and age (Younger/Older) using 3−way interaction effects.

Results Psychological distress increased in relative terms most for professional, scientific and technical (OR:3.15, 95% CI 2.17−4.59) industry in the pandemic versus pre−pandemic period. Absolute risk increased most in hospitality (+11.4%). For social class, small employers/self−employed were most affected in relative and absolute terms (OR:3.24, 95% CI 2.28− 4.63; +10.3%). Across occupations Sales and customer service (OR:3.01, 95% CI 1.61− 5.62; +10.7%) had the greatest increase. Analysis with 3−way interactions showed considerable gender differences, while for UK country of residence and age results are mixed.

Conclusions Psychological distress increases during the COVID−19 pandemic were concentrated among professional and technical and hospitality industries, small employers/self−employed and sales and customers service workers. Female workers often exhibited greater differences in risk by industry and occupation. Policies supporting these industries and groups are needed.
Future prevalence of type 2 diabetes – a comparative analysis of chronic disease projection methods
Authors: Voeltz Dina , Tönnies Thaddäus , Brinks Ralph , Hoyer Annika
Published: November 2021

Background

Accurate projections of the future number of people with chronic diseases are necessary for effective resource allocation and health care planning in response to changes in disease burden.

Aim

To introduce and compare different projection methods to estimate the number of people with diagnosed type 2 diabetes (T2D) in Germany in 2040.

Methods

We compare three methods to project the number of males with T2D in Germany in 2040. Method 1) simply combines the sex- and age-specific prevalence of T2D in 2010 with future population distributions projected by the German Federal Statistical Office (FSO). Methods 2) and 3) additionally account for the incidence of T2D and mortality rates using partial differential equations (PDEs). Method 2) models the prevalence of T2D employing a scalar PDE which incorporates incidence and mortality rates. Subsequently, the estimated prevalence is applied to the population projection of the FSO. Method 3) uses a two-dimensional system of PDEs and estimates future case numbers directly while future mortality of people with and without T2D is modelled independently from the projection of the FSO.

Results

Method 1) projects 3.6 million male people with diagnosed T2D in Germany in 2040. Compared to 2.8 million males in 2010, this equals an increase by 29%. Methods 2) and 3) project 5.9 million (+104% compared to 2010) and 6.0 million (+116%) male T2D patients, respectively.

Conclusions

The results of the three methods differ substantially. It appears that ignoring temporal trends in incidence and mortality may result in misleading projections of the future number of people with chronic diseases. Hence, it is essential to include these rates as is done by method 2) and 3).
Distinct and interchangeable growing patterns in colorectal cancer stem-like cells are regulated by Musashi-1
Authors: Coppo Roberto , Kondo Jumpei , Iida Keita , Okada Mariko , Onuma Kunishige , Tanaka Yoshihisa , Kamada Mayumi , Ohue Masayuki , Kawada Kenji , Obama Kazutaka , Inoue Masahiro
Published: November 2021

The dynamic and heterogeneous features of cancer stem-like cells (CSCs) have been widely recognized, but their nongenetic cellular plasticity mechanisms remain elusive. By using colorectal cancer organoids, we phenotypically tracked their spheroid formation and growth capacity to a single-cell resolution, and we discovered that the spheroid-forming cells exhibit a heterogeneous growth pattern, consisting of slow- and fast-growing spheroids. The isolated fast-growing spheroids seem to preserve a dual-growing pattern through multiple passages, whereas the isolated slow-growing spheroids are restricted to a slow-growing pattern. Notably, the spheroids of both patterns were tumorigenic. Moreover, the expression of CSC markers varied among the subpopulations with different growth patterns. The isolated slow-growing spheroids adopted the dual-growing pattern by various extrinsic triggers, in which Musashi-1 plays a key role. The slow-growing fraction was resistant to chemotherapy, and its successful isolation can provide an in vitro platform allowing us to elucidate their role in drug resistance.
Experimental Investigation of Pulse Sterilization of Pathogens
Authors: Chumakov Volodymyr , Ostryzhnyi Mykhailo , Kharchenko Oksana , Rybalchenko Nataliya , Muraveinyk Vasiliy , Tarasevich Aleksandr
Published: November 2021

The results of experimental investigations of the effect of high-intensity pulsed UV radiation on reference strains of opportunistic pathogens S, aureus and E. coli are presented. The modified pulse UV sterilizer MПК-300-3 based on an end-face plasma accelerator was used as a radiation source, which provides a power pulsed discharge in an open atmosphere. The high efficiency of inactivation of the pathogens was provided within a short period of time. The possibility of providing urgent 100% sterilization of a pathogens has been shown. The prospects for the application of pulse sterilization technology to combat pathogens are considered.
TripletGO: Integrating Transcript Expression Profiles with Protein Homology Inferences for High-Accuracy Gene Function Annotations
Authors: Zhu Yi-Heng , Zhang Chengxin , Liu Yan , Omenn Gilbert S , Freddolino Peter L , Yu Dong-Jun , Zhang Yang
Published: November 2021

