bluuebunny/crossref_metadata_2025 huggingface dataset:
Pre-Injury Mechanoreceptor Ablation Reduces Nociceptor-Driven Spinal Cord Injury-Induced Neuropathic Pain
Authors: Sliwinski Christopher , Heutehaus Laura , Taberner Francisco J. , Weiss Lisa , Kampanis Vasileios , Tolou-Dabbaghian Bahardokht , Cheng Xing , Motsch Melanie , Heppenstall Paul A. , Kuner Rohini , Franz Steffen , Lechner Stefan G. , Weidner Norbert , Puttagunta Radhika
Published: December 2022

Evidence from previous studies supports the concept that spinal cord injury (SCI) induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree nociceptors and mechanoreceptors contribute. Sensorimotor activation-based interventions (e.g. treadmill training) have been shown to reduce NP following experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. At the same time, nociceptors have been shown to become hyperexcitable early after SCI and peptidergic axons sprout into deeper laminae of the below injury level dorsal horn. The aim of the present study is to comprehensively understand the relative contribution of each pathway in respect to NP presentation in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B (TrkB) expressing mechanoreceptorsbefore SCImechanical allodynia was reduced. The identical genetic ablationafter SCIdid not yield any change in pain behavior. CGRP sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. Moreover, detection of hyperexcitability in nociceptors, not in mechanoreceptors, in skin-nerve preparations of contusion SCI mice 7 days after injury makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. SNS reporter mice allowing specific visualization of the entire nociceptor population confirmed significant sprouting of respective neurons into laminae III/IV as early as 5 days post-injury. Genetic ablation of SNS-Cre mice severely affected their overall health condition, which precluded them to undergo experimental SCI and subsequent further analysis. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors with consecutive peptidergic fiber sprouting in the dorsal horn are confirmed as the likely main driver of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions.
Uncovering directional epistasis in bi-parental populations using genomic data
Authors: Rio Simon , Charcosset Alain , Moreau Laurence , Mary-Huard Tristan
Published: December 2022

Epistasis, commonly defined as interaction effects between alleles of different loci, is an important genetic component of the variation of phenotypic traits in natural and breeding populations. In addition to its impact on variance, epistasis can also affect the expected performance of a population and is then referred to as directional epistasis. Before the advent of genomic data, the existence of epistasis (both directional and non-directional) was investigated based on complex and expensive mating schemes involving several generations evaluated for a trait of interest. In this study, we propose a methodology to detect the presence of epistasis based on simple inbred bi-parental populations, both genotyped and phenotyped, ideally along with their parents. Thanks to genomic data, parental proportions as well as shared parental proportions between inbred individuals can be estimated. They allow the evaluation of epistasis through a test of the expected performance for directional epistasis or the variance of genetic values. This methodology was applied to two large multi-parental populations, i.e., the American maize and soybean nested association mapping populations, evaluated for different traits. Results showed significant epistasis, especially for the test of directional epistasis, e.g., the increase in anthesis to silking interval observed in most maize inbred progenies or the decrease in grain yield observed in several soybean inbred progenies. In general, the effects detected suggested that shuffling allelic assocations of both elite parents had a detrimental effect on the performance of their progeny. This methodology is implemented in the EpiTest R-package and can be applied to any bi-/multi-parental inbred population evaluated for a trait of interest.
Investigation of a mathematical model describing global cancer growth and treatment: An inhomogeneous model based on the generalized logistic equation
Authors: Wang Haofan , Mao Yitao , Zhang Zhen , Xu Zhenxiong , Luo Shuyang , Li Weifeng , Zou Sibin , Chen Bin , Wen Huiquan , Lin Longxin , Liao Weihua , Huang Mingsheng
Published: December 2022

Tumor growth is manifestation of the evolution of a complex system. Researchers have limited scope of modelling studies on specific aspects or stages of the process. It has led to unsatisfactory explanation of clinical observations. We hereby demonstrated that an inhomogeneous model built on the generalized logistic equation could serve better. It was developed to describe the whole process of tumor progression, clinically observed independence of index tumor growth from spread of the disease and growth deceleration during early stage of solid tumors. It was validated by simulating the coexistence of exponential and sigmoidal growth in chronic lymphocytic leukaemia, theories of tumor heterogeneity, as well as by accommodating notions pertaining to tumor treatment and prognosis. We thought therefore it was an interesting and not unjustifiable description of actual tumor growth in human body and hoped it might encourage more researchers to look at tumor modelling from a clinical perspective.
Relationship between the concentration of ergothioneine in plasma and the likelihood of developing pre-eclampsia
Authors: Kenny Louise C. , Brown Leslie W , Ortea Paloma , Tuytten Robin , Kell Douglas B.
Published: December 2022

