bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drosophila Cocaine Avoidance is Mediated by Peripheral Bitter Gustatory Neurons
Authors: Philyaw Travis J. , Titos Iris , Cummins Pearl N. , Rodan Aylin R. , Rothenfluh Adrian 
Published: June 2022

AbstractGenetic variation contributes to heterogeneity in the prevalence of complex disorders such as addiction. The genetic risk for developing a substance use disorder can vary between drugs. The estimated heritability rate of cocaine addiction is 72%, higher than any other drug. Despite recognition of this significant genetic component, little is known about the specific genes and mechanisms that lead to the development of cocaine addiction. Drosophila is an effective model organism for identifying the genes that underlie complex behaviors, including addiction. While Drosophila exposed to cocaine display features of intoxication similar to those observed in mammals, there is currently no model of cocaine self-administration in flies. Because cocaine is a natural insecticide, we wondered if Drosophila might naively avoid it through bitter chemosensory detection. To answer this question, we performed cocaine consumption and preference assays comparing wild-type flies and bitter-taste mutants. Our results demonstrate that Drosophila detect and avoid cocaine through bitter sensing gustatory neurons, and that this process requires gustatory receptor 66a (Gr66a). Additionally, we identify a peripheral mechanism of avoidance through cocaine detection with Drosophila legs. Our findings reveal that preingestive mechanisms of toxin detection play a significant role in Drosophila cocaine avoidance and provide evidence that disrupting gustatory perception of cocaine is essential for self-administration and, therefore, developing a model of self-administration in Drosophila.
Fine-scale spatial genetic structure in a locally abundant native bunchgrass (Achnatherum thurberianum) including distinct lineages revealed within seed transfer zones
Authors: Osuna-Mascaró Carolina , Agneray Alison C. , Galland Lanie M. , Leger Elizabeth A. , Parchman Thomas L. 
Published: June 2022

AbstractAnalyses of the factors shaping spatial genetic structure in widespread plant species are important for understanding evolutionary history and local adaptation and have applied significance for guiding conservation and restoration decisions. Thurber’s needlegrass (Achnatherum thurberianum) is a widespread, locally abundant grass that inhabits heterogeneous arid environments of western North America and is of restoration significance. It is a common component of shrubland steppe communities in the Great Basin Desert, where drought, fire, and invasive grasses have degraded natural communities. Using a reduced representation sequencing approach, we generated SNP data at 5,677 loci across 246 individuals from 17A. thurberianumpopulations spanning five previously delineated seed zones from the western Great Basin. Analyses revealed pronounced population genetic structure, with individuals forming consistent geographical clusters across a variety of population genetic analyses and spatial scales. Low levels of genetic diversity within populations, as well as high population estimates of linkage disequilibrium and inbreeding, were consistent with self-fertilization as a contributor to population differentiation. Moreover, variance partitioning and partial RDA indicated local adaptation to the environment as an additional factor influencing the spatial distribution of genetic variation. The environmental variables driving these results were similar to those implicated in recent genecological work which inferred local adaptation in order to delineate seed zones. However, our analyses also reveal a complex evolutionary history ofA. thurberaniumin the Great Basin, where previously delineated seed zones contain distantly related populations. Overall, our results indicate that numerous factors shape genetic variation inA. thurberianumand that evolutionary history, along with differentiation across distinct geographic and environmental scales, should be considered for conservation and restoration plans.
An action-observation network in the common marmoset identified by ultra-high field fMRI
Authors: Zanini Alessandro , Dureux Audrey , Selvanayagam Janahan , Everling Stefan 
Published: June 2022