Gene Ontology (GO) has been widely used to annotate functions of genes and gene products. We proposed a new method (TripletGO) to deduce GO terms of protein-coding and non-coding genes, through the integration of four complementary pipelines built on transcript expression profiling, genetic sequence alignment, protein sequence alignment and naive probability, respectively. TripletGO was tested on a large set of 5,754 genes from 8 species (human, mouse, arabidopsis, rat, fly, budding yeast, fission yeast, and nematoda) and 2,433 proteins with available expression data from the CAFA3 experiment and achieved function annotation accuracy significantly beyond the current state-of-the-art approaches. Detailed analyses show that the major advantage of TripletGO lies in the coupling of a new triplet-network based profiling method with the feature space mapping technique which can accurately recognize function patterns from transcript expressions. Meanwhile, the combination of multiple complementary models, especially those from transcript expression and protein-level alignments, improves the coverage and accuracy of the final GO annotation results. The standalone package and an online server of TripletGO are freely available at https://zhanglab.ccmb.med.umich.edu/TripletGO/.
Adaptor linked K63 di-Ubiquitin activates Nedd4/Rsp5 E3 ligase
Authors: Zhu Lu , Zhang Qing , Cordeiro Ciro , Banjade Sudeep , Sardana Richa , Mao Yuxin , Emr Scott D.
Published: November 2021

Nedd4/Rsp5 family E3 ligases mediate numerous cellular processes, many of which require the E3 ligase to interact with PY-motif containing adaptor proteins. Several Arrestin-Related Trafficking adaptors(ARTs) of Rsp5 were self-ubiquitinated for activation, but the regulation mechanism remains elusive. Remarkably, we demonstrate that Art1, Art4, and Art5 undergo K63-linked di-ubiquitination by Rsp5. This modification enhances the PM recruitment of Rsp5 by Art1 or Art5 upon substrate induction, required for cargo protein ubiquitination. In agreement with these observations, we find that di-ubiquitin strengthens the interaction between the Pombe orthologs of Rsp5 and Art1, Pub1 and Any1. Further, we discover that the HECT domain exosite protects the K63-linked di-ubiquitin on the adaptors from cleavage by the deubiquitination enzyme Ubp2. Strikingly, loss of this protection results in the loss of K63-linked di-ubiquitin from the adaptors and diverts the adaptors for K48-linked poly-ubiquitination and proteasome-mediated degradation. Together, our study uncovers a novel ubiquitination modification implemented by Rsp5 adaptor proteins, underscoring the regulatory mechanism of how adaptor proteins control the recruitment and activity of Rsp5 for the turnover of membrane proteins.
Nociceptive stimuli activate the hypothalamus-habenula circuit to inhibit the mesolimbic reward system
Authors: Lee Soo Min , Fan Yu , Lee Bonghyo , Kim Sang Chan , Bills Kyle B. , Steffensen Scott C. , Kim Hee Young
Published: November 2021

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here we show that the LH-LHb pathway is necessary for nociceptive modulation of this system. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail-pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail-pinch decreased extracellular DA release in the nucleus accumbens ventrolateral shell, which was blocked by disruption of the LH. Furthermore, tail-pinch attenuated cocaine-induced locomotor activity, 50-kHz ultrasonic vocalizations and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH-LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH-LHb pathway to inhibit mesolimbic DA system and drug reinstatement.
ENNGene: an Easy Neural Network model building tool for Genomics
Authors: Chalupová Eliška , Vaculík Ondřej , Poláček Jakub , Jozefov Filip , Majtner Tomáš , Alexiou Panagiotis
Published: November 2021

Background

The recent big data revolution in Genomics, coupled with the emergence of Deep Learning as a set of powerful machine learning methods, has shifted the standard practices of machine learning for Genomics. Even though Deep Learning methods such as Convolutional Neural Networks (CNNs) and Recurrent Neural Networks (RNNs) are becoming widespread in Genomics, developing and training such models is outside the ability of most researchers in the field.

