bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative Changes in the Upper Airway Following Mandibular Distraction Osteogenesis in Pediatric Hemifacial Microsomia
Authors: Barrero Carlos , Vu Giap , Kosyk Mychajlo , Humphries Laura , Jeon Hyeran Helen , Boucher Normand , Taylor Jesse , Nah Hyun-Duck
Published: November 2021

Background:

Patients with hemifacial microsomia (HFM) may undergo unilateral mandibular distraction osteogenesis (MDO) before skeletal maturity in an effort to improve facial symmetry. Mandibular distraction osteogenesis's effect on airway volumes have been studied in the past, though to our knowledge, none have accounted for the effect of head and neck posture on airway morphology. This study aimed to tackle this shortcoming, using imaging to analyze the upper airway of patients with HFM before and after surgical intervention with MDO.

Methods/Description:

The authors retrospectively reviewed patients with a diagnosis of unilateral HFM whom underwent unilateral MDO with an oblique vector at age 4 to 14 years at a single institution from 2004 to 2019. Patients with pre- and post-MDO three-dimensional computed tomography scans of the upper airway within 12 months of distractor placement and removal, respectively, were included. Head and neck postures were determined by craniocervical, pitch, roll, and yaw angles. Pre- and post-operative pharyngeal airway volumes, pharyngeal surface area, minimum retropalatal cross-sectional areas (RP CSA) and retroglossal (RG) CSA and associated anteroposterior distances were measured using Mimics 22.0 (Materialise; Leuven, Belgium). Comparison was done using Kruskal-Wallis tests and linear mixed-effects models controlling for head and neck postures.

Results:

Ten patients met inclusion criteria. Mean age at pre-distractor placement computed tomography scan was 99 ± 35 months, and mean duration between pre- and post-surgery scans was 220 ± 90 days. Head and neck posture were found to be significant predictors of all airway dimensions. After controlling for significant factors with fixed effects linear modeling, surface area was found to be significantly smaller in patients after MDO by 189.48 mm2 (F[10.8] = −3.47, P = 0.0053), compared to their preoperative measurements. Surgery was not a significant predictor of changes in airway volume (F[11.6] = 0.52, P = 0.61), minimum RP CSA (F[12.2] =  −0.64, P = 0.53), minimum RG CSA (F[12.6] =  −1.64, P = 0.13), RP anteroposterior distance (F[14.0] = 0.30, P = 0.77), or RG anteroposterior distance (F[20.0] =  −0.04, P = 0.97).

Conclusions:

Oblique vector MDO in patients with HFM is associated only with statistically significant changes in the surface area of the upper airway, and is not associated with statistically significant changes in dimensions like volume, CSA, or anteroposterior dimension. This is an important finding, as it may guide discussions surrounding risk/benefit ratio for MDO in childhood.
Emotional authenticity modulates affective and social trait inferences from voices
Authors: Pinheiro Ana P. , Anikin Andrey , Conde Tatiana , Sarzedas João , Chen Sinead , Scott Sophie K. , Lima César F.
Published: November 2021

The human voice is a primary tool for verbal and nonverbal communication. Studies on laughter emphasize a distinction between spontaneous laughter, which reflects a genuinely felt emotion, and volitional laughter, associated with more intentional communicative acts. Listeners can reliably differentiate the two. It remains unclear, however, if they can detect authenticity in other vocalizations, and whether authenticity determines the affective and social impressions that we form about others. Here, 137 participants listened to laughs and cries that could be spontaneous or volitional and rated them on authenticity, valence, arousal, trustworthiness and dominance. Bayesian mixed models indicated that listeners detect authenticity similarly well in laughter and crying. Speakers were also perceived to be more trustworthy, and in a higher arousal state, when their laughs and cries were spontaneous. Moreover, spontaneous laughs were evaluated as more positive than volitional ones, and we found that the same acoustic features predicted perceived authenticity and trustworthiness in laughter: high pitch, spectral variability and less voicing. For crying, associations between acoustic features and ratings were less reliable. These findings indicate that emotional authenticity shapes affective and social trait inferences from voices, and that the ability to detect authenticity in vocalizations is not limited to laughter.