Ergothioneine, an antioxidant nutraceutical mainly at present derived from the dietary intake of mushrooms, has been suggested as a preventive for pre-eclampsia. We analysed early pregnancy samples for a cohort of 432 first time mothers as part of the Screening for Endpoints in Pregnancy (SCOPE, European branch) project to determine the concentration of ergothioneine in their plasma. There was a weak association between the ergothioneine levels and maternal age, but none for BMI. Of these 432 women, 97 went on to develop pre-term (23) or term (74) pre-eclampsia. If a threshold was set at the 90thpercentile of the reference range in the control population (≥ 462 ng/mL), only one of these 97 women (1%) developed pre-eclampsia, versus 97/432 (22.5%) whose ergothioneine level was below this threshold. One possible interpretation of these findings, consistent with previous experiments in a reduced uterine perfusion model in rats, is that ergothioneine may indeed prove protective against pre-eclampsia in humans. An intervention study of some kind now seems warranted.
Temporal DCE Profile of Brain Metastasis with A Comparison of Pseudoprogression Cases
Authors: Turk Sevcan , Kurokawa Ryo , Naganawa Shotaro , Wallace Jacob , Ma Tianwen , Johnson Timothy , Moritani Toshio , Kim John
Published: December 2022

Purpose

To demonstrate Dynamic Contrast-Enhanced (DCE) perfusion changes in brain metastasis patients after chemoradiation therapy within the treatment responders (true-response group and pseudoprogression group) and between the true-response and pseudoprogression groups.

Materials and Methods

38 true-response patients with 38 brain metastases (13 melanoma, 11 lung, 7 breast, 7 others) with 3 consecutive DCE-MRI examinations (pretreatment, first follow-up and second follow-up) and 7 pseudoprogression patients with 10 melanoma metastases with 2 consecutive DCE-MRI examinations (pretreatment, first follow-up) were evaluated. DCE-MRI parameters and permeability graphs increase (rapid, slow, medium) and course pattern (washout, plateau, persistent) were analyzed and compared between the timing of the examinations and between the true-response and pseudoprogression groups, using paired t-tests and Mann-Whitney U-tests as appropriate. Automatic assessment of washout curves by Olea Brain Software was reviewed.

Results

Pretreatment mean wash-in (15.3±24.7 vs 6.50±14.2, P<0.02), Vp (0.13±0.17 vs 0.06±0.06, P<0.01), Ktrans (0.37±0.48 vs 0.16±0.18, P<0.01), peak enhancement (123±98 vs 76±60.5, P<0.01), AUC (14×104±18×104vs 5×104±10×104, P<0.001) values were significantly higher than that of post-treatment. Other DCE metrics and permeability graph factors between pre-and post-treatment MRI were not significantly different. There was no statistically significant difference in any imaging factors in pre-or first post-treatment DCE-MRI examinations between the true-response and pseudoprogression groups.

Conclusion

Wash-in, Vp, Ktrans, peak enhancement, AUC values in DCE perfusion were significantly decreased after chemoradiation therapy in the responders. No statistically significant difference was shown between the true-response and pseudoprogression groups on either pre-or post-treatment, indicating the homogeneous permeability profiles in the responders.
Using Twitter Data Analysis to Understand the Perceptions, Awareness, and Barriers to the Wide Use of Pre-Exposure Prophylaxis in the United States
Authors: Erdengasileng Arslan , Tian Shubo , Green Sara S. , Naar Sylvie , He Zhe
Published: December 2022

User-generated social media posts such as tweets can provide insights about the public’s perception, cognitive, and behavioral responses to health-related issues. Pre-Exposure Prophylaxis (PrEP) is one of the most effective ways to reduce the risk of HIV infection. However, its utilization is low in the US, especially among populations disproportionately affected by HIV such as the age group of under 24 years old. It is therefore important to understand the barriers to the wider use of PrEP in the US using social media posts. In this study, we collected tweets from Twitter about PrEP in the past 4 years to identify such barriers by first identifying tweets about personal discussions, and then performing textual analysis using word analysis, UMLS semantic type analysis, and topic modeling. We found that the public often discussed advocacy, risks/benefits, access, pricing, insurance coverage, legislation, stigma, health education, and prevention of HIV. This result is consistent with the literature and can help identify strategies for promoting the use of PrEP, especially among young adults.
Neuroinflammation in the amygdala is associated with recent depressive symptoms
Authors: Zhang Wei , Rutlin Jerrel , Eisenstein Sarah A. , Wang Yong , Barch Deanna , Hershey Tamara , Bogdan Ryan , Bijsterbosch Janine
Published: December 2022

Background

Converging evidence suggests that elevated inflammation may contribute to depression. Yet, the link between peripheral and neuro-inflammation in depression is unclear. Here using data from the UK Biobank (n=11,512), we estimated associations among depression, C-reactive protein as a measure of peripheral inflammation (CRP), and neuroinflammation as indexed by diffusion-basis spectral imaging-based restricted fraction (DBSI-RF).