Results

Here we present ENNGene - Easy Neural Network model building tool for Genomics. This tool simplifies training of custom CNN or hybrid CNN-RNN models on genomic data via an easy-to-use Graphical User Interface. ENNGene allows multiple input branches, including sequence, evolutionary conservation, and secondary structure, and performs all the necessary preprocessing steps, allowing simple input such as genomic coordinates. The network architecture is selected and fully customized by the user, from the number and types of the layers to each layer's precise set-up. ENNGene then deals with all steps of training and evaluation of the model, exporting valuable metrics such as multi-class ROC and precision-recall curve plots or TensorBoard log files. To facilitate interpretation of the predicted results, we deploy Integrated Gradients, providing the user with a graphical representation of an attribution level of each input position. To showcase the usage of ENNGene, we train multiple models on the RBP24 dataset, quickly reaching the state of the art while improving the performance on more than half of the proteins by including the evolutionary conservation score and tuning the network per protein.

Conclusions

As the role of DL in big data analysis in the near future is indisputable, it is important to make it available for a broader range of researchers. We believe that an easy-to-use tool such as ENNGene can allow Genomics researchers without a background in Computational Sciences to harness the power of DL to gain better insights into and extract important information from the large amounts of data available in the field.

Contact

panagiotis.alexiou@ceitec.muni.cz
Multiparametric quantitative phase imaging for real-time, single cell, drug screening in breast cancer
Authors: Polanco Edward R. , Moustafa Tarek E. , Butterfield Andrew , Scherer Sandra D. , Cortes-Sanchez Emilio , Bodily Tyler , Spike Benjamin T. , Welm Bryan E. , Bernard Philip S. , Zangle Thomas A.
Published: November 2021

Quantitative phase imaging (QPI) measures the growth rate of individual cells by quantifying changes in mass versus time. Here, we use the breast cancer cell lines MCF-7, BT-474, and MDA-MB-231 to validate QPI as a multiparametric approach for determining response to single-agent therapies. Our method allows for rapid determination of drug sensitivity, cytotoxicity, heterogeneity, and time of response for up to 100,000 individual cells or small clusters in a single experiment. We find that QPI EC50values are concordant with CellTiter-Glo (CTG), a gold standard metabolic endpoint assay. In addition, we apply multiparametric QPI to characterize cytostatic/cytotoxic and rapid/slow responses and track the emergence of resistant subpopulations. Thus, QPI reveals dynamic changes in response heterogeneity in addition to average population responses, a key advantage over endpoint viability or metabolic assays. Overall, multiparametric QPI reveals a rich picture of cell growth by capturing the dynamics of single-cell responses to candidate therapies.
Layer 1 of somatosensory cortex: An important site for input to a tiny cortical compartment
Authors: Ledderose Julia MT , Zolnik Timothy A , Toumazou Maria , Trimbuch Thorsten , Rosenmund Christian , Eickholt Britta J , Jaeger Dieter , Larkum Matthew E , Sachdev Robert NS
Published: November 2021

Neocortical Layer (L) 1 has been proposed to be at the center for top-down and bottom-up integration. It is a locus for interactions between long-range inputs, L1 interneurons and apical tuft dendrites of pyramidal neurons. While input to L1 has been studied intensively, the level and effect of input to this layer has still not been completely characterized. Here we examined the input to L1 of mouse somatosensory cortex with retrograde tracing and optogenetics. Our assays reveal that local input to L1 is predominantly from L2/3 and L5 pyramidal neurons and interneurons, and that subtypes of local L5 and L6b neurons project to L1 with different probabilities. Long-range input from sensory-motor cortices to L1 of S1 arose predominantly from L2/3 neurons. Our optogenetic experiments showed that intra-telencephalic L5 pyramidal neurons drive L1 interneurons but have no effect locally on L5 apical tuft dendrites. Dual retrograde tracing revealed that a fraction of local and long-range neurons were both presynaptic to L5 neurons and projected to L1. Our work highlights the prominent role of local inputs to L1 and shows the potential for complex interactions between long-range and local inputs which are both in position to modify the output of somatosensory cortex.
Panton-Valentine leukocidin-induced neutrophil extracellular traps lack antimicrobial activity and are readily induced in patients with recurrent PVL+-Staphylococcus aureusinfections
Authors: Jhelum Hina , Čerina Dora , Harbort CJ , Lindner Andreas , Hanitsch Leif Gunnar , Leistner Rasmus , Schröder Jennyver-Tabea , von Bernuth Horst , Stegemann Miriam Songa , Schürmann Mariana , Zychlinsky Arturo , Krüger Renate , Marsman Gerben
Published: November 2021

Staphylococcus aureus(S. aureus) strains that produce the toxin Panton-Valentine leukocidin (PVL; PVL-SA) frequently cause recurrent skin and soft tissue infections (SSTI). PVL binds to and kills human neutrophils, resulting in the formation of neutrophil extracellular traps, but the pathomechanism has not been extensively studied. Furthermore, it is unclear why some individuals colonized with PVL-SA suffer from recurring infections whereas others are asymptomatic. We thus aimed to (a) investigate how PVL exerts its pathogenicity on neutrophils and (b) identify factors that could help to explain the predisposition of patients with recurring infections.