AbstractThe observation of others’ actions activates a network of temporal, parietal and premotor/prefrontal areas in macaque monkeys and humans. This action-observation network (AON) has been shown to play important roles in understanding the actions of others, learning by imitation, and social cognition in both species. It is unclear whether a similar network exists in New World primates, which separated from Old Word Primates ∼ 35 million years ago. Here we used ultra-high field fMRI at 9.4T in awake common marmosets (Callithrix jacchus) while they watched videos depicting the upper-limb of conspecifics performing goal-directed (grasping food) or non-goal-directed actions. We found that the observation of goal-directed actions, compared to non-goal directed ones, activated a temporo-parieto-frontal network, including areas 6 and 45 in premotor and prefrontal cortices, areas PGa-IPa, FST and the TE complex in occipito-temporal region and areas V6A, MIP, LIP and PG in the occipito-parietal cortex. These results show remarkable overlap with the AON observed in humans and macaques. These results demonstrate the existence of an evolutionarily conserved AON that likely predates the separation of Old and New World primates.
Scene-relative object motion biases depth percepts
Authors: French Ranran L. , DeAngelis Gregory C. 
Published: June 2022

AbstractAn important function of the visual system is to represent 3D scene structure from a sequence of 2D images projected onto the retinae. During observer translation, the relative image motion of stationary objects at different distances (motion parallax) provides potent depth information. However, if an object moves relative to the scene, this complicates the computation of depth from motion parallax since there will be an additional component of image motion related to scene-relative object motion. To correctly compute depth from motion parallax, only the component of image motion caused by self-motion should be used by the brain. Previous experimental and theoretical work on perception of depth from motion parallax has assumed that objects are stationary in the world. Thus, it is unknown whether perceived depth based on motion parallax is biased by object motion relative to the scene.Naïve human subjects viewed a virtual 3D scene consisting of a ground plane and stationary background objects, while lateral self-motion was simulated by optic flow. A target object could be either stationary or moving laterally at different velocities, and subjects were asked to judge the depth of the object relative to the plane of fixation. Subjects showed a far bias when object and observer moved in the same direction, and a near bias when object and observer moved in opposite directions. This pattern of biases is expected if subjects confound image motion due to self-motion with that due to scene-relative object motion. These biases were large when the object was viewed monocularly, and were greatly reduced, but not eliminated, when binocular disparity cues were provided. Our findings establish that scene-relative object motion can confound perceptual judgements of depth during self-motion.
Weaver ants regulate the rate of prey delivery during collective vertical transport
Authors: Burchill Andrew T. , Pavlic Theodore P. , Pratt Stephen C. , Reid Chris R. 
Published: June 2022

AbstractThe collective transport of massive food items by ant teams is a striking example of biological cooperation, but it remains unclear how these decentralized teams coordinate to overcome the various challenges associated with transport. Previous research has focused on transport across horizontal surfaces and very shallow inclines, disregarding the complexity of natural foraging environments. In the ant Oecophylla smaragdina, prey are routinely carried up tree trunks to arboreal nests. Using this species, we induce collective transport over a variety of angled surfaces with varying prey masses to investigate how ants respond to inclines. We found that weight and incline pose qualitatively different challenges during transport. Prey were carried over vertical inclines faster than across horizontal surfaces even though inclines were associated with longer routes and a higher probability of dropping the load. This additional speed is associated with more transporters being allocated to vertical loads and not from the persistence of individual ants. Ant teams also regulated a stable “prey delivery rate” (rate of return per transporter) across all treatments. Our proposed constrained optimization model explains these results: prey intake rate at the colony level is maximized when the allocation of transporters yields a similar prey delivery rate across loads.
Breastfeeding outcomes in late preterm infants: a multi-centre prospective cohort study
Authors: Keir Amy , Rumbold Alice , Collins Carmel T , McPhee Andrew J , Varghese Jojy , Morris Scott , Sullivan Thomas R , Leemaqz Shalem , Middleton Philippa , Makrides Maria , Best Karen P 
Published: June 2022