This article is part of the theme issue ‘Voice modulation: from origin and mechanism to social impact (Part I)’.
The colonial legacy of herbaria
Authors: Park Daniel S. , Feng Xiao , Akiyama Shinobu , Ardiyani Marlina , Avendaño Neida , Barina Zoltan , Bärtschi Blandine , Belgrano Manuel , Betancur Julio , Bijmoer Roxali , Bogaerts Ann , Cano Asunción , Danihelka Jirí , Garg Arti , Giblin David E. , Gogoi Rajib , Guggisberg Alessia , Hyvärinen Marko , James Shelley A. , Sebola Ramagwai J. , Katagiri Tomoyuki , Kennedy Jonathan A. , Komil Tojibaev Sh. , Lee Byoungyoon , Lee Serena M.L. , Magri Donatella , Marcucci Rossella , Masinde Siro , Melnikov Denis , Mráz Patrik , Mulenko Wieslaw , Musili Paul , Mwachala Geoffrey , Nelson Burrell E. , Niezgoda Christine , Sepúlveda Carla Novoa , Orli Sylvia , Paton Alan , Payette Serge , Perkins Kent D. , Ponce Maria Jimena , Rainer Heimo , Rasingam L. , Rustiami Himmah , Shiyan Natalia M. , Bjorå Charlotte S. , Solomon James , Stauffer Fred , Sumadijaya Alex , Thiébaut Mélanie , Thiers Barbara M. , Tsubota Hiromi , Vaughan Alison , Virtanen Risto , Whitfeld Timothy J. S. , Zhang Dianxiang , Zuloaga Fernando O. , Davis Charles C.
Published: November 2021

Herbarium collections shape our understanding of the world’s flora and are crucial for addressing global change and biodiversity conservation. The formation of such natural history collections, however, are not free from sociopolitical issues of immediate relevance. Despite increasing efforts addressing issues of representation and colonialism in natural history collections, herbaria have received comparatively less attention. While it has been noted that the majority of plant specimens are housed in the global North, the extent of this disparity has not been rigorously quantified to date. Here, by analyzing over 85 million specimen records and surveying herbaria across the globe, we assess the colonial legacy of botanical collections and how we may move towards a more inclusive future. We demonstrate that colonial exploitation has contributed to an inverse relationship between where plant biodiversity exists in nature and where it is housed in herbaria. Such disparities persist in herbaria across physical and digital realms despite overt colonialism having ended over half a century ago, suggesting ongoing digitization and decolonization efforts have yet to alleviate colonial-era discrepancies. We emphasize the need for acknowledging the inconvenient history of herbarium collections and the implementation of a more equitable, global paradigm for their collection, curation, and use.
Leveraging eDNA metabarcoding to characterize nearshore fish communities in Southeast Alaska: Do habitat and tide matter?
Authors: Larson Wes , Barry Patrick , Dokai Willie , Maselko Jacek , Olson John , Baetscher Diana
Published: November 2021

Nearshore marine habitats are critical for a variety of commercially important fish species, but assessing fish communities in these habitats is costly and time-intensive. Here, we leverage eDNA metabarcoding to characterize nearshore fish communities near Juneau, Alaska, USA, a high-latitude environment with large tidal swings, strong currents, and significant freshwater input. We investigated whether species richness and community composition differed across three habitat types (sand beaches, eelgrass beds, and rocky shorelines) and between high and low tides. Additionally, we tested whether replication of field samples and PCR reactions influenced either species richness or composition. We amplified a 12S mitochondrial locus in our samples and identified 188 fish amplicon sequence variants (ASVs), corresponding to 21 unique taxa, with approximately half of these resolved to single species. Species richness and composition inferred from eDNA differed substantially among habitats, with rock habitats containing fewer taxa and fewer overall detections than sand and eelgrass habitats. The effect of tide was more subtle and suggested a habitat-tide interaction, with differences in taxa between tides largely isolated to sand habitats. Power analyses indicated that additional field sampling is useful to detect subtle changes in species richness such as those due to tide. PCR replicates typically identified a small number of additional taxa. The most notable result from our study was that shore morphology appeared to substantially influence community structure. Rocky shorelines sloped quickly into deep water, while sand and eelgrass habitats descended much more gradually. We hypothesize that differences in taxa observed among habitats were largely due to lack of mixing between bottom and surface water, providing further evidence that eDNA transport is minimal and that many marine eDNA detections are derived from highly localized sampling locations. We suggest that future studies could explore the extent to which habitat and nearshore physical processes influence eDNA detections.
Comparing single cell datasets using DensityMorph
Authors: Feher Kristen
Published: November 2021