We provide genetic and pharmacological evidence that PVL-induced NET formation is independent of NADPH-oxidase and reactive oxygen species (ROS) production. Moreover, through NET proteome analysis we identified that the protein content of PVL-induced NETs is different from NETs induced by mitogen or the microbial toxin nigericin. The abundance of the proteins cathelicidin (CAMP), elastase (NE), and proteinase 3 (PRTN3) was lower on PVL-induced NETs, and as such they were unable to killS. aureus.Furthermore, we found that neutrophils from affected patients express higher levels of CD45, one of the PVL receptors, and are more susceptible to be killed at a low PVL concentration than control neutrophils. Neutrophils from patients that suffer from recurring PVL-positive infections may thus be more sensitive to PVL-induced NET formation, which might impair their ability to combat the infection.

Importance

Individuals colonized byStaphylococcus aureusstrains that produce Panton-Valentine leukocidin (PVL-SA) often present with recurrent skin and soft-tissue infections, whilst other individuals remain asymptomatic. PVL is a toxin that kills neutrophils, which results in the formation of neutrophil extracellular traps. Traps induced by other stimuli are known to be toxic toS. aureus.We found however that NETs specifically induced by PVL are not toxic toS. aureus. Furthermore, we show that neutrophils from individuals that suffer from recurring PVL-SA infections are more sensitive to PVL-induced NET formation compared to healthy individuals. The significance of our work is in identifying a mechanism through which PVL-SA may actively counter the engagement of neutrophils. Moreover, we identified that patients with recuring PVL-SA infections may be more sensitive to this mechanism, which may help to explain their clinical condition and might provide avenues for future treatment development.
Increasing the Spatial Extent of Attention Strengthens Surround Suppression
Authors: Kiniklioglu Merve , Boyaci Huseyin
Published: November 2021

Here we investigate how the extent of spatial attention affects center-surround interaction in visual motion processing. To do so, we measured motion direction discrimination thresholds in humans using drifting gratings and two attention conditions. Under the narrow attention condition, attention was limited to the central part of the visual stimulus, whereas under the wide attention condition, it was directed to both the center and surround of the stimulus. We found stronger surround suppression under the wide attention condition. The magnitude of the attention effect increased with the size of the surround when the stimulus had low contrast, but did not change when it had high contrast. Results also showed that attention had a weaker effect when the center and surround gratings drifted in opposite directions. Next, to establish a link between the behavioral results and the neuronal response characteristics, we performed computer simulations using the divisive normalization model. Our simulations showed that the model can successfully predict the observed behavioral results using parameters derived from the medial temporal (MT) area of the cortex. These findings reveal the critical role of spatial attention on surround suppression and establish a link between neuronal activity and behavior. Further, these results also suggest that the reduced surround suppression found in certain clinical disorders (e.g., schizophrenia and autism spectrum disorder) may be caused by abnormal attention mechanisms.
Quantitative evaluation of Mycobacterium abscessus clinical isolate virulence using a silkworm infection model
Authors: Matsumoto Yasuhiko , Fukano Hanako , Hasegawa Naoki , Hoshino Yoshihiko , Sugita Takashi
Published: November 2021

Mycobacterium abscessus causes chronic skin infections, lung diseases, and systemic or disseminated infections. Here we investigated whether the virulence of M. abscessus clinical isolates could be evaluated by calculating the median lethal dose (LD50) in a silkworm infection model. M. abscessus subsp. abscessus cells were injected into the silkworm hemolymph. When reared at 37°C, the silkworms died within 2 days post-infection with M. abscessus subsp. abscessus. Viable cell numbers of M. abscessus subsp. abscessus increased in the hemolymph of silkworms injected with M. abscessus subsp. abscessus. Silkworms were not killed by injections with heat-killed M. abscessus subsp. abscessus cells. The administration of clarithromycin, an antibacterial drug used to treat the infection, prolonged the survival time of silkworms injected with M. abscessus subsp. abscessus. The LD50 values of 7 clinical isolates were determined using the silkworm infection model and differed by up to 9-fold. The Mb-17 isolate, which was identified as a pathogenic strain in the silkworm infection model, induced more detachment of human THP-1-derived macrophages during infection than the Mb-10 isolate. These findings suggest that the silkworm M. abscessus infection model with can be used to quantitatively evaluate the virulence of M. abscessus clinical isolates in a short time period.
Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages
Authors: Jin Jessica , Ba Mame Aida , Wai Chi Ho , Mohanty Sanjib , Sahu Praveen K. , Pattnaik Rajyabardham , Pirpamer Lukas , Fischer Manuel , Heiland Sabine , Lanzer Michael , Frischknecht Friedrich , Mueller Ann-Kristin , Pfeil Johannes , Majhi Megharay , Cyrklaff Marek , Wassmer Samuel C. , Bendszus Martin , Hoffmann Angelika
Published: November 2021

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach in cerebral brain swelling to reduce edema and may ultimately lead to a reduced permanent brain damage and a better longtime neurological outcome.