AbstractObjectivesTo describe (1) infant feeding practices during initial hospitalisation and up to 6 months corrected age (CA) in infants born late preterm with mothers intending to breastfeed, (2) the impact of early feeding practices on hospital length of stay and (3) maternal and infant factors associated with duration of breastfeeding.MethodsWe conducted a prospective cohort study of infants born at 34+0 to 36+6 weeks gestational age during 2018-2020. Families were followed up until the infant reached 6 months of age (corrected for prematurity). Feeding practices during the birth hospitalisation, length of initial hospital stay, and the prevalence of exclusive or any breastfeeding at 6 weeks, 3 months, and 6 months CA were examined. Associations between maternal and infant characteristics and breastfeeding at 6 weeks, 3 months and 6 months CA were assessed using multivariable logistic regression models.Results270 infants were enrolled, of these, 30% were multiple births. Overall, 78% of infants received only breastmilk as their first feed, and 83% received formula during the hospitalisation. Seventy-four per cent of infants were exclusively breastfed at discharge, 41% at 6 weeks CA, 35% at 3 months CA, and 29% at 6 months CA. The corresponding combined exclusive and partial breastfeeding rates (any breastfeeding) were 72%, 64%, and 53% of babies at 6 weeks CA, 3 months CA, and 6 months CA, respectively. The mean duration of hospitalisation was 2.9 days longer (95% confidence interval (CI) 0.31, 5.43 days) in infants who received any formula compared with those receiving only breastmilk (adjusted for GA, maternal age, multiple birth, site, and neonatal intensive care unit admission). In multivariable models, receipt of formula as the first milk feed was associated with a reduction in exclusive breastfeeding at 6 weeks CA (odds ratio = 0.22; 95% CI 0.09 to 0.53) and intention to breastfeed >6 months with an increase (odds ratio = 4.98; 95% CI 2.39 to 10.40). Intention to breastfeed >6 months remained an important predictor of exclusive breastfeeding at 3 and 6 months CA.ConclusionsOur study demonstrates that long-term exclusive breastfeeding rates were low in a cohort of women intending to provide breastmilk to their late preterm infants, with approximately half providing any breastmilk at 6 months CA. Formula as the first milk feed and intention to breastfeed >6 months were significant predictors of breastfeeding duration. Improving breastfeeding outcomes may require strategies to support early lactation and a better understanding of the ongoing support needs of this population.
SETH predicts nuances of residue disorder from protein embeddings
Authors: Ilzhoefer Dagmar , Heinzinger Michael , Rost Burkhard 
Published: June 2022

AbstractPredictions for millions of protein three-dimensional structures are only a few clicks away since the release of AlphaFold2 results for UniProt. However, many proteins have so-called intrinsically disordered regions (IDRs) that do not adopt unique structures in isolation. These IDRs are associated with several diseases, including Alzheimer’s Disease. We showed that three recent disorder measures of AlphaFold2 predictions (pLDDT, “experimentally resolved” prediction and “relative solvent accessibility”) correlated to some extent with IDRs. However, expert methods predict IDRs more reliably by combining complex machine learning models with expert-crafted input features and evolutionary information from multiple sequence alignments (MSAs). MSAs are not always available, especially for IDRs, and are computationally expensive to generate, limiting the scalability of the associated tools. Here, we present the novel method SETH that predicts residue disorder from embeddings generated by the protein Language Model ProtT5, which explicitly only uses single sequences as input. Thereby, our method, relying on a relatively shallow convolutional neural network, outperformed much more complex solutions while being much faster, allowing to create predictions for the human proteome in about one hour on a consumer-grade PC with one NVIDIA GeForce RTX 3060. Trained on a continuous disorder scale (CheZOD scores), our method captured subtle variations in disorder, thereby providing important information beyond the binary classification of most methods. High performance paired with speed revealed that SETH’s nuanced disorder predictions for entire proteomes capture aspects of the evolution of organisms. Additionally, SETH could also be used to filter out regions or proteins with probable low-quality AlphaFold2 3D structures to prioritize running the compute-intensive predictions for large data sets. SETH is freely publicly available at: https://github.com/Rostlab/SETH.
Assessing Functional Androgen Receptor Pathway Activity in Response to Radiotherapy Using hK2-targeted PET Imaging
Authors: Storey Claire M , Altai Mohamed , Bicak Mesude , Veach Darren R , Lückerath Katharina , Adrian Gabriel , McDevitt Michael R , Kalidindi Teja , Park Julie E , Herrmann Ken , Abou Diane , Zedan Wahed , Peekhaus Norbert , Klein Robert J , Damoiseaux Robert , Larson Steven M , Lilja Hans , Thorek Daniel , Ulmert David 
Published: June 2022