Methods

DBSI-RF was derived from diffusion-weighted imaging data for whole-brain gray matter (global-RF), and regions of interest in bilateral amygdala (amygdala-RF) and hippocampus (hippocampus-RF), and CRP was estimated from blood (serum) samples. Self-reported recent depression symptoms were measured using a 4-item assessment. Linear regressions were used to estimate associations between CRP and DBSI-RFs with depression, while adjusting for the following covariates: Age, sex, body mass index, smoking, drinking, and medical conditions.

Results

Elevated CRP was associated with higher depression symptoms (r=0.03, p<0.001) and reduced global-RF (r=-0.03, p<0.005). Higher amygdala-RF was associated with elevated depression – an effect resilient to added covariates and CRP (t=2.53, β=0.02, p<0.05). Interestingly, this association was stronger in individuals with a lifetime history of depression (t=3.02, β=0.07, p<0.005) than in those without (t=2.32, β=0.03, p<0.05). Associations between global-RF or hippocampus-RF with depression were not significant, and no DBSI-RF indices indirectly linked CRP with depression (i.e., mediation effect).

Conclusion

Peripheral inflammation and DBSI-RF neuroinflammation in the amygdala are independently associated with depression, consistent with animal studies suggesting distinct pathways of peripheral and neuro-inflammation in the pathophysiology of depression, and with investigations highlighting the role of the amygdala in stress-induced inflammation and depression.
ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients
Authors: Song Yufeng , Myers Regan , Murphy Lila , Brooks Bailey , Wilson Jeffrey M. , Kadl Alexandra , Woodfolk Judith , Zeichner Steven L.
Published: December 2022

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for SARS-CoV-2 spike protein’s receptor binding domain (RBD) is angiotensin converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity – ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn2+for activity. However, we found that the plasma from some patients studied could cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium ethylenediaminetetraacetate (EDTA) anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn2+was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis.
Changing social contact patterns among US workers during the COVID-19 pandemic: April 2020 to December 2021
Authors: Kiti Moses C. , Aguolu Obianuju G. , Zelaya Alana , Chen Holin Y. , Ahmed Noureen , Battross Jonathan , Liu Carol Y. , Nelson Kristin N. , Jenness Samuel M. , Melegaro Alessia , Ahmed Faruque , Malik Fauzia , Omer Saad B. , Lopman Ben A.
Published: December 2022

Non-pharmaceutical interventions minimize social contacts, hence the spread of SARS-CoV-2. We quantified two-day contact patterns among USA employees from 2020–2021 during the COVID-19 pandemic. Contacts were defined as face-to-face conversations, involving physical touch or proximity to another individual and were collected using electronic diaries. Mean (standard deviation) contacts reported by 1,456 participants were 2.5 (2.5), 8.2 (7.1), 9.2 (7.1) and 10.1 (9.5) across round 1 (April–June 2020), 2 (November 2020–January 2021), 3 (June–August 2021), and 4 (November–December 2021), respectively. Between round 1 and 2, we report a 3-fold increase in the mean number of contacts reported per participant with no major increases from round 2–4. We modeled SARS-CoV-2 transmission at home, work, and community. The model revealed reduced relative transmission in all settings in round 1. Subsequently, transmission increased at home and in the community but remained very low in work settings. Contact data are important to parameterize models of infection transmission and control.

Teaser

Changes in social contact patterns shape disease dynamics at workplaces in the USA.
Utilizing co-abundances of antimicrobial resistance genes to identify potential co-selection in the resistome
Authors: Martiny Hannah-Marie , Munk Patrick , Brinch Christian , Aarestrup Frank M. , Calle M. Luz , Petersen Thomas N.
Published: December 2022

The rapid spread of antimicrobial resistance (AMR) is a threat to global health, and the nature of co-occurring antimicrobial resistance genes (ARGs) may cause collateral AMR effects once antimicrobial agents are used. Therefore, it is essential to identify which pairs of ARGs co-occur. Given the wealth of NGS data available in public repositories, we have investigated the correlation between ARG abundances in a collection of 214,095 metagenomic datasets. Using more than 6.76·108read fragments aligned to acquired ARGs to infer pairwise correlation coefficients, we found that more ARGs correlated with each other in human and animal sampling origins than in soil and water environments. Furthermore, we argued that the correlations could serve as risk profiles of resistance co-occurring to critically important antimicrobials. Using these profiles, we found evidence of several ARGs conferring resistance for critically important antimicrobials (CIA) being co-abundant, such as tetracycline ARGs correlating with most other forms of resistance. In conclusion, this study highlights the important ARG players indirectly involved in shaping the resistomes of various environments that can serve as monitoring targets in AMR surveillance programs.
Transcriptome Regulation by PARP13 in Basal and Antiviral States in Human Cells
Authors: Busa Veronica F. , Ando Yoshinari , Aigner Stefan , Yee Brian A. , Yeo Gene W , Leung Anthony K. L.
Published: December 2022