Author summary

Brain swelling, which occurs in diseases such as cerebral malaria, is not necessarily fatal, and may reverse. Even upon reversal of brain swelling, neurological sequelae can still occur. The factors contributing to the reversibility of brain edema are not known, and treatment options remain therefore limited. Identifying the mechanisms leading to such reversibility could inform clinical management aimed at decreasing brain swelling and consecutive brain injury. Here we introduce a reproducible and simple animal model that allows comprehensive in vivo studies of reversible brain swelling in cerebral malaria at the peak of disease and upon recovery. We identify a specific type of blood-brain barrier disruption (BBBD) as a mechanism that occurs in brain swelling. We show that BBBD can reverse, but also highlight remaining brain damage in areas of most severe BBBD. As the ECM model introduced here bares crucial similarities to the CM in humans, our findings open strategies to study new therapeutic avenues and point to compounds that specifically target transcellular BBBD to reduce brain edema, and increase survival rates.
Curation, inference, and assessment of a globally reconstructed gene regulatory network forStreptomyces coelicolor
Authors: Zorro-Aranda Andrea , Escorcia-Rodríguez Juan Miguel , González-Kise José Kenyi , Freyre-González Julio Augusto
Published: November 2021

Streptomyces coelicolorA3(2) is a model microorganism for the study of Streptomycetes, antibiotic production, and secondary metabolism in general. Even thoughS. coelicolorhas an outstanding variety of regulators among bacteria, little effort to globally study its transcription has been made. We manually curated 29 years of literature and databases to assemble a meta-curated experimentally-validated gene regulatory network (GRN) with 5386 genes and 9707 regulatory interactions (∼41% of the total expected interactions). This provides the most extensive and up-to-date reconstruction available for the regulatory circuitry of this organism. Only ∼6% (534/9707) are supported by experiments confirming the binding of the transcription factor to the upstream region of the target gene, the so-called “strong” evidence. While for the remaining interactions there is no confirmation of direct binding. To tackle network incompleteness, we performed network inference using several methods (including two proposed here) for motif identification in DNA sequences and GRN inference from transcriptomics. Further, we contrasted the structural properties and functional architecture of the networks to assess the reliability of the predictions, finding the inference from DNA sequence data to be the most trustworthy approach. Finally, we show two applications of the inferred and the curated networks. The inference allowed us to propose novel transcription factors for the keyStreptomycesantibiotic regulatory proteins (SARPs). The curated network allowed us to study the conservation of the system-level components betweenS. coelicolor and Corynebacterium glutamicum. There we identified the basal machinery as the common signature between the two organisms. The curated networks were deposited in Abasy Atlas (https://abasy.ccg.unam.mx/) while the inferences are available as Supplementary Material.
IL-37 expression reduces acute and chronic neuroinflammation and rescues cognitive impairment in an Alzheimer’s disease mouse model
Authors: Lonnemann Niklas , Hosseini Shirin , Ohm Melanie , Hiller Karsten , Dinarello Charles A. , Korte Martin
Published: November 2021

The anti-inflammatory cytokine interleukin-37 (IL-37) is a member of the IL-1 family but not expressed in mice. We used a human IL-37 (hIL-37tg) expressing mouse, which has been subjected to various models of local and systemic inflammation as well as immunological challenges. Those studies demonstrate an immune-modulatory role of IL-37 which can be characterized as an important suppressor of innate immunity. We investigated the functions of IL-37 in the CNS and explored the effects of IL-37 on neuronal architecture and function, microglia phenotype, cytokine production and behavior after inflammatory challenge by intraperitoneal LPS-injection. Reduced spine density, activated microglia phenotype and impaired long-term potentiation (LTP) were observed in wild-type mice after LPS injection, whereas hIL-37tg mice showed no impairment. In addition, we crossed the hIL-37tg mouse with an animal model of Alzheimer’s disease (APP/PS1) to investigate the anti-inflammatory properties of IL-37 under chronic neuroinflammatory conditions. Our results show that IL-37 is able to limit inflammation in the brain after acute inflammatory events and prevent the loss of cognitive abilities in a mouse model of AD.
Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy
Authors: Heo Lim , Feig Michael
Published: November 2021

