bluuebunny/crossref_metadata_2025 huggingface dataset:
The angiotensin type 2 receptor agonist C21 restores respiratory function in COVID19 - a double-blind, randomized, placebo-controlled Phase 2 trial
Authors: Tornling Göran , Batta Rohit , Porter Joanna , Bengtsson Thomas , Parmar Kartikeya , Kashiva Reema , Hallberg Anders , Cohrt Anne Katrine , Westergaard Kate , Dalsgaard Carl-Johan , Raud Johan
Published: January 2021

Background

Although several therapies have been evaluated for treatment of COVID-19, the morbidity and mortality in COVID-19 are still significant, and the need for safe and effective drugs remains high even after launch of vaccine programs.

Methods

We conducted a double-blind, randomized, placebo-controlled trial with the novel oral angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients with C-reactive protein 50-150 mg/L but not needing mechanical ventilation. Patients were randomly assigned to oral C21 (100 mg twice daily) or placebo for 7 days in addition to standard of care, including glucocorticoids and remdesivir.

Results

106 patients underwent randomization (51 in the C21 group and 55 in the placebo group). At day 14 after start of treatment, the proportion of patients still requiring supplemental oxygen was significantly reduced by 90% in the C21 group compared to the placebo group (p=0.003). Moreover, fewer patients required mechanical ventilation (one C21 patient and four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one and three deaths in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated.

Conclusions

As studied in hospitalized COVID-19 patients, C21 on top of standard of care led to a clinically beneficial improvement in respiratory function compared to placebo, paving the way for a pivotal randomised controlled trial.

This study is registered atClinicalTrials.govwith identifierNCT04452435.
Local brain-age: A U-Net model
Authors: Popescu Sebastian G. , Glocker Ben , Sharp David J. , Cole James H.
Published: January 2021

Abstract

We propose a new framework for estimating neuroimaging-derived “brain-age” at a local level within the brain, using deep learning. The local approach, contrary to existing global methods, provides spatial information on anatomical patterns of brain ageing. We trained a U-Net model using brain MRI scans from n=3463 healthy people (aged 18-90 years) to produce individualised 3D maps of brain-predicted age. When testing on n=692 healthy people, we found a median (across participant) mean absolute error (within participant) of 9.5 years. Performance was more accurate (MAE around 7 years) in the prefrontal cortex and periventricular areas. We also introduce a new voxelwise method to reduce the age-bias when predicting local brain-age “gaps”. To validate local brain-age predictions, we tested the model in people with mild cognitive impairment or dementia using data from OASIS3 (n=267). Different local brain-age patterns were evident between healthy controls and people with mild cognitive impairment or dementia, particularly in subcortical regions such as the accumbens, putamen, pallidum, hippocampus and amygdala. Comparing groups based on mean local brain-age over regions-of-interest resulted in large effects sizes, with Cohen’sdvalues >1.5, for example when comparing people with stable and progressive mild cognitive impairment. Our local brain-age framework has the potential to provide spatial information leading to a more mechanistic understanding of individual differences in patterns of brain ageing in health and disease.
Network modeling of dynamic brain interactions predicts emergence of neural information that supports human cognitive behavior
Authors: Mill Ravi D. , Hamilton Julia L. , Winfield Emily C. , Lalta Nicole , Chen Richard H. , Cole Michael W.
Published: January 2021

How cognitive task behavior is generated by brain network interactions is a central question in neuroscience. Answering this question calls for the development of novel analysis tools that can firstly capture neural signatures of task information with high spatial and temporal precision (the “where and when”), and then allow for empirical testing of alternative network models of brain function that link information to behavior (the “how”). We outline a novel network modeling approach suited to this purpose that is applied to non-invasive functional neuroimaging data in humans. We first dynamically decoded the spatiotemporal signatures of task information in the human brain by combining MRI-individualized source electroencephalography with multivariate pattern analysis. A newly developed network modeling approach - dynamic activity flow modeling - then simulated the flow of task-evoked activity over more causally interpretable (relative to standard functional connectivity approaches) resting-state functional connections (dynamic, lagged, direct and directional). We demonstrate the utility of this modeling approach by applying it to elucidate network processes underlying sensory-motor information flow in the brain, revealing accurate predictions of empirical response information dynamics underlying behavior. Extending the model towards simulating network lesions suggested a role for the cognitive control networks (CCNs) as primary drivers of response information flow, transitioning from early dorsal attention network-dominated sensory-to-response transformation to later collaborative CCN engagement during response selection. These results demonstrate the utility of the dynamic activity flow modeling approach in identifying the generative network processes underlying neurocognitive phenomena.
Early life experience sets hard limits on motor learning as evidenced from artificial arm use
Authors: Maimon-Mor Roni O. , Schone Hunter R. , Slater David Henderson , Faisal A. Aldo , Makin Tamar R.
Published: January 2021