The RNA-binding protein PARP13 is a primary factor in the innate antiviral response. PARP13 suppresses translation and drives decay of bound viral and host RNA. PARP13 interacts with many proteins encoded by interferon-stimulated genes (ISG) to activate antiviral pathways including post-translational addition of ISG15, or ISGylation. We performed enhanced crosslinking immunoprecipitation (eCLIP) and RNA-seq in human cells to investigate PARP13’s role in transcriptome regulation for both basal and antiviral states. We find that the antiviral response shifts PARP13 target localization but not its binding preferences and that PARP13 supports the expression of ISGylation-related genes, including PARP13’s cofactor, TRIM25. We elucidate a transcriptome-wide periodicity of PARP13 binding around TRIM25 and show they associate in part via RNA-protein interactions. Taken together, our study implicates PARP13 in creating and maintaining a cellular environment poised for an antiviral response through limiting PARP13 translation, regulating access to distinct mRNA pools, and elevating ISGylation machinery expression.
Causal evidence for the involvement of Broca’s area in second language acquisition: A longitudinal HD-tDCS study
Authors: Gallagher Daniel , Matsumoto Kyosuke , Ohta Shinri
Published: December 2022

A wealth of correlational evidence suggests that Broca’s area (the left inferior frontal gyrus) plays a role in second language acquisition. With the use of highly focal non-invasive brain stimulation, evidence for a targeted brain region’s causal role in some cognitive behavior can be assessed. Over three sessions, each one week apart, we used online anodal high-definition transcranial direct current stimulation (HD-tDCS) over Broca’s area during a novel foreign grammar training session. During training, participants who were naïve to Spanish were tasked with acquiring present tense conjugation rules for the three Spanish verb endings. In Session 1, we observed significant improvement in performance in two linguistic (reception and production) tasks but not in a non-linguistic (working memory) task. Sessions 2 and 3 were subject to a ceiling effect, which obscured any potentially long-lasting effects of the stimulation. We interpret these results as support for the idea that Broca’s area has languagelike specificity that is not limited to receptive or productive processes and as evidence that Broca’s area plays a causal role in foreign grammar acquisition.
Mathematical Model of Mechanosensing and Mechanically Induced Collective Motility of Cells on Planar Elastic Substrates
Authors: Ahmed Riham K. , Abdalrahman Tamer , Davies Neil H. , Vermolen Fred , Franz Thomas
Published: December 2022

Cells mechanically interact with their environment to sense, for example, topography, elasticity and mechanical cues from other cells. Mechano-sensing has profound effects on cellular behaviour, including motility. The current study aims to develop a mathematical model of cellular mechano-sensing on planar elastic substrates and demonstrate the model’s predictive capabilities for the motility of individual cells in a colony.

In the model, a cell is assumed to transmit an adhesion force, derived from a dynamic focal adhesion integrin density, that locally deforms a substrate, and to sense substrate deformation originating from neighbouring cells. The substrate deformation from multiple cells is expressed as total strain energy density with a spatially varying gradient. The magnitude and direction of the gradient at the cell location define the cell motion. Cell-substrate friction, partial motion randomness, and cell death and division are included.

The substrate deformation by a single cell and the motility of two cells are presented for several substrate elasticities and thicknesses. The collective motility of 25 cells on a uniform substrate mimicking the closure of a circular wound of 200 μm is predicted for deterministic and random motion. Cell motility on substrates with varying elasticity and thickness is explored for four cells and 15 cells, the latter again mimicking wound closure. Wound closure by 45 cells is used to demonstrate the simulation of cell death and division during migration.

The mathematical model can adequately simulate the mechanically-induced collective cell motility on planar elastic substrates. The model is suitable for extension to other cell and substrates shapes and the inclusion of chemotactic cues, offering the potential to complementin vitroandin vivostudies.
Full-length αIIbβ3 CryoEM structure reveals intact integrin initiate-activation intrinsic architecture
Authors: Huo Tong , Wu Hongjiang , Moussa Zeinab , Sen Mehmet , Dalton Valerie , Wang Zhao
Published: December 2022