The family of G-protein coupled receptors (GPCRs) is one of the largest protein families in the human genome. GPCRs transduct chemical signals from extracellular to intracellular regions via a conformational switch between active and inactive states upon ligand binding. While experimental structures of GPCRs remain limited, high-accuracy computational predictions are now possible with AlphaFold2. However, AlphaFold2 only predicts one state and is biased towards either the active or inactive conformation depending on the GPCR class. Here, a multi-state prediction protocol is introduced that extends AlphaFold2 to predict either active or inactive states at very high accuracy using state-annotated templated GPCR databases. The predicted models accurately capture the main structural changes upon activation of the GPCR at the atomic level. For most of the benchmarked GPCRs (10 out of 15), models in the active and inactive states were closer to their corresponding activation state structures. Median RMSDs of the transmembrane regions were 1.12 Å and 1.41 Å for the active and inactive state models, respectively. The models were more suitable for protein-ligand docking than the original AlphaFold2 models and template-based models. Finally, our prediction protocol predicted accurate GPCR structures and GPCR-peptide complex structures in GPCR Dock 2021, a blind GPCR-ligand complex modeling competition. We expect that high accuracy GPCR models in both activation states will promote understanding in GPCR activation mechanisms and drug discovery for GPCRs. At the time, the new protocol paves the way towards capturing the dynamics of proteins at high-accuracy via machine-learning methods.
The long and the short of it: Nanopore based eDNA metabarcoding of marine vertebrates works; sensitivity and specificity depend on amplicon lengths
Authors: Doorenspleet Karlijn , Jansen Lara , Oosterbroek Saskia , Kamermans Pauline , Bos Oscar , Wurz Erik , Murk Albertinka , Nijland Reindert
Published: November 2021

To monitor the effect of nature restoration projects in North Sea ecosystems, accurate and intensive biodiversity assessments are vital. DNA based techniques and especially environmental DNA (eDNA) metabarcoding is becoming a powerful monitoring tool. However, current approaches are based on genetic target regions <500 nucleotides, which offer limited taxonomic resolution. We developed a method for eDNA metabarcoding, based on nanopore sequencing of a longer amplicon, enabling improved identification of fish species. We designed a universal primer pair targeting a 2kb region of fish mitochondria, and compared it to the commonly used MiFish primer pair that targets only ∼170bp.In sillicoand mock community testing showed that the 2kb fragments improved the accurate identification of genetically closely related species. eDNA was amplified, and sequenced using the Oxford Nanopore MinION in combination with the sequence read processing pipeline Decona. Analyzing eDNA from a North Sea aquarium showed that sequences from both primer pairs could be assigned to most species, but both approaches also identified unique species in the aquarium eDNA. Next, both primer pairs were used on multiple eDNA samples from the North Sea. Here, similar location specific fish communities were obtained from both approaches. More species were identified through the MiFish approach in the field samples. Interestingly, this difference was not observed in the aquarium, suggesting that 2kb fragment based metabarcoding potentially detects more recent occurrences of animals. This new method has the potential to improve and expand the molecular toolbox for eDNA based monitoring approaches.
Timing is everything: event-related transcranial direct current stimulation improves motor adaptation
Authors: Weightman Matthew , Brittain John-Stuart , Hall Alison , Miall R. Chris , Jenkinson Ned
Published: November 2021

Background

There is a current discord between the foundational theories underpinning motor learning and how we currently apply transcranial direct current stimulation (TDCS): the former is dependent on tight coupling of events while the latter is conducted with very low temporal resolution.

Objective

Here we aimed to investigate the temporal specificity of stimulation by applying TDCS in short epochs, and coincidentally with movement, during a motor adaptation task.

Methods

Participants simultaneously adapted a reaching movement to two opposing velocity-dependent force-fields (clockwise and counter-clockwise), distinguished by a contextual leftward or rightward shift in the task display and cursor location respectively. Brief bouts (< 3 second) of event-related TDCS (er-TDCS) were applied over M1 or the cerebellum during movements for only one of these learning contexts.

Results

We show that when short duration stimulation is applied to the cerebellum and yoked to movement, only those reaching movements performed simultaneously with stimulation are selectively enhanced, whilst similar and interleaved movements are left unaffected. We found no evidence of improved adaptation following M1 er-TDCS, as participants displayed equivalent levels of error during both stimulated and unstimulated movements. Similarly, participants in the sham stimulation group adapted comparably during left and right-shift trials.