1

The proliferation of single cell datasets has brought a wealth of information, but also great challenges in data analysis. Obtaining a cohesive overview of multiple single cell samples is difficult and requires consideration of cell population structure - which may or may not be well defined - along with subtle shifts in expression within cell populations across samples, and changes in population frequency across samples. Ideally, all this would be integrated with the experimental design, e.g. time point, genotype, treatment etc. Data visualisation is the most effective way of communicating analysis but often this takes the form of a plethora of TSNE plots, colour coded according to marker and sample. In this manuscript, I introduce a novel exploratory data analysis and visualisation method that is centred around a novel quasi-distance (DensityMorph) between single cell samples. DensityMorph makes it possible to plot single cell samples in a manner analogous to performing principal component analysis on microarray samples. Biological interpretation is ensured by the introduction of Explanatory Components, which show how marker expression and coexpression drive the differences between samples. This method is a breakthrough in terms of displaying the most pertinent biological changes across single cell samples in a compact plot. Finally, it can be used either as a stand-alone method or to structure other types of analysis such as manual flow cytometry gating or cell population clustering.
Genome-wide association study reveals complex genetic architecture of cadmium and mercury accumulation and tolerance traits in Medicago truncatula
Authors: Paape Tim , Heiniger Benjamin , Domingo Miguel Santo , Clear Michael R. , Lucas M. Mercedes , Pueyo José J.
Published: November 2021

Heavy metals are an increasing problem due to contamination from human sources that and can enter the food chain by being taken up by plants. Understanding the genetic basis of accumulation and tolerance in plants is important for reducing the uptake of toxic metals in crops and crop relatives, as well as for removing heavy metals from soils by means of phytoremediation. Following exposure of Medicago truncatula seedlings to cadmium (Cd) and mercury (Hg), we conducted a genome-wide association study using relative root growth (RRG) and leaf accumulation measurements. Cd and Hg accumulation and RRG had heritability ranging 0.44 - 0.72 indicating high genetic diversity for these traits. The Cd and Hg trait associations were broadly distributed throughout the genome, indicated the traits are polygenic and involve several quantitative loci. For all traits, candidate genes included several membrane associated ATP-binding cassette transporters, P-type ATPase transporters, several oxidative stress response genes and stress related UDP-glycosyltransferases. The P-type ATPase transporters and ATP-binding cassette protein-families have roles in vacuole transport of heavy metals, and our findings support their wide use in physiological plant responses to heavy metals and abiotic stresses. We also found associations between Cd RRG with the genes CAX3 and PDR3, two linked adjacent genes, and leaf accumulation of Hg associated with the genes NRAMP6 and CAX9. When plant genotypes with the most extreme phenotypes were compared, we found significant divergence in genomic regions using population genomics methods that contained metal transport and stress response gene ontologies. Several of these genomic regions show high linkage disequilibrium (LD) among candidate genes suggesting they have evolved together. Minor allele frequency (MAF) and effect size of the most significant SNPs was negatively correlated with large effect alleles being most rare. This is consistent with purifying selection against alleles that increase toxicity and abiotic stress. Conversely, the alleles with large affect that had higher frequencies that were associated with the exclusion of Cd and Hg. Overall, macroevolutionary conservation of heavy metal and stress response genes is important for improvement of forage crops by harnessing wild genetic variants in gene banks such as the Medicago HapMap collection.
Inter-trial variations in EEG predict the individual differences in social tasks
Authors: Zhang Haoming , Zhang Kunkun , Zhang Ziqi , Zhao Mingqi , Liu Quanying , Luo Wenbo , Wu Haiyan
Published: November 2021