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation, thus pivotal for hemostasis, and arterial thrombosis as well as a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the intact full-length αIIbβ3, which covers three distinct states along the activation pathway. Here, we resolve intact αIIbβ3 structure at 3Å resolution, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the head region ligand-binding domain tucked in a specific angle proximity to the TM region. In response to the addition of a Mn2+agonist, we resolved two coexisting states, “intermediate” and “pre-active”. Our structures show conformational changes of the intact αIIbβ3 activating trajectory, as well as a unique twisting of the lower integrin legs representing an intermediate state (TM region at a twisting conformation) and a coexisting pre-active state (bent and opening in leg), which is required for inducing the transitioning platelets to accumulate. Our structure provides for the first time direct structural evidence for the lower legs’ involvement in full-length integrin activation mechanisms. Additionally, our structure offers a new strategy to target the αIIbβ3 lower leg allosterically instead of modulating the affinity of the αIIbβ3 head region.
Longitudinal flux balance analyses of a patient with Crohn’s disease highlight microbiome metabolic alterations
Authors: Basile Arianna , Heinken Almut , Hertel Johannes , Smarr Larry , Li Weizhong , Treu Laura , Valle Giorgio , Campanaro Stefano , Thiele Ines
Published: December 2022

Inflammatory bowel diseases (IBD) are characterised by episodic inflammation of the gastrointestinal tract. Gut microbial dysbiosis characterises the pathoetiology, but its role remains understudied. We report the first use of constraint-based microbial community modelling on a single individual with IBD, covering seven dates over 16 months, enabling us to identify a number of time-correlated microbial species and metabolites. We find that the individual’s dynamical microbial ecology in the disease state drives time-varyingin silicooverproduction, compared to healthy controls, of more than 24 biologically important metabolites, including oxygen, methane, thiamine, formaldehyde, trimethylamine N-oxide, folic acid, serotonin, histamine, and tryptamine. A number of these metabolites may yield new biomarkers of disease progression. The microbe-metabolite contribution analysis revealed that some genusDialisterspecies changed metabolic pathways according to the disease phases. At the first time point, characterised by the highest levels of blood and faecal inflammation biomarkers, they produced L-serine or formate. The production of the compounds, through a cascade effect, was mediated by the interaction with pathogenicEscherichia colistrains andDesulfovibrio piger. We integrated the microbial community metabolic models of each time point with a male whole-body, organ-resolved model of human metabolism to track the metabolic consequences of dysbiosis at different body sites. The presence ofD. pigerin the gut microbiome influenced the sulphur metabolism with a domino effect affecting the liver. These results underline the importance of tracking an individual’s gut microbiome along a time course, creating a new analysis framework for self-quantified medicine.

Graphical abstract
Automated model discovery for skin: Discovering the best model, data, and experiment
Authors: Linka Kevin , Tepole Adrian Buganza , Holzapfel Gerhard A. , Kuhl Ellen
Published: December 2022

Choosing the best constitutive model and the right set of model parameters is at the heart of continuum mechanics. For decades, the gold standard in constitutive modeling has been to first select a model and then fit its parameters to data. However, the success of this approach is highly dependent on user experience and personal preference. Here we propose a new method that simultaneously and fully autonomously discovers the best model and parameters to explain experimental data. Mathematically, the model finding is translated into a complex non-convex optimization problem. We solve this problem by formulating it as a neural network, and leveraging the success, robustness, and stability of the optimization tools developed in classical neural network modeling. Instead of using a classical off-the-shelf neural network, we design a new family of Constitutive Artificial Neural Networks with activation functions that feature popular constitutive models and parameters that have a clear physical interpretation. Our new network inherently satisfies general kinematic, thermodynamic, and physical constraints and trains robustly, even with sparse data. We illustrate its potential for biaxial extension experiments on skin and demonstrate that the majority of network weights train to zero, while the small subset of non-zero weights defines the discovered model. Unlike classical network weights, these weights are physically interpretable and translate naturally into engineering parameters and microstructural features such as stiffness and fiber orientation. Our results suggest that Constitutive Artificial Neural Networks enable automated model, parameter, and experiment discovery and could initiate a paradigm shift in constitutive modeling, from user-defined to automated model selection and parameterization. Our source code, data, and examples are available athttps://github.com/LivingMatterLab/CANN.
Analysing the role of SERPINE1 network in the pathogenesis of human glioblastoma
Authors: Khosravi Zahra , Kaliaperumal Chandrasekaran , Kumar Arun HS
Published: December 2022

Background

Glioblastoma multiforme (GBM) is one of the most aggressive and difficult to treat brain tumour in humans with a 5 year survival rate of less than 6%. SERPINE1 is a novel tumour receptor found on GBM that modulates the progression of this cancer through growth signals and remodelling of the extracellular matrix. Hence, we investigated the role of SERPINE1 and its network proteins in pathogenesis of GBM and assessed its targetability.

Material and methods

Network proteins of SERPINE1 in homo sapiens was identified using the String database, and the affinity of the protein-protein interaction of this network was analysed using Chimera software. The expression profile of SERPINE1 in the different brain regions was evaluated to correlate its relevance to GBM pathology. Selected small molecules fromCalotropis giganteawere screened using AutoDock vina to assess targetability of human SERPINE1.