Conclusions

It is proposed that the coupling of cerebellar stimulation and movement influences timing-dependent (i.e., Hebbian-like) mechanisms of plasticity to facilitate enhanced learning in the stimulated context.
Neural crest-related NXPH1/α-NRXN signaling opposes neuroblastoma malignancy by inhibiting metastasis
Authors: Fanlo-Escudero Lucía , Gómez-González Soledad , Sangrador Irene , Gautier Emmanuel L. , Usieto Susana , Rebollo Elena , Vila-Ubach Mònica , Carcaboso Ángel M. , Celià-Terrassa Toni , Lavarino Cinzia , Martí Elisa , Le Dréau Gwenvael
Published: November 2021

Neuroblastoma is a pediatric cancer that can present as low- or high-risk tumors (LR-NBs and HR-NBs), the latter group showing poor prognosis due to metastasis and strong resistance to current therapy. NBs are known to originate from alterations to cells in the sympatho-adrenal lineage derived from the neural crest, but whether LR-NBs and HR-NBs differ in the way they exploit the transcriptional program underlying their developmental origin remains unclear. Here, we compared the transcriptional landscapes of primary samples of LR-NBs, HR-NBs and human fetal adrenal gland, and thereby identified the transcriptional signature associated to NB formation that further distinguishes LR-NBs from HR-NBs. The majority of the genes comprising this signature belong to the core sympatho-adrenal developmental program, are associated with favorable patient prognosis and with diminished disease progression. The top candidate gene of this list, Neurexophilin-1 (NXPH1), encodes a ligand of the transmembrane receptors α-Neurexins (α-NRXNs). Our functional in vivo and in vitro assays reveal that NXPH1/α-NRXN signaling has a dual impact on NB behavior: whereas NXPH1 and α-NRXN1 promote NB tumor growth by stimulating cell proliferation, they conversely inhibit the ability of NB cells to form metastases. Our findings uncover a module of the neural crest-derived sympatho-adrenal developmental program that opposes neuroblastoma malignancy by impeding metastasis, and pinpoint NXPH1/α-NRXN signaling as a promising target to treat HR-NBs.
Paleozoic Protein Fossils Illuminate the Evolution of Vertebrate Genomes and Transposable Elements
Authors: Frith Martin C.
Published: November 2021

Genomes hold a treasure trove of protein fossils: fragments of formerly protein-coding DNA, which mainly come from transposable elements (TEs) or host genes. These fossils reveal ancient evolution of TEs and genomes, and many fossils have been exapted to perform diverse functions important for the host’s fitness. However, old and highly-degraded fossils are hard to identify, standard methods (e.g. BLAST) are not optimized for this task, and few Paleozoic protein fossils have been found.

Here, a recently optimized method is used to find protein fossils in vertebrate genomes. It finds Paleozoic fossils predating the amphibian/amniote divergence from most major TE categories, including virus-related Polinton and Gypsy elements. It finds 10 fossils in the human genome (8 from TEs and 2 from host genes) that predate the last common ancestor of all jawed vertebrates, probably from the Ordovician period. It also finds types of transposon and retrotransposon not found in human before. These fossils have extreme sequence conservation, indicating exaptation: some have evidence of gene-regulatory function, and they tend to lie nearest to developmental genes. Some ancient fossils suggest “genome tectonics”, where two fragments of one TE have drifted apart by up to megabases, possibly explaining gene deserts and large introns.

This paints a picture of great TE diversity in our aquatic ancestors, with patchy TE inheritance by later vertebrates, producing new genes and regulatory elements on the way. Host-gene fossils too have contributed anciently-conserved DNA segments. This paves the way to further studies of ancient protein fossils.
Chloroplast transit peptides often require downstream unstructured sequence in Chlamydomonas reinhardtii
Authors: Caspari OD
Published: November 2021

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The N-terminal sequence stretch that defines subcellular targeting for most nuclear encoded chloroplast proteins is usually considered identical to the sequence that is cleaved upon import. Yet here this study shows that for nine out of ten tested Chlamydomonas chloroplast transit peptides, additional sequence past the cleavage site is required to enable chloroplast targeting. Using replacements of native post-cleavage residues with alternative sequences points to a role for unstructured sequence at mature protein N-termini.
Near atomic structure of the inner ring of the Saccharomyces cerevisiae nuclear pore complex
Authors: Li Zongqiang , Chen Shuaijiabin , Zhao Liang , Huang Guoqiang , Pi Xiong , Sun Shan , Wang Peiyi , Sui Sen-Fang
Published: November 2021

Nuclear pore complexes (NPCs) mediate bidirectional nucleocytoplasmic transport of substances in eukaryotic cells. However, the accurate molecular arrangement of NPCs remains enigmatic owing to their huge size and highly dynamic nature. Here we determined the structure of the asymmetric unit of the inner ring (IR monomer) at 3.73 Å resolution by single-particle cryo-electron microscopy, and created an atomic model of the intact IR consisting of 192 copies from 8 subunits. In each IR monomer, two approximately parallel rhomboidal structures of the inner and outer layers are sandwiched with the Z-shaped Nup188-Nup192 middle layer and Nup188, Nup192 and Nic96 link all subunits to constitute a relatively stable IR monomer, while the intact IR is assembled by loose and instable interactions between IR monomer. These structures reveal various interaction modes and extensive flexible connections in the assembly, providing a structural basis for the stability and malleability of IR.