AbstractExternal beam radiotherapy (EBRT) remains a common treatment for all stages of PCa, but DNA damage induced by EBRT upregulates androgen receptor (AR) pathway activity to promote therapeutic resistance. [89Zr]11B6-PET is a novel modality targeting prostate-specific protein human kallikrein 2 (hK2), which is a surrogate biomarker for AR activity. Here, we studied if [89Zr]11B6-PET can accurately assess EBRT-induced AR activity. PCa mouse models received EBRT (2-50 Gy) and treatment response was monitored by [89Zr]11B6-PET/CT. Radiotracer uptake and expression of AR and AR target genes was quantified in resected tissue. EBRT increased AR pathway activity in LNCaP-AR tumors. EBRT increased prostate-specific [89Zr]11B6 uptake and hK2 levels in PCa-bearing mice (Hi-Myc x Pb_KLK2) with no significant changes in uptake in healthy (Pb_KLK2) mice. Thus, [89Zr]11B6-PET specifically detects activation of AR pathway activity after EBRT in PCa. Further clinical evaluation of hK2-PET for monitoring EBRT is warranted.
Reconstructing the functional effect ofTP53somatic mutations on its regulon using causal signalling network modelling
Authors: Triantafyllidis Charalampos P. , Barberis Alessandro , Cuervo Ana Miar , Gjerga Enio , Charlton Philip , Hartley Fiona , Van Bijsterveldt Linda , Rodriguez Julio Saez , Buffa Francesca M. 
Published: June 2022

AbstractThe gene encoding tumor proteinp53(TP53) is the most frequently mutated gene in human cancer. Mutations in both coding and non-coding regions ofTP53can disrupt the regulatory function of the transcription factor, but the functional impact of different somatic mutations on the globalTP53regulon is complex and poorly understood. To address this, we first proceed with a machine learning (ML) approach, and then propose an integrated computational network modelling approach that reconstructs signalling networks using a comprehensive collection of experimental and predicted regulons, and compares their topology. We evaluate both these approaches in a scrutinized pan-cancer analysis of matched genomics and transcriptomics data from 1,457 cell lines (22 cancer types) and 12,531 clinical samples (54 cancer sub-types). Using a ML approach based on penalized generalized linear regression we were able to predictTP53mutation, but failed to resolve different mutation types. Thus, to infer the impact of differentTP53mutations we compared the topological characteristics of the optimized and reconstructed (upwards of twenty thousand) gene networks and extracted gene signatures for each mutation type using network analysis. We demonstrate that by accounting forTP53mutation characteristics such as i) mutation type (e.g. missense, nonsense), ii) deleterious consequences of the mutation, or iii) mapping to previously identified hotspots, we can infer a much richer understanding of gene expression regulation, than when simply grouping samples based on their mutation/wild type or gene expression status. Our study highlights a powerful strategy exploiting signalling networks to systematically characterize the functional impact of the full spectrum of somatic mutations. This approach can be applied in general to genetic variation, with clear implications for, but not limited to, the biomedical domain and precision medicine.
Insect cell plasma membranes do, while soluble enzymes do not, need stabilization by accumulated cryoprotectant molecules during freezing stress
Authors: Grgac Robert , Rozsypal Jan , Des Marteaux Lauren , Štětina Tomáš , Koštál Vladimír 
Published: June 2022