The study or artificial arms provides a unique opportunity to address long-standing questions on sensorimotor plasticity and development. Learning to use an artificial arm arguably depends on fundamental building blocks of body representation and would therefore be impacted by early-life experience. We tested artificial arm motor-control in two adult populations with upper-limb deficiency: congenital one-handers – who were born with a partial arm, and amputees – who lost their biological arm in adulthood. Brain plasticity research teaches us that the earlier we train to acquire new skills (or use a new technology) the better we benefit from this practice as adults. Instead, we found that although one-hander started using an artificial arm as toddlers, they produced increased error noise and directional errors when reaching to visual targets, relative to amputees who performed similarly to controls. However, the earlier a one-hander was fitted with an artificial arm the better their motor control was. We suggest that visuomotor integration, underlying the observed deficits, is highly dependent on either biological or artificial arm experience at a very young age. Subsequently, opportunities for sensorimotor plasticity become more limited.
Training neural networks to recognize speech increased their correspondence to the human auditory pathway but did not yield a shared hierarchy of acoustic features
Authors: Thompson Jessica A.F. , Bengio Yoshua , Formisano Elia , Schönwiesner Marc
Published: January 2021

The correspondence between the activity of artificial neurons in convolutional neural networks (CNNs) trained to recognize objects in images and neural activity collected throughout the primate visual system has been well documented. Shallower layers of CNNs are typically more similar to early visual areas and deeper layers tend to be more similar to later visual areas, providing evidence for a shared representational hierarchy. This phenomenon has not been thoroughly studied in the auditory domain. Here, we compared the representations of CNNs trained to recognize speech (triphone recognition) to 7-Tesla fMRI activity collected throughout the human auditory pathway, including subcortical and cortical regions, while participants listened to speech. We found no evidence for a shared representational hierarchy of acoustic speech features. Instead, all auditory regions of interest were most similar to a single layer of the CNNs: the first fully-connected layer. This layer sits at the boundary between the relatively task-general intermediate layers and the highly task-specific final layers. This suggests that alternative architectural designs and/or training objectives may be needed to achieve fine-grained layer-wise correspondence with the human auditory pathway.

Highlights

Trained CNNs more similar to auditory fMRI activity than untrained

No evidence of a shared representational hierarchy for acoustic features

All ROIs were most similar to the first fully-connected layer

CNN performance on speech recognition task positively associated with fmri similarity
Voltage-sensitive sodium channel (Vssc) mutations associated with pyrethroid insecticide resistance inAedes aegypti(L.) from Jeddah, Kingdom of Saudi Arabia – baseline information for aWolbachiarelease program
Authors: Endersby-Harshman Nancy M. , Ali AboElgasim , Alhumrani Basim , Alkuriji Mohammed Abdullah , Al-Fageeh Mohammed B. , Al-Malik Abdulaziz , Alsuabeyl Mohammed S. , Elfekih Samia , Hoffmann Ary A.
Published: January 2021

Background

Dengue suppression often relies on control of the mosquito vector,Aedes aegypti, through applications of insecticides of which the pyrethroid group has played a dominant role. Insecticide resistance is prevalent inAe. aegyptiaround the world and the resulting reduction of insecticide efficacy is likely to exacerbate the impact of dengue. Dengue has been a public health problem in Saudi Arabia, particularly in Jeddah, since its discovery there in the 1990s and insecticide use for vector control is widespread throughout the city. An alternative approach to insecticide use, based on blocking dengue transmission in mosquitoes by the endosymbiontWolbachia, is being trialled in Jeddah following the success of this approach in Australia and Malaysia. Knowledge of insecticide resistance status of mosquito populations in Jeddah is a prerequisite for establishing aWolbachia-based dengue control program as releases ofWolbachiamosquitoes succeed when resistance status of the release population is similar to that of the wild population.

Methods

WHO resistance bioassays of mosquitoes with deltamethrin, permethrin and DDT were used in conjunction with TaqMan®SNP Genotyping Assays to characterise mutation profiles ofAe. aegyptifrom Jeddah.