People experience events and form an impression of others in a way that is affected by social influence every day. In the present study, we designed a series of tasks centered on social influence to investigate people’s bias in following others’ opinions and its underlying neural predictors. Our results showed social conformity and proved that social influence-induced change can be predicted by the amount of inter-trial electroencephalogram (EEG) variations when people view others’ faces. This prediction effect is robust in the alpha-band over the right frontal and left occipital electrodes for negative influence. Inter-trial EEG variations can also predict the subsequent trust difference between negatively and positively influenced faces. Our findings suggest that higher Inter-trial EEG variations in the pre-influence task may serve as a predictor of high vulnerability to social influence. The present study provides a novel approach that considers both the stability of one’s endogenous EEG and the variations in external task components to predict human social behaviors.
Oral Lichen Planus and its relation with Oral Squamous Cell Carcinoma: new insights into the potential for malignant transformation
Authors: de Lanna Cristóvão Antunes , da Silva Beatriz Nascimento Monteiro , de Melo Andreia Cristina , Bonamino Martín H. , Alves Lísia Daltro Borges , Ribeiro Pinto Luis Felipe , Cardoso Abel Silveira , Antunes Héliton Spíndola , Boroni Mariana , Goldemberg Daniel Cohen
Published: November 2021

Oral Lichen Planus (OLP) is a chronic inflammatory disorder of unknown etiology. However, evidence suggests that it consists of an immunological process that leads to degeneration of the keratinocytes in the basal layer of the oral mucosa. Despite being recognized by WHO as a potentially malignant disorder with progression to oral squamous cell carcinoma (OSCC), the relationship between both pathologies is still controversial. Different studies have investigated factors associated with the potential for malignant transformation of OLP but it remains unclear. Through a bioinformatics approach, we investigated similarities in gene expression profiles of OLP and OSCC in early and advanced stages. Our results revealed gene expression patterns related to processes of keratinization, keratinocyte differentiation, cell proliferation and immune response in common between OLP and early and advanced OSCC, with the cornified envelope formation and antigen processing cross-presentation pathways in common between OLP and early OSCC. Together, these results reveal that key genes such as PI3, SPRR1B and KRT17, in addition to genes associated with different immune processes such as CXCL-13, HIF1A and IL1B may be involved in this oncogenic process. In addition, we performed an analysis of differentially and co-expressed genes and proposed putative therapeutic targets and associated drugs.
Development and evaluation of PCR primers for environmental DNA (eDNA) metabarcoding of Amphibia
Authors: Sakata Masayuki K. , Kawata Mone U. , Kurabayashi Atsushi , Kurita Takaki , Nakamura Masatoshi , Shirako Tomoyasu , Kakehashi Ryosuke , Nishikawa Kanto , Hossman Mohamad Yazid , Nishijima Takashi , Kabamoto Junichi , Miya Masaki , Minamoto Toshifumi
Published: November 2021

Biodiversity monitoring is important for the conservation of natural ecosystems in general, but particularly for amphibians, whose populations are pronouncedly declining. However, amphibians’ ecological traits (e.g., nocturnal or aquatic) often prevent their precise monitoring. Environmental DNA (eDNA) metabarcoding—analysis of extra-organismal DNA released into the environment—allows the easy and effective monitoring of the biodiversity of aquatic organisms. Here, we developed and tested the utility of original PCR primer sets. First, we conducted in vitro PCR amplification tests with universal primer candidates using total DNA extracted from amphibian tissues. Five primer sets successfully amplified the target DNA fragments (partial 16S rRNA gene fragments of 160–311 bp) from all 16 taxa tested (from the three living amphibian orders Anura, Caudata, and Gymnophiona). Next, we investigated the taxonomic resolution retrieved using each primer set. The results revealed that the universal primer set “Amph16S” had the highest resolution among the tested sets. Finally, we applied Amph16S to actual metabarcoding and evaluated its detection capability by comparing the species detected using eDNA and physical survey (capture-based sampling and visual survey) in multiple agricultural ecosystems across Japan (160 sites in 10 areas). The eDNA metabarcoding with Amph16S detected twice as many species as the physical surveys (16 vs. 8 species, respectively), indicating the effectiveness of Amph16S in biodiversity monitoring and ecological research for amphibian communities.
Characterization of γ-Glutamyl Peptidases and γ-Glutamyl Cyclotransferases for Glutathione Degradation inArabidopsis
Authors: Ito