One-Sentence Summary

Accurate structure of inner ring reveals its assembly and function in dilation and constriction of nuclear pore complex.
Proteomic Characterization of Serum Small Extracellular Vesicles in Human Breast Cancer
Authors: Xu Ganfei , Huang Weiyi , Du Shaoqian , Huang Minjing , Lyu Jiacheng , Zhou Fei , Zhu Rongxuan , Cao Yuan , Xv Jingxuan , Li Ning , Yu Guoying , Jiang Binghua , Gires Olivier , Zhou Lei , Zhang Hongwei , Ding Chen , Wang Hongxia
Published: November 2021

There is a lack of comprehensive understanding of breast cancer (BC) specific sEVs characteristics and composition on BC unique proteomic information from human samples. Here, we interrogated the proteomic landscape of sEVs in 167 serum samples from patients with BC, benign mammary disease (BD) and from healthy donors (HD). The analysis provides a comprehensive landscape of serum sEVs with totally 9,589 proteins identified, considerably expanding the panel of sEVs markers. Of note, serum BC-sEVs protein signatures were distinct from those of BD and HD, representing stage- and molecular subtype-specific patterns. We constructed specific sEVs protein identifiers that could serve as a liquid biopsy tool for diagnosis and classification of BC from benign mammary disease, molecular subtypes, as well as assessment of lymph node metastasis. We also identified 11 potential survival biomarkers for distant metastasis. This work may provide reference value for the accurate diagnosis and monitoring of BC progression using serum sEVs.
Mars, a molecule archive suite for reproducible analysis and reporting of single-molecule properties from bioimages
Authors: Huisjes Nadia M , Retzer Thomas M , Scherr Matthias J , Agarwal Rohit , Rajappa Lional , Safaric Barbara , Minnen Anita , Duderstadt Karl E
Published: November 2021

The rapid development of new imaging approaches is generating larger and more complex datasets revealing the time evolution of individual cells and biomolecules. Single-molecule techniques, in particular, provide access to rare intermediates in complex, multistage molecular pathways. However, few standards exist for processing these information-rich datasets, posing challenges for wider dissemination. Here, we present Mars, an open-source platform for storing and processing image-derived properties of biomolecules. Mars provides Fiji/ImageJ2 commands written in Java for common single-molecule analysis tasks using a Molecule Archive architecture that is easily adapted to complex, multistep analysis workflows. Three diverse workflows involving molecule tracking, multichannel fluorescence imaging, and force spectroscopy, demonstrate the range of analysis applications. A comprehensive graphical user interface written in JavaFX enhances biomolecule feature exploration by providing charting, tagging, region highlighting, scriptable dashboards, and interactive image views. The interoperability of ImageJ2 ensures Molecule Archives can easily be opened in multiple environments, including those written in Python using PyImageJ, for interactive scripting and visualization. Mars provides a flexible solution for reproducible analysis of image-derived properties, facilitating the discovery and quantitative classification of new biological phenomena with an open data format accessible to everyone.
Genetic and thermal variation influence adaptation to fluctuating temperature in the seed beetle, Callosobruchus maculatus
Authors: Ivimey-Cook Edward , Piani Claudio , Hung Wei-Tse , Berg Elena C.
Published: November 2021

Climate change is associated with both the increase in mean and variability of thermal conditions. The use of more realistic thermal regimes is therefore the most appropriate laboratory method to correctly predict population responses to thermal heterogeneity. However, both the long- and short-term implications of evolving under such conditions are not well understood. Here, we examined the effect of fluctuating daily temperatures on several key life history traits in the seed beetle, Callosobruchus maculatus, that was exposed to a short-term thermal switch into a novel environment. Populations were kept for 19 generations at one of two temperatures: constant control temperature (T=29°C) or a fluctuating daily cycle (Tmean=33°C, Tmax=40°C, and Tmin=26°C) and were subsequently exposed to a switch to the opposite condition. We found that beetles that had evolved in stressful environments were smaller in size when switched to a constant 29°C and had far greater reproductive fitness compared to beetles from both the constant control and continuously stressful 33°C environments. This suggests that beetles raised in environments with stressful fluctuating temperatures were more phenotypically plastic and had greater genetic variability than control treatment beetles and indicates that populations that experience fluctuations in temperature may be better able to respond to short-term changes in environmental conditions.