AbstractAbility to survive freezing of extracellular body fluids evolved in several species of vertebrate ectotherms, many plants, and occurs relatively often in freeze-tolerant insects. Most of the multicellular organisms, however, are freeze-sensitive. Here we test coupled hypotheses postulating that: (i) irreversible denaturation of proteins and loss of integrity of biological membranes are two ultimate molecular mechanisms of freezing injury in freeze-sensitive insects; and (ii) seasonally accumulated small cryoprotective molecules (CPs) protect the proteins and membranes against the injury in freeze-tolerant insects. We show that seven different enzymes exhibit no or only partial loss of activity upon lethal freezing stress appliedin vivoto whole freeze-sensitive larva of drosophilid fly,Chymomyza costata. In contrast, the enzymes lost activity when extracted and frozenin vitroin a diluted buffer solution. This loss of activity was fully prevented by adding to buffer relatively low concentrations of a wide array of different compounds includingC. costatanative CPs, other metabolites, bovine serum albumin (BSA), and even biologically inert artificial compounds Histodenz and Ficoll. Next, we show that the plasma membranes of fat body cells lose integrity when frozenin vivoin freeze-sensitive but not in freeze-tolerant larvae. Freezing fat body cellsin vitro, however, resulted in loss of membrane integrity in both freeze-sensitive and freeze-tolerant larvae. Different additives showed widely different capacities (from none to high) to protect membrane integrity when added toin vitrofreezing medium. A complete rescue of membrane integrity was observed for a mixture of proline, trehalose and BSA.Significance statementHere we suggest that insect soluble enzymes are not primary targets of freezing injury. They are not inactivated in freeze-sensitive insects exposed to lethal freezing stress as they are sufficiently protected from loss of activity by complex composition of native biological solutions. Next we show that cell plasma membranes are likely targets of freezing injury. The membranes lose integrity in freeze-sensitive insects exposed to freezing stress, while their integrity is protected by accumulated small cryoprotective molecules, and also by proteins, in freeze-tolerant insects.
The Future is 2D: Spectral-Temporal Fitting of Dynamic Magnetic Resonance Spectroscopy Data Provides Exponential Gains in Precision Over Conventional Approaches
Authors: Tal Assaf 
Published: June 2022

AbstractPurposeMany MRS paradigms produce 2D spectral-temporal datasets, including diffusion-weighted, functional, hyperpolarized and enriched (13C, 2H) experiments. Conventionally, temporal parameters – such as T2, T1, or diffusion constants – are assessed by first fitting each spectrum independently, and subsequently fitting a temporal model (1D fitting). We investigated whether simultaneously fitting the entire dataset using a single spectral-temporal model (2D fitting) would improve the precision of the relevant temporal parameter.MethodsWe derived a Cramer Rao Lower Bound for the temporal parameters for both 1D and 2D approaches, for two experiments: A multi-echo (MTE) experiment, designed to estimate metabolite T2s; And a functional (fMRS) experiment, designed to estimate fractional change (δ) in metabolite concentrations. We investigated the dependence of the relative standard deviation of T2 in MTE and δ in fMRS.ResultsWhen peaks were spectrally distant, 2D fitting improved precision by approximately 20% relative to 1D fitting, regardless of the experiment and other parameter values. These gains increased exponentially as peaks drew closer. Dependence on temporal model parameters was weak to negligible.ConclusionOur results strongly support a 2D approach to MRS fitting where applicable, and particularly in nuclei such as 1H and 2H, which exhibit substantial spectral overlap.
Loss of Shp1 impairs myeloid cell function and causes lethal inflammation in zebrafish larvae
Authors: Allers Maaike , Bakker Petra A. , Spaink Herman P. , Hertog Jeroen den 
Published: June 2022

ABSTRACTPTPN6encodes SHP1, a protein tyrosine phosphatase that has an essential role in immune cell function. SHP1 missense and splice site mutations are associated with neutrophilic dermatoses and emphysema in humans, which resembles the phenotype seen in mice that lack functional SHP1 partially. Complete lack of SHP1 function in mousemotheatenmutants leads to severe defects and lethality at 2-6 weeks after birth. Here, we investigated the function of Shp1 in developing zebrafish embryos. We generated aptpn6knockout zebrafish line lacking functional Shp1. Zebrafish develop ex utero and are transparent, which facilitates analysis of the function of Shp1 during early hematopoietic development. Shp1 knockout caused severe inflammation and lethality around 17 days post fertilization (dpf). During early development the myeloid lineage was affected, which resulted in a decrease in the number of neutrophils, and a concomitant increase in the number of macrophages. The number of emerging hematopoietic stem and progenitor cells (HSPCs) was decreased, but due to hyperproliferation, the number of HSPCs was higher inptpn6mutants than in siblings at 5 dpf. Finally, directional migration of neutrophils and macrophages was decreased in response to wounding and less macrophages were recruited to the wound site. Yet, regeneration of the caudal fin fold was normal. We conclude that loss of Shp1 impairs neutrophil and macrophage function and caused severe inflammation and lethality at the larval stage.