Results

VTN, PLG, TGFB1, VWF, FGF2 and CXCR1 were identified as the major network proteins of SERPINE1. The strongest interaction was observed between SERPINE1 and FGF2 (42884 H-bonds) followed by CXCR1 (20279 H-bonds). Our results suggest that SERPINE1 and its network proteins identified here play a vital role in GBM development and progression through brain parenchyma by creating the prime microenvironment for carcinogenesis, tumour invasion and migration. The highest expression of SERPINE1 was observed in the pons, medulla, midbrain, corpus callosum and spinal cord. Expression of SERPINE1 was consistent with high grade lesions of GBM, suggesting association of SERPINE1 with advanced stages of GBM. The selected small molecules fromCalotropis giganteawere observed to have therapeutically feasible binding affinity (140 - 550 μM) and predicted efficacy (290 - 1115 μM) against human SERPINE1.

Conclusion

SERPINE1 plays a vital role in the progression of GBM through its critical network proteins identified in this study. The expression of SERPINE1 aligns with the advanced stages of GBM. Small molecules fromCalotropis giganteatested in this study can serve as lead compounds for developing novel anti-SERPINE1 therapeutics for advanced stages of GBM.
Human mutations inSLITRK3implicated in GABAergic synapse development in mice
Authors: Efthymiou Stephanie , Han Wenyan , Ilyas Muhammad , Li Jun , Yu Yichao , Scala Marcello , Malintan Nancy T. , Ilyas Muhammad , Vavouraki Nikoleta , Mankad Kshitij , Maroofian Reza , Rocca Clarissa , Salpietro Vincenzo , Lakhani Shenela , Mallack Eric J. , Palculict Timothy Blake , Li Hong , Zhang Guojun , Zafar Faisal , Rana Nuzhat , Takashima Noriko , Matsunaga Hayato ,   Queen Square Genomics,   SYNAPS Study Group, Striano Pasquale , Lythgoe Mark F. , Aruga Jun , Lu Wei , Houlden Henry
Published: December 2022

We report on biallelic homozygous and monoallelicde-novovariants inSLITRK3in 3 unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay.SLITRK3encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients’ SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, we bring additional evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG, as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, our results exhibit impaired development of peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. Our study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.
Habitat quality, not patch isolation, drives distribution and abundance of two light-demanding butterflies in fragmented coppice landscapes
Authors: Graser Anne , Kelling Marit , Pabst Rebecca , Schulz Meike , Kamp Johannes
Published: December 2022

Coppice forests are socio-ecological systems especially rich in biodiversity. They have been transformed into high forest and abandoned across large areas of Europe over the past 200 years. Coppice loss is likely an important driver of insect declines. It is currently unclear whether habitat quality or decreasing connectivity of the remaining fragments is more important for the survival of insect populations. We related the abundance of two coppice-attached butterflies of conservation concern,Satyrium ilicisandMelitaea athalia, to indicators of habitat quality and habitat connectivity. We estimated butterfly densities using Distance Sampling along a successional gradient (time since last cut: 1–9 years; N = 130 plots) across one of the largest remaining simple oak-birch coppice landscapes in Central Europe. Both species reached abundance peaks within four to six years after the last cut, declining rapidly in abundance with subsequent succession. We found no evidence that coupe size, coppice availability and patch (= coupe) connectivity were related to the density of the species. Besides stand age, the cover of larval foodplants explained predicted butterfly densities well. OnlySatyrium ilicisbenefitted from high Red Deer densities.

Implications for insect conservation: Our results suggest that habitat quality and sufficient availability of coppice of suitable age matters more than coupe size and fragmentation within a traditional managed coppice landscape. Coppice restoration aiming at the study species should ensure a shifting mosaic of successional habitat to provide a large availability of resprouting oak stools and blueberry vegetation that holds denseMelampyrum pratensestands.
Hybrid-DIA: Intelligent Data Acquisition for Simultaneous Targeted and Discovery Phosphoproteomics in Single Spheroids
Authors: Martínez-Val Ana , Fort Kyle , Koenig Claire , Van der Hoeven Leander , Franciosa Giulia , Moehring Thomas , Ishihama Yasushi , Chen Yu-ju , Makarov Alexander , Xuan Yue , Olsen Jesper V.
Published: December 2022

