bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders
Authors: Yang Kun , Hasegawa Yuto , Bhattarai Janardhan P , Hua Jun , Dower Milan , Etyemez Semra , Prasad Neal , Duvall Lauren , Paez Adrian , Smith Amy , Wang Yingqi , Zhang Yun-Feng , Lane Andrew P. , Ishizuka Koko , Kamath Vidyulata , Ma Minghong , Kamiya Atsushi , Sawa Akira 
Published: September 2022

AbstractSmell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.
Changes in capture availability due to infection can lead to correctable biases in population-level infectious disease parameters
Authors: Holmes Iris A. , Durso Andrew M. , Myers Christopher R. , Hendry Tory A. 
Published: September 2022

AbstractCorrectly identifying the strength of selection parasites impose on hosts is key to predicting epidemiological and evolutionary outcomes. However, behavioral changes due to infection can alter the capture probability of infected hosts and thereby make selection difficult to estimate by standard sampling techniques. Mark-recapture approaches, which allow researchers to determine if some groups in a population are less likely to be captured than others, can mitigate this concern. We use an individual-based simulation platform to test whether changes in capture rate due to infection can alter estimates of three key outcomes: 1) reduction in offspring numbers of infected parents, 2) the relative risk of infection for susceptible genotypes compared to resistant genotypes, and 3) change in allele frequencies between generations. We find that calculating capture probabilities using mark-recapture statistics can correctly identify biased relative risk calculations. For detecting fitness impact, the bounded nature of the distribution possible offspring numbers results in consistent underestimation of the impact of parasites on reproductive success. Researchers can mitigate many of the potential biases associated with behavioral changes due to infection by using mark-recapture techniques to calculate capture probabilities and by accounting for the shapes of the distributions they are attempting to measure.
Seasonal stability and species specificity of environmentally acquired chemical mating signals in orchid bees
Authors: Darragh Kathy , Linden Tess A , Ramirez Santiago R 
Published: September 2022

AbstractTraits that mediate reproductive isolation between species, such as those involved in mate choice and/or recognition, are predicted to experience stabilizing selection towards the species mean. Male orchid bees collect chemical compounds from many sources, such as plants and fungi, which they use as a perfume signal (pheromone) during courtship display. Environmentally acquired signals are more prone to variation as source availability can vary through space and time. Here, we investigate the seasonality and species-specificity of male perfumes across an entire year in three sympatric species ofEuglossaorchid bees. Our analysis revealed considerable within-species variation in perfumes. However, species-specificity was maintained consistently throughout the year, suggesting that these perfumes could play an important role in reproductive isolation. Our analysis also identified strong correlations in the abundance of some compounds, possibly due to shared collection sources between species. Our study suggests that orchid bee perfumes are robust in the face of environmental changes in resource availability.
Multiplatform Modeling of Atrial Fibrillation Identifies Phospholamban as Central Regulator of Cardiac Rhythm
Authors: Kervadec Anaïs , Kezos James , Ni Haibo , Yu Michael , Spiering Sean , Kannan Suraj , Andersen Peter , Grandi Eleonora , Ocorr Karen , Colas Alexandre R. 
Published: September 2022

ABSTRACTAtrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans, present in > 33 million people worldwide. Although AF is often developed secondary to cardiovascular diseases, endocrine disorders, or lifestyle factors, recent GWAS studies have identified >200 genetic variants that substantially contribute to AF risk. However, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. In this context, one major barrier to progress is the lack of experimental systems enabling to rapidly explore the function of large cohort of genes on rhythm parameters in models with human atrial relevance. To address these modeling challenges, we have developed a new multi-model platform enabling 1) high-throughput characterization of the role of AF-associated genes on action potential duration and rhythm parameters at the cellular level, using human iPSC-derived atrial-like cardiomyocytes (ACMs), and at the whole organ level, using the Drosophila heart model, and 2) validation of the physiological relevance of our experimental results using computational models of heterogenous human adult atrial myocytes (HAMs) and tissue. As proof of concept, we screened a cohort of 20 AF-associated genes and identified Phospholamban (PLN) loss of function as a top conserved hit that significantly shortens action potential duration in ACMs, HAMs and fly cardiomyocytes. Remarkably, while PLN knock-down (KD) was not sufficient to induce arrhythmia phenotypes, addition of environmental stressors (i.e fibroblasts, β-adrenergic stimulation) to the model systems, led to the robust generation of irregular beat to beat intervals, delayed after depolarizations, and triggered action potentials, as compared to controls. Finally, to delineate the mechanism underlying PLN KD-dependent arrhythmia, we used a logistic regression approach in HAM populations, and predicted that PLN functionally interacts with both NCX (loss of function) and L-type calcium channels (gain of function) to mediate these arrhythmic phenotypes. Consistent with our predictions, co-KD of PLN and NCX in ACMs and flies, led to increased arrhythmic events, while treatment of ACMs with L-type calcium channel inhibitor, verapamil, reverted these phenotypes. In summary, these results collectively demonstrate that our integrated multi-model system approach was successful in identifying and characterizing conserved roles (i.e regulation of Ca2+ homeostasis) for AF-associated genes and phenotypes, and thus paves the way for the discovery and molecular delineation of new gene regulatory networks controlling atrial rhythm with application to AF.
Mouse paralaminar amygdala excitatory neurons migrate and mature during adolescence
Authors: Alderman P.J. , Saxon D. , Torrijos-Saiz L.I. , Sharief M. , Biagiotti S.W. , Page C.E. , Melamed A. , Kuo C.T. , Garcia-Verdugo J.M. , Herranz-Pérez V. , Corbin J.G. , Sorrells S.F. 
Published: September 2022

AbstractThe human amygdala paralaminar nucleus (PL) contains immature excitatory neurons that exhibit protracted maturation into adolescence; however, whether a similar population exists in mice is unknown. We discovered a previously undescribed region with immature doublecortin (Dcx)+ excitatory neurons adjacent to the mouse basolateral amygdala, and similar to humans, these neurons mature during adolescence and are distinct from adjacent intercalated cells. Despite their immature features, these neurons are born during embryogenesis, populate the mouse PL prior to birth, and remain in an immature stage of development until adolescence. In the postnatal brain, a subpopulation of these excitatory neurons surprisingly migrate into the neighboring endopiriform cortex, peaking between P21–P28. In humans, cells with the molecular identity of mouse PL neurons populate the PL as early as 18 gestational weeks, and also exhibit migratory morphology into adolescence (13 years). The finding of a similar region in both mice and humans suggests a potentially conserved cellular mechanism for neuron recruitment and migration during adolescence, a key time period for amygdala circuit maturation and behavioral changes.
Neural population dynamics of human working memory
Authors: Li Hsin-Hung , Curtis Clayton E. 
Published: September 2022

AbstractTemporally evolving neural processes maintain working memory (WM) representations of information no longer available in the environment. Nonetheless, the dynamics of WM remain largely unexplored in the human cortex. With fMRI, we found evidence of both stable and dynamic WM representations in human cortex during a memory-guided saccade task. The stability of WM varied across brain regions with early visual cortex exhibiting the strongest dynamics. Leveraging population receptive field modeling, we visualized and made the neural dynamics interpretable. Early in the trial, neural responses in V1 were dominated by narrowly tuned activation at the location of the peripheral target. Over time, activity spread toward foveal locations and targets were represented by diffuse activation among voxels with receptive fields along a line between the fovea and the target. We suggest that the WM dynamics in early visual cortex reflects a transformation of sensory inputs into abstract task-related representations.
Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer
Authors: Marin Arnaldo , Mamun Abdullah Al , Akamatsu Hiroaki , Ye Dan , Sudhan Dhivya R. , Brown Benjamin P. , Eli Lisa , Marcelain Katherine , Meiler Jens , Arteaga Carlos L. , Hanker Ariella B. 
Published: September 2022