Results

Screening of the voltage sensitive sodium channel (Vssc), the pyrethroid target-site, revealed mutations at codons 989, 1016 and 1534 inAe. aegyptifrom two districts of Jeddah. The triple mutant homozygote (1016G/1534C/989P) was confirmed from Al Safa and Al Rawabi. Bioassays with pyrethroids (Type I and II) and DDT showed that mosquitoes were resistant to each of these compounds based on WHO definitions. An association betweenVsscmutations and resistance was established for the Type II pyrethroid, deltamethrin, with one genotype (989P/1016G/1534F) conferring a survival advantage over two others (989S/1016V/1534C and the triple heterozygote). An indication of synergism of Type I pyrethroid activity with piperonyl butoxide suggests that detoxification by cytochrome P450s accounts for some of the pyrethroid resistance response inAe. aegyptipopulations from Jeddah.

Conclusions

The results provide a baseline for monitoring and management of resistance as well as knowledge ofVsscgenotype frequencies required inWolbachiarelease populations to ensure homogeneity with the target field population.
Decoding silence in free recall
Authors: Fumarola Francesco , He Zhengqi , Kuśmierz Łukasz , Toyoizumi Taro
Published: January 2021

In experiments on free recall from lists of items, not all memory retrievals are necessarily reported. Previous studies investigated unreported retrievals by attempting to induce their externalization. We show that, without any intervention, their statistics may be directly estimated through a model-free analysis of inter-response times – the silent intervals between recalls. A delay attributable to unreported recalls emerges in three situations: if the final item was already recalled (“silent recency effect”); if the item that, within the list, follows the latest recalled item was already recalled (“silent contiguity effect”); and in sequential recalls within highly performing trials (“sequential slowdown”). We then turn to reproducing all these effects by a minimal model where the discarding of memories (“bouncing”) occurs either if they are repetitious or, in strategically organized trials, if they are not sequential. Based on our findings, we propose various approaches to further probing the submerged dynamics of memory retrieval.
CloudReg: Automatic Terabyte-Scale Cross-Modal Brain Volume Registration
Authors: Chandrashekhar Vikram , Tward Daniel J , Crowley Devin , Crow Ailey K , Wright Matthew A , Hsueh Brian Y , Gore Felicity , Machado Timothy A , Branch Audrey , Rosenblum Jared S , Deisseroth Karl , Vogelstein Joshua T
Published: January 2021

Quantifying terabyte-scale multi-modal human and animal imaging data requires scalable analysis tools. We developed CloudReg, an open-source, automatic, terabyte-scale, cloud-based image analysis pipeline that pre-processes and registers cross-modal volumetric datasets with artifacts via spatially-varying polynomial intensity transform. CloudReg accurately registers the following datasets to their respective atlases:in vivohuman andex vivomacaque brain magnetic resonance imaging,ex vivomouse brain micro-computed tomography, and cleared murine brain light-sheet microscopy.
Dynamics of global gene expression and chromatin accessibility of the peripheral nervous system in animal models of persistent pain
Authors: Stephens Kimberly E. , Zhou Weiqiang , Renfro Zachary , Ji Zhicheng , Ji Hongkai , Guan Yun , Taverna Sean D.
Published: January 2021

Efforts to understand genetic variability involved in an individual’s susceptibility to chronic pain support a role for upstream regulation by epigenetic mechanisms. To examine the transcriptomic and epigenetic basis of chronic pain that resides in the peripheral nervous system, we used RNA-seq and ATAC-seq of the rat dorsal root ganglion (DRG) to identify novel molecular pathways associated with pain hypersensitivity in two well-studied persistent pain models induced by Chronic Constriction Injury (CCI) of the sciatic nerve and intra-plantar injection of Complete Freund’s Adjuvant (CFA) in rats. Our RNA-seq studies identify a variety of biological process related to synapse organization, membrane potential, transmembrane transport, and ion binding. Interestingly, genes that encode transcriptional regulators were disproportionately downregulated in both models. Our ATAC-seq data provide a comprehensive map of chromatin accessibility changes in the DRG. A total of 1123 regions showed changes in chromatin accessibility in one or both models when compared to the naïve and 31 shared differentially accessible regions (DAR)s. Functional annotation of the DARs identified disparate molecular functions enriched for each pain model which suggests that chromatin structure may be altered differently following sciatic nerve injury and hind paw inflammation. Motif analysis identified 17 DNA sequences known to bind transcription factors in the CCI DARs and 33 in the CFA DARs. Two motifs were significantly enriched in both models. Our improved understanding of the changes in chromatin accessibility that occur in chronic pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG.

Shared transcriptomic and epigenetic changes in two animal models improves our understanding of how chromatin structural changes alter DRG gene expression under persistent pain conditions.
Age dependency and lateralization in the three branches of the human superior longitudinal fasciculus
Authors: Amemiya Kaoru , Naito Eiichi , Takemura Hiromasa
Published: January 2021

The superior longitudinal fascicle/fasciculus (SLF) is a major white matter tract connecting the frontal and parietal cortices in humans. Although the SLF has often been analyzed as a single entity, several studies have reported that the SLF is segregated into three distinct branches (SLF I, II, and III). They have also reported the right lateralization of the SLF III volume and discussed its relationship with lateralized cortical functions in the fronto-parietal network. However, to date, the homogeneity or heterogeneity of the age dependency and lateralization properties of SLF branches have not been fully clarified. Through this study, we aimed to clarify the age dependency and lateralization of SLF I-III by analyzing diffusion-weighted MRI (dMRI) and quantitative R1 (qR1) map datasets collected from a wide range of age groups, mostly comprising right-handed children, adolescents, adults, and seniors (6 to 81 years old). The age dependency in dMRI measurement (fractional anisotropy, FA) was heterogeneous among the three SLF branches, suggesting that these branches are regulated by distinct developmental and aging processes. Lateralization analysis on SLF branches revealed that the right SLF III was larger than the left SLF III in adults, replicating previous reports. FA measurement also suggested that, in addition to SLF III, SLF II was lateralized to the right hemisphere in adolescents and adults. We further found a left lateralization of SLF I in qR1 data, a microstructural measurement sensitive to myelin levels, in adults. These findings suggest that the SLF sub-bundles are distinct entities in terms of age dependency and lateralization.
The worm affair: Genetic diversity in two species of symbionts that co-occur in tubeworms from the Mediterranean Sea
Authors: Zvi-Kedem Tal , Shemesh Eli , Tchernov Dan , Rubin-Blum Maxim
Published: January 2021

The symbioses between the vestimentiferan tubeworms and their chemosynthetic partners (Gammaproteobacteria, Chromatiales,Sedimenticolaceae) hallmark the success of these organisms in hydrothermal vent and hydrocarbon seep deep-sea habitats. The fidelity of these associations varies, as both the hosts and the symbionts can be loose in partner choice. Some tubeworms may host distinct symbiont phylotypes, which often co-occur in a single host individual. To better understand the genetic basis for the ‘promiscuity’ of tubeworm symbioses, we curated and investigated metagenome-assembled genomes of two symbiont phylotypes (species, based on the average nucleotide identity <95%) inLamellibrachia anaximandri, a vestimentiferan endemic to the Mediterranean Sea, in individuals collected from Palinuro hydrothermal vents (Italy) and hydrocarbon seeps (Eratosthenes seamount and Palmahim disturbance). Using comparative genomics, we show that mainly mobilome and defense mechanism-related features distinguish the symbiont genotypes. While many central metabolic functions are conserved in the tubeworm symbionts, nitrate respiration (Nar, Nap and Nas proteins) is modular, yet this modularity is not linked to speciation, but rather to local adaptation. Our results hint that variation in a single moonlighting protein may be responsible for the host-symbiont fidelity.
Impaired differential learning of fear versus safety signs in obsessive-compulsive disorder
Authors: Elsner Björn , Reuter Benedikt , Said Mahboba , Linnman Clas , Kathmann Norbert , Beucke Jan-Carl
Published: January 2021

Pavlovian learning mechanisms are of great importance both for models of psychiatric disorders and treatment approaches, but understudied in obsessive-compulsive disorder (OCD). Using an established Pavlovian fear conditioning and reversal procedure, we studied skin conductance responses (SCRs) in 41 patients with OCD and in 32 matched healthy control participants. Within both groups, fear acquisition and reversal effects were evident. When comparing groups, patients showed impaired differential learning of threatening and safe stimuli, consistent with previous research. In contrast to prior findings, differential learning impairments were restricted to fear acquisition, and not observed in the reversal stage of the experiment. As previous and present fear reversal experiments in OCD differed in the use of color coding to facilitate stimulus discrimination, the studies converge to suggest that differential learning of threatening versus safe stimuli is impaired in OCD, but manifests itself differently depending on the difficulty of the association to be learned. When supported by the addition of color, patients with OCD previously appeared to acquire an association early but failed to reverse it according to changed contingencies. In absence of such color coding of stimuli, our data suggest that patients with OCD already show differential learning impairments during fear acquisition, which may relate to findings of altered coping with uncertainty previously observed in OCD. Impaired differential learning of threatening versus safe stimuli should be studied further in OCD, in order to determine whether impairments in differential learning predict CBT treatment outcomes in patients, and whether they are etiologically relevant for OCD.
Suberin plasticity to developmental and exogenous cues is regulated by a set of MYB transcription factors
Authors: Shukla Vinay , Han Jian-Pu , Cléard Fabienne , Legendre Linnka Lefebvre- , Gully Kay , Flis Paulina , Berhin Alice , Andersen Tonni Grube , Salt David E , Nawrath Christiane , Barberon Marie
Published: January 2021

Suberin is a hydrophobic biopolymer that can be deposited at the periphery of cells, forming protective barriers against biotic and abiotic stress. In roots, suberin forms lamellae at the periphery of endodermal cells where it plays crucial roles in the control of water and mineral transport. Suberin formation is highly regulated by developmental and environmental cues. However, the mechanisms controlling its spatiotemporal regulation are poorly understood. Here, we show that endodermal suberin is regulated independently by developmental and exogenous signals to fine tune suberin deposition in roots. We found a set of four MYB transcription factors (MYB41, MYB53, MYB92 and MYB93), that are regulated by these two signals, and are sufficient to promote endodermal suberin. Mutation of these four transcription factors simultaneously through genome editing, lead to a dramatic reduction of suberin formation in response to both developmental and environmental signals. Most suberin mutants analyzed at physiological levels are also affected in another endodermal barrier made of lignin (Casparian strips), through a compensatory mechanism. Through the functional analysis of these four MYBs we generated plants allowing unbiased investigations of endodermal suberin function without accounting for confounding effects due to Casparian strip defects, and could unravel specific roles of suberin in nutrient homeostasis.
Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain
Authors: Rahman-Enyart Afrida , Yang Wenbin , Yaggie Ryan E. , White Bryan , Welge Michael , Auvil Loretta , Berry Matthew , Bushell Colleen , Rosen John M. , Rudick Charles N. , Schaeffer Anthony J. , Klumpp David J.
Published: January 2021

Dysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or “IC”) is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase,Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a “leaky gut” phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.
A coupled mechano-biochemical framework for root meristem morphogenesis
Authors: Marconi Marco , Gallemi Marçal , Benková Eva , Wabnik Krzysztof
Published: January 2021

Plants grow roots to adjust their bodies to dynamic changes in the surrounding environment. How do plant roots emerge from the stem cell reservoir during embryogenesis is however poorly understood. Here, we present a bottom-up strategy to address this challenge by combining empirical observations with advanced computer modeling techniques. We demonstrate that the anisotropy of root growth results from differential growth rates of adjacent tissues, whereas the root meristem development incorporates a multi-level feedback loop between complex transport network of phytohormone auxin, auxin-dependent cell growth and cytoskeleton rearrangements.In silicomodel predictions are in close agreement within vivopatterns of anisotropic growth, auxin distribution, and cell polarity, as well as several root phenotypes caused by chemical, mechanical, or genetic perturbations. Our findings reveal a minimal set of design principles connecting tissue mechanics, cell anisotropy, and directional transport that are sufficient for self-organization of the root meristem shape. A mobile auxin signal transported through immobile cells orchestrates polarity and growth mechanics to instruct the morphogenesis of an independent organ.
An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay
Authors: Fritz Sarah E. , Ranganathan Soumya , Wang Clara D. , Hogg J. Robert
Published: January 2021

The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. Previous studies indicate that the extension of a conserved regulatory loop in the UPF1LLhelicase core confers a decreased propensity to dissociate from RNA upon ATP hydrolysis relative to the major UPF1 isoform, designated UPF1SL. Using biochemical and transcriptome-wide approaches, we find that UPF1LLovercomes the protective RNA binding proteins PTBP1 and hnRNP L to preferentially bind and down-regulate long 3’UTRs normally shielded from NMD. Unexpectedly, UPF1LLsupports induction of NMD on new populations of substrate mRNAs in response to activation of the integrated stress response and impaired translation efficiency. Thus, while canonical NMD is abolished by moderate translational repression, UPF1LLactivity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.
Generation of a New Frizzled 2 Flox Mouse Model to Clarify Its Role in Development
Authors: Michalski Megan N. , Diegel Cassandra R. , Zhong Zhendong A. , Suino-Powell Kelly , Blazer Levi , Adams Jarrett ,   VAI Vivarium and Transgenics Core, Beddows Ian , Melcher Karsten , Sidhu Sachdev S. , Angers Stephane , Williams Bart O.
Published: January 2021

It is currently accepted that Wnt receptors, Frizzleds (Fzd), have high functional redundancy, making individual receptors challenging to target therapeutically. Specifically, Fzd2 is believed to be functionally redundant with Fzd1 and Fzd7, findings which were based largely on previously published global knockout mouse studies. Conversely, a Fzd2 global knockout mouse model developed by the International Mouse Phenotype Consortium (IMPC) is early embryonic lethal, suggesting Fzd2 is critical for early embryonic development. If global deletion of Fzd2 leads to early lethality, floxed models are necessary to identify tissue-specific phenotypes. We found that a previously published Fzd2 flox model does not fully delete Fzd2 function. To reconcile the contradictory findings in Fzd2 mouse models and allow for tissue-specific studies of Fzd2, we have generated a new flox model using a modified two-cell homologous recombination CRISPR approach. We demonstrated successful simultaneous insertion of twoloxPsites fully surrounding the Fzd2 gene and confirmed cre-mediated recombination deletes the sequence between theloxPsites leading to a Fzd2 null allele. Preliminary studies suggest global knockouts are early embryonic lethal and full characterization of the tissue-specific effects of Fzd2 deletion is currently underway. This work suggests Fzd2 uniquely regulates development and emphasizes the importance of thorough validation of newly generated mouse models.
Sweeps in time: leveraging the joint distribution of branch lengths
Authors: Bisschop Gertjan , Lohse Konrad , Setter Derek
Published: January 2021

Current methods of identifying positively selected regions of the genome are limited by their underlying model in two key ways: the model cannot account for the timing of the adaptive event and the analytic predictions are limited to single nucleotide polymorphisms. Here we develop a tractable method of describing the effect of positive selection on the genealogical histories in the surrounding genome, explicitly modeling both the timing and context of the adaptive event. In addition, our framework allows us to go beyond simple polymorphism data. We are able to leverage information contained in patterns of linked variants, and even with very small sample sizes, our analytic framework has high power to identify historically adaptive regions of the genome and to correctly infer both the time and strength of selection. Finally, we derived the marginal distribution of genealogical branch lengths at a locus affected by selection acting at a linked site. This provides a much-needed link between current theoretical models to recent advances in simulation procedures that have allowed researchers both to examine the evolution of genealogical histories at the level of full chromosomes and build methods that attempt to reconstruct full ancestries from genome sequence data.
MS2AI: Automated repurposing of public peptide LC-MS data for machine learning applications
Authors: Rehfeldt Tobias Greisager , Krawczyk Konrad , Bøgebjerg Mathias , Schwämmle Veit , Röttger Richard
Published: January 2021

Motivation

Liquid-chromatography mass-spectrometry (LC-MS) is the established standard for analyzing the proteome in biological samples by identification and quantification of thousands of proteins. Machine learning (ML) promises to considerably improve the analysis of the resulting data, however, there is yet to be any tool that mediates the path from raw data to modern ML applications. More specifically, ML applications are currently hampered by three major limitations: (1) absence of balanced training data with large sample size; (2) unclear definition of sufficiently information-rich data representations for e.g. peptide identification; (3) lack of benchmarking of ML methods on specific LC-MS problems.

Results

We created the MS2AI pipeline that automates the process of gathering vast quantities of mass spectrometry (MS) data for large scale ML applications. The software retrieves raw data from either in-house sources or from the proteomics identifications database, PRIDE. Subsequently, the raw data is stored in a standardized format amenable for ML encompassing MS1/MS2 spectra and peptide identifications. This tool bridges the gap between MS and AI, and to this effect we also present an ML application in the form of a convolutional neural network for the identification of oxidized peptides.

Availability

An open source implementation of the software can be found freely available for non-commercial use athttps://gitlab.com/roettgerlab/ms2ai.

Contact

veits@bmb.sdu.dk

Supplementary information

Supplementary data are available atBioinformaticsonline.
Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients
Authors: Kenkhuis Boyd , Somarakis Antonios , de Haan Lorraine , Dzyubachyk Oleh , IJsselsteijn Marieke E , de Miranda Noel FCC , Lelieveldt Boudewijn PF , Dijkstra Jouke , van Roon-Mom Willeke MC , Höllt Thomas , van der Weerd Louise
Published: January 2021

Brain iron accumulation has been found to accelerate disease progression in Amyloid β-positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key-players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Amyloid-β load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.
Maximum likelihood estimation of the geometric niche preemption model
Authors: Graffelman Jan
Published: January 2021

The geometric series or niche preemption model is an elementary ecological model in biodiversity studies. The preemption parameter of this model is usually estimated by regression or iteratively by using May’s equation. This article proposes a maximum likelihood estimator for the niche preemption model, assuming a known number of species and multinomial sampling. A simulation study shows that the maximum likelihood estimator outperforms the classical estimators in this context in terms of bias and precision. We obtain the distribution of the maximum likelihood estimator and use it to obtain confidence intervals for the preemption parameter and to develop a preemptionttest that can address the hypothesis of equal geometric decay in two samples. We illustrate the use of the new estimator with some empirical data sets taken from the literature and provide software for its use.
Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours
Authors: Loddo Marco , Hardisty Keeda-Marie , Haddow Tiffany , Thatcher Robert , Williams Gareth H
Published: January 2021

Oncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we showacross a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The majority of actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved Wnt/β-catenin, RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.
SARS-CoV-2 emerging complexity
Authors: Bertacchini Francesca , Bilotta Eleonora , Pantano Pietro Salvatore
Published: January 2021

The novel SARS_CoV-2 virus, prone to variation when interacting with spatially extended ecosystems and within hosts1can be considered a complex dynamic system2. Therefore, it behaves creating several space-time manifestations of its dynamics. However, these physical manifestations in nature have not yet been fully disclosed or understood. Here we show 4-3 and 2-D space-time patterns of rate of infected individuals on a global scale, giving quantitative measures of transitions between different dynamical behaviour. By slicing the spatio-temporal patterns, we found manifestations of the virus behaviour such as cluster formation and bifurcations. Furthermore, by analysing the morphogenesis processes by entropy, we have been able to detect the virus phase transitions, typical of adaptive biological systems3. Our results for the first time describe the virus patterning behaviour processes all over the world, giving for them quantitative measures. We know that the outcomes of this work are still partial and more advanced analyses of the virus behaviour in nature are necessary. However, we think that the set of methods implemented can provide significant advantages to better analyse the viral behaviour in the approach of system biology4, thus expanding knowledge and improving pandemic problem solving.
Neural Basis for Regulation of Vasopressin Secretion by Anticipated Disturbances in Osmolality
Authors: Kim Angela , Madara Joseph C. , Wu Chen , Andermann Mark L. , Lowell Bradford B.
Published: January 2021

Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality aredetected. Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality areanticipated. Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking and eating, which will ultimately decrease and increase osmolality. Here, we demonstrate that AVP neuron activity is regulated by multiple anatomically-and functionally-distinct neural circuits. Notably, presystemic regulation during drinking and eating are mediated by non-overlapping circuits that involve the lamina terminalis and hypothalamic arcuate nucleus, respectively. These findings reveal neural mechanisms that support differential regulation of AVP release by diverse behavioral and physiological stimuli.
Historical trade routes for diversification of domesticated chickpea inferred from landrace genomics
Authors: Igolkina Anna A. , Noujdina Nina V. , Samsonova Maria G. , von Wettberg Eric , Longcore Travis , Nuzhdin Sergey
Published: January 2021

According to archaeological records, chickpea (Cicer arietinum) was first domesticated in the Fertile Crescent 10 thousand years ago. Its subsequent diversification in South Asia, Ethiopia, and the Western Mediterranean, however, remains obscure and cannot be resolved using only archeological and historical evidence. In particular, chickpea has two market types: ‘desi’, which has a similar flower and seed coat color to chickpea’s wild relatives; and ‘kabuli’, which has light-colored seed, and is linguistically tied to Central Asia but has an unknown geographic origin.

Based on the genetic data from 421 chickpea landraces from six geographic regions, we tested complex historical hypotheses of chickpea migration and admixture on two levels: within and between major regions of cultivation. For the former, we developed popdisp, a Bayesian model of population dispersal from a regional center towards sample locations, and confirmed that chickpea spread within each region along trade routes rather than by simple diffusion.

For the latter, migration between regions, we developed another model, migadmi, that evaluates multiple and nested admixture events. Applying this model to desi populations, we found both Indian and Middle Eastern traces in Ethiopian chickpea, suggesting presence of a seaway from South Asia to Ethiopia — and the cultural legacy of the Queen of Sheba. As for the origin of kabuli chickpeas, we found significant evidence for an origin from Turkey rather than Central Asia.
Behavioral fingerprints predict insecticide and anthelmintic mode of action
Authors: McDermott-Rouse Adam , Minga Eleni , Barlow Ida , Feriani Luigi , Harlow Philippa H , Flemming Anthony J , Brown André EX
Published: January 2021

Novel invertebrate-killing compounds are required in agriculture and medicine to overcome resistance to existing treatments. Because insecticides and anthelmintics are discovered in phenotypic screens, a crucial step in the discovery process is determining the mode of action of hits. Visible whole-organism symptoms are combined with molecular and physiological data to determine mode of action. However, manual symptomology is laborious and requires symptoms that are strong enough to see by eye. Here we use high-throughput imaging and quantitative phenotyping to measureC. elegansbehavioral responses to compounds and train a classifier that predicts mode of action with an accuracy of 88% for a set of ten common modes of action. We also classify compounds within each mode of action to discover pharmacological relationships that are not captured in broad mode of action labels. High-throughput imaging and automated phenotyping could therefore accelerate mode of action discovery in invertebrate-targeting compound development and help to refine mode of action categories.
Fine mapping without phenotyping: Identification of selection targets in secondary Evolve and Resequence experiments
Authors: Langmüller Anna Maria , Dolezal Marlies , Schlötterer Christian
Published: January 2021

Evolve and Resequence (E&R) studies investigate the genomic selection response of populations in an Experimental Evolution setup. Despite the popularity of E&R, empirical studies in sexually reproducing organisms typically suffer from an excess of candidate loci due to linkage disequilibrium, and single gene or SNP resolution is the exception rather than the rule. Recently, so-called “secondary E&R” has been suggested as promising experimental follow-up procedure to confirm putatively selected regions from a primary E&R study. Secondary E&R provides also the opportunity to increase mapping resolution by allowing for additional recombination events, which separate the selection target from neutral hitchhikers. Here, we use computer simulations to assess the effect of different crossing schemes, population size, experimental duration, and number of replicates on the power and resolution of secondary E&R. We find that the crossing scheme and population size are crucial factors determining power and resolution of secondary E&R: a simple crossing scheme with few founder lines consistently outcompetes crossing schemes where evolved populations from a primary E&R experiment are mixed with a complex ancestral founder population. Regardless of the experimental design tested, a population size of at least 4,800 individuals, which is roughly 5 times larger than population sizes in typical E&R studies, is required to achieve a power of at least 75%. Our study provides an important step towards improved experimental designs aiming to characterize causative SNPs in Experimental Evolution studies.

Significance

Despite the popularity of Evolve and Resequence (E&R) to investigate genomic selection responses, most studies that use sexually reproducing organisms have broad selection signatures and an excess of candidate loci due to linkage disequilibrium. In this study, we use computer simulations and statistical modelling to evaluate the effects of different experimental and population genetic parameters on the success of potential follow-up experiments (=secondary E&R) aiming to validate and fine-map selection signatures of primary studies. We found that a large population size in combination with a simple crossing scheme is key to the success of secondary E&R inDrosophila.
Gating the channel pore of ionotropic glutamate receptors with bacterial substrate binding proteins
Authors: Bernhard Max , Laube Bodo
Published: January 2021

Tetrameric ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the mammalian central nervous system and are involved in learning, memory formation, and pathological processes. Based on structural and sequence similarities of the ligand-binding and channel domains of iGluR subunits to bacterial binding proteins and potassium channels, iGluRs are thought to have originally arisen from their fusion. Here we report the functional coupling of the bacterial ectoine binding protein EhuB to the channel pore-forming transmembrane domains of the bacterial GluR0 receptor by stabilization of dimeric binding domains. Insertion of a disulfide bridge in the dimer interface abolished desensitization of the channel current analogous to mammalian iGluRs. These results demonstrate the functional compatibility of bacterial binding proteins to the gate of the channel pore of an iGluR. Moreover, our results highlight the modular structure and crucial role of binding domain dimerization in the functional evolution of iGluRs.