Achieving sufficient coverage of regulatory phosphorylation sites by mass spectrometry (MS)-based phosphoproteomics for signaling pathway reconstitution is challenging when analyzing tiny sample amounts. We present a novel hybrid data-independent acquisition (DIA) strategy (hybrid-DIA) that combines targeted and discovery proteomics through an Application Programming Interface (API) to dynamically intercalate DIA scans with accurate triggering of multiplexed tandem MS scans of predefined (phospho)peptide targets. By spiking-in heavy stable isotope labeled phosphopeptide standards covering seven major signaling pathways, we benchmarked hybrid-DIA against state-of-the-art targeted MS methods (i.e. SureQuant) using EGF-stimulated HeLa cells and found the quantitative accuracy and sensitivity to be comparable while hybrid-DIA also profiled the global phosphoproteome. To demonstrate the robustness, sensitivity and potential of hybrid-DIA, we profiled chemotherapeutic agents in single colon carcinoma multicellular spheroids and evaluated the difference of cancer cells in 2D vs 3D culture. Altogether, we showed that hybrid-DIA is the way-to-go method in highly sensitive phospho-proteomics experiments.
Spatial, temporal and taxonomic patterns of insect extinction in Germany
Authors: Hallmann Caspar A. , Hörren Thomas , Ssymank Axel , Sumser Hubert , Schwan Heinz , Stenmans Werner , Vischer-Leopold Mareike , Schäffler Livia , Sorg Martin
Published: December 2022

Red lists represent an important instrument for evaluating the decline of species in space and time, for improving decisionmaking and for guiding conservation planning. However, globally, only a fraction of species has been categorized according to a red list, even in countries where insects are relatively well-studied. Such large knowledge gaps hinder conservation planning and ultimately jeopardize the maintenance of ecosystem functions. Given the recent reports on severe insect decline, it is now more than ever of great importance to obtain a reliable complete picture of the state of insects. We here derive an estimate of extinction rates and of the proportion of threatened species for the total insect community in Germany, and asses spatial and temporal of extinction patterns.

We found a regional extinction rate of 4.5% (1773-1937 species) for the area of Germany. Among extant insect species, 6% are classified as critically endangered (1856-2024 species), while among remaining species, a staggering 36.1% (10758-11086 species) is classified as threatened.

Higher trophic levels of zoophagous insects are often more sensitive to negative environmental changes due to their position in the food web, and at the same time are underrepresented in Red Lists. They are therefore disproportionately affected by these knowledge gaps.

This concerns particularly parasitoids which are taxa of regulatory importance and often higher extinction risk levels due to their trophic position.

Exemplary examination of the spatial scaling of red list categories indicate a far higher rate and risk and exemplary over ten times higher regional extinction rate when the reference area is gradually scaled down.

This illustrates the actual situation regarding the magnitude of regional species extinction events and extirpation risks that we have to assume for certain parts of the reference areas.

For a given region, the loss of the gene pool of populations specially adapted to a given region usually represents an irreversible biodiversity loss. In order to avoid further irreparable damage, the species threatened with extinction must be preserved with top priority. There is thus a considerable need for research in order to assess the conservation status of more than 56% of the insect species diversity in Germany and to immediately achieve a more balanced trait group representation in red lists.
Distinct spatial maps and multiple object codes in the lateral entorhinal cortex
Authors: Huang Xu , Schlesiger Magdalene Isabell , Barriuso-Ortega Isabel , Leibold Christian , MacLaren Duncan Archibald Allan , Bieber Nina , Monyer Hannah
Published: December 2022

The lateral entorhinal cortex (LEC) is a major cortical input area to the hippocampus and it is crucial for associative object-place-context memories. An unresolved question is whether these associations are performed exclusively in the hippocampus or also upstream thereof. Anatomical evidence suggests that the LEC processes both object and spatial information. We here describe a gradient of spatial selectivity along the antero-posterior axis of the LEC. We demonstrate that the LEC generates distinct spatial maps for different contexts that are independent of object coding and vice versa, thus providing evidence for pure spatial and pure object codes upstream of the hippocampus. Whilst space and object coding occur by and large separately in the LEC, we identified neurons that encode for space and objects conjunctively. Together, these findings point to a scenario in which the LEC sustains both distinct space and object coding as well as associative space-object coding.
E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE TRANSLATION FIDELITY DURING BRAIN DEVELOPMENT
Authors: Michela Di Michele , Aurore Attina , Pierre-François Roux , Imène Tabet , Sophie Laguesse , Javier Florido , Morane Houdeville , Armelle Choquet , Betty Encislai , Giuseppe Arena , Carlo De Blasio , Olivia Wendling , Francois-Xavier Frenois , Laura Papon , Lucille Stuani , Maryse Fuentes , Céline Jahanault-Tagliani , Mélanie Rousseau , Justine Guégan , Yoan Buscail , Pierrick Dupré , Henri-Alexandre Michaud , Geneviève Rodier , Floriant Bellvert , Hanna Kulyk , Carole Ferraro Peyret , Hugo Mathieu , Pierre Close , Francesca Rapino , Cédric Chaveroux , Nelly Pirot , Lucie Rubio , Adeline Torro , Tania Sorg , Fabrice Ango , Christophe Hirtz , Vincent Compan , Elise Lebigot , Andrea Legati , Daniele Ghezzi , Laurent Nguyen , Alexandre David , Claude Sardet , Matthieu Lacroix , Laurent Le Cam
Published: December 2022