AbstractHER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.
Models of Throughput for Multi-Cell, Multi-Type Droplet Microfluidics
Authors: Krinsman William 
Published: September 2022

ABSTRACTNew experimental platforms encapsulate multiple cells per microfluidic droplet, with each cell belonging to one of multiple possible types. The motivating example comes from microbial ecology, where we want to observe the interactions of microbial strains. Because droplets are formed randomly, we want to accurately predict the data throughput, the numbers of droplets containing desired combinations of cell types.Herein I identify the default statistical model for predicting the data throughput of multi-cell, multi-type droplet microfluidics experiments, which fits to cell type count data. I explain the assumptions behind this model and issues that in practice may cause these assumptions to fail. One such issue, “compositional heterogeneity”, is unique to multi-type experiments. I show how to modify the default statistical model to describe the consequences of these issues, without needing to mechanistically model their causes.In practice, only two of these issues may substantially change the data throughput predictions. The changes depend on both (1) which combination of these issues are present, and (2) the precise definition of data throughput. Finally, I show that for a given experimental platform one can estimate the severity of these two issues, enabling more accurate data throughput predictions that account for these two issues.
Extending Comparison Methods for Unsigned Networks to Signed Networks
Authors: Krinsman William 
Published: September 2022

ABSTRACTWe can allow the edges of networks to have both negative and positive weights. For example, signed networks can describe the interactions of microbes. To evaluate the performance of estimators for signed networks, we need quantitative comparison methods for signed networks. Finding such comparison methods is done most easily by extending a comparison method for unsigned networks.Almost all methods reported in the literature for quantitatively comparing networks implicitly assume that edge weights are non-negative. Naive attempts to modify these methods to be applicable to signed networks can lead to nonsensical conclusions. Herein I identify requirements that should be satisfied by reasonable methods for comparing signed networks, most importantly the “double penalization principle”. I extend several comparison methods for unsigned networks while satisfying these requirements. Finally, I give examples where these extensions behave reasonably but naive extensions do not.
Benchmark data and software for assessing genome-wide CRISPR-Cas9 screening pipelines
Authors: Iannuzzi Raffaele , Manipur Ichcha , Pacini Clare , Behan Fiona M. , Guarracino Mario R. , Garnett Mathew J. , Savino Aurora , Iorio Francesco 
Published: September 2022

ABSTRACTGenome-wide recessive genetic screens using lentiviral CRISPR-guide RNA libraries are widely performed in mammalian cells to functionally characterise individual genes and for the discovery of new anti-cancer therapeutic targets. As the effectiveness of such powerful and precise tools for cancer pharmacogenomic is emerging, reference datasets for their quality assessment and the validation of the underlying experimental pipelines are becoming increasingly necessary. Here, we provide a dataset, an R package, and metrics for the assessment of novel experimental pipelines upon the execution of a single calibration viability screen of the HT-29 human colon cancer cell line, employing a commercially available genome-wide library of single guide RNAs: the Human Improved Genome-wide Knockout CRISPR (Sanger) Library. This dataset contains results from screening the HT-29 in multiple batches with the Sanger library, and outcomes from several levels of quality control tests on the resulting data. Data and accompanying R package can be used as a toolkit for benchmarking newly established experimental pipelines for CRISPR-Cas9 recessive screens, via the generation of a final quality-control report.
Deletion of 12-lipoxygenase normalizes platelet function after storage and transfusion in thrombocytopenic mice
Authors: Larsen Hannah J. , Byrne Daire , Bailey S. Lawrence , Stolla Massiel C. , Holinstat Michael , Fu Xiaoyun , Stolla Moritz 
Published: September 2022

ObjectivePlatelets for transfusion are stored for 5-7 days. During storage, platelets undergo numerous detrimental functional changes. In the current study, we sought to understand how genetic deletion of 12 –lipoxygenase (12-LOX) affects platelets during storage, before, and after transfusion.Approach and ResultsWe obtained platelets from wild-type (WT) and 12-LOX-/-mice and performed storage studies for 24 and 48 hours. Using LC-MS/MS-MRM, we showed that ω-3 and ω-6 fatty acids increased significantly in stored platelets from 12-LOX-/-mice, while oxylipins were significantly lower than in WT platelets. The circulation time of fresh 12-LOX-/-platelets was significantly shorter than that of fresh WT platelets, but no differences were observed after storage. Baseline αIIbβ3 integrin activation was significantly lower before and after 24 hours of storage in 12-LOX-/-platelets than in WT platelets. Surprisingly, after transfusion, we observed more baseline αIIbβ3 integrin activation in 12-LOX-/-platelets than in WT platelets. In line with this, transfusion of stored 12-LOX-/-platelets led to more frequent and significantly faster vessel occlusions than transfusion of stored WT platelets in a FeCl3-induced carotid artery injury model in thrombocytopenic mice.ConclusionDeleting 12-LOX improves the post-transfusion function of stored murine platelets. Pharmacologic inhibition of 12-LOX or dietary alterations of ω-3 and ω-6 PUFAs could significantly enhance human platelet quality and function after storage. Future studies must determine the feasibility and safety of 12-LOX inhibition in stored and transfused human platelets.
Two cyclic electron flows around photosystem I differentially participate in C4photosynthesis
Authors: Ogawa Takako , Kobayashi Kana , Taniguchi Yukimi Y. , Shikanai Toshiharu , Nakamura Naoya , Yokota Akiho , Munekage Yuri N. 
Published: September 2022

AbstractC4plants assimilate CO2more efficiently than C3plants because of their C4cycle that concentrates CO2. However, the C4cycle requires additional ATP molecules, which may be supplied by the cyclic electron flow around photosystem I. One cyclic electron flow route, which depends on a chloroplast NADH dehydrogenase-like (NDH) complex, is suggested to be crucial for C4plants despite the low activity in C3plants. The other route depends on proton gradient regulation 5 (PGR5) and PGR5-like photosynthetic phenotype 1 (PGRL1), which is considered a major cyclic electron flow route to generate the proton gradient across the thylakoid membrane in C3plants. However, its contribution to C4photosynthesis is still unclear. In this study, we investigated the contribution of the two cyclic electron flow routes to the NADP-malic enzyme subtype of C4photosynthesis inFlaveria bidentis. We observed that the suppression of the NDH-dependent route drastically delayed growth and decreased the CO2assimilation rate to approximately 30% of the wild-type rate. On the other hand, the suppression of the PGR5/PGRL1-dependent route did not affect plant growth and resulted in a CO2assimilation rate that was approximately 80% of the wild-type rate. Our data indicate that the NDH-dependent cyclic electron flow substantially contributes to the NADP-malic enzyme subtype of C4photosynthesis and that the PGR5/PGRL1-dependent route cannot complement the NDH-dependent route inF. bidentis. These findings support the fact that during the C4evolution, the photosynthetic electron flow may be optimized to provide the energy required for C4photosynthesis.
Morphological evolution of bird wings follows a mechanical sensitivity gradient determined by the aerodynamics of flapping flight
Authors: Rader Jonathan , Hedrick Tyson L. 
Published: September 2022

AbstractThe physical principles that govern the function of biological structures also mediate their evolution, but the evolutionary drivers of morphological traits within complex structures can be difficult to predict. We used morphological traits measured from 1096 3-dimensional bird wing scans from 178 species to test how two frameworks for relating morphology to evolution interact. We examined whether the modular organization of the wing into handwing and armwing regions, or the relationship between trait morphology and functional output (i.e. mechanical sensitivity, driven here by flapping flight aerodynamics) dominate evolutionary rate (σ2) and mode. Our results support discretization of the armwing and handwing as morphological modules, but morphological disparity andσ2varied continuously with the mechanical sensitivity gradient and were not modular. Thus, mechanical sensitivity should be considered an independent driver of evolutionary dynamics, distinct from morphological modularity.TeaserMechanical sensitivity drives wing shape evolution in birds and may be fundamental to the evolution of biomechanical systems.