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation ofDlatandElp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.
The K+exchange antiporter 3 senses the chloroplast energy status to synchronize photosynthesis
Authors: Uflewski Michal , Rindfleisch Tobias , Korkmaz Kübra , Tietz Enrico , Mielke Sarah , Galvis Viviana Correa , Dünschede Beatrix , Luzarowski Marcin , Skirycz Aleksandra , Schwarzländer Markus , Strand Deserah D. , Hertle Alexander P. , Schünemann Danja , Walther Dirk , Thalhammer Anja , Wolff Martin , Armbruster Ute
Published: December 2022

Plant photosynthesis contains two functional modules, the light-driven reactions in the thylakoid membrane and the carbon-fixing reactions in the chloroplast stroma. In nature, light availability for photosynthesis often undergoes massive and rapid fluctuations. Efficient and productive use of such variable light supply requires an instant crosstalk and rapid synchronization of both functional modules. Here, we show that this communication involves the stromal exposed regulatory C-terminus (RCT) of the thylakoid K+-exchange antiporter KEA3. RCT-mediated control of KEA3 contributes to the balance between light capture and photoprotection. By combiningin silico, in vitro, andin vivoapproaches, we demonstrate that the RCT senses the energy state of the chloroplast in form of both, phosphorylation and redox potential, in a pH-dependent manner and regulates KEA3 activity in response. Together our data pinpoint a regulatory feedback loop by which the stromal energy state orchestrates light capture and photoprotection via KEA3.
Microbial diversity ensures the stability of carbon cycling processes under increasing temperature in model soils
Authors: Rohner Nadja , Lepori Selina , Loaiza Viviana , Sebag David , Verrechia Eric , Nelson Daniel B. , Kahmen Ansgar , Niklaus Pascal A. , Laine Anna-Liisa , Domeignoz-Horta Luiz A.
Published: December 2022

Biodiversity loss and climate change are two of the most alarming threats to ecosystem functioning and stability. These factors are, however, typically investigated separately, overlooking potential interactions between species extinctions and climate change on ecosystems. Here, we evaluated how different temperature regimes impact the relationship between microbial diversity and ecosystem functioning, in terms of temperature sensitivity of carbon (C) cycling functions. We hypothesized that more diverse soil communities promote the stability of C cycling functions under both temperature regimes. We did not observe a ubiquitous response of all C-cycling processes to temperature increases within the distinct community diversities. While growth was stable with increasing temperatures among the diversity levels, respiration rates increased more strongly at low diversity levels than high diversity levels at higher temperatures. Carbon use efficiency, which integrates both growth and respiration, tended to decrease with temperature at lower levels of diversity. Jointly, these results demonstrate the importance of belowground soil community diversity for maintaining C-cycling thermal response under changing climate.
Unveiling the intertwined roles of the spatial-temporal environment and behavioural modes in animal movement
Authors: Linssen Hans , de Knegt Henrik J. , Eikelboom Jasper A.J.
Published: December 2022

Animal movement arises from complex interactions between animals and their heterogeneous environment, making it challenging to capture the movement process in a single analysis. This has lead to a bias towards lower-dimensional representations of the process in such analyses. In order to better understand animal movement, its multiple components should be included and addressed simultaneously.

We present an analytic framework that integrates thebehavioural,spatial, andtemporalcomponents of the movement process and their interactions, and allows for assessing the relative importance of these components. We propose adaily cyclic covariateto represent temporally cyclic movement patterns, for example diel variation in activity, and combine the three components in multi-modal Hidden Markov Models. We compare the statistical fits of models that include or exclude any of the behavioural, spatial and temporal components, and perform variance partitioning on the model that included all components to assess their relative importance to the movement process, both in isolation and in interaction.

We apply our framework to a case study on the movements of zebra, wildebeest and eland antelope in a South African reserve. Behavioural modes impacted movement the most, followed by diel rhythms and then the spatial environment (i.e. tree cover and terrain slope). Interactions between the components often explained more of the movement variation than the marginal effect of the spatial environment did on its own. Omitting components from the analysis led either to failure to detect relationships between input and response variables, resulting in overgeneralisations when drawing conclusions about the movement process, or to erroneously detecting spurious relationships, resulting in factually incorrect conclusions.

Our analytic framework can be used to study animal movement by integrating the different components of the movement process, thereby preventing incomplete or overly generic ecological interpretations. We demonstrate that understanding the drivers of animal movement, and ultimately the ecological phenomena that emerge from it, critically depends on considering the various components of the movement process, and especially the interactions between them.

Data/code for peer review statement: the data and code needed to reproduce the study and results are uploaded as a file with the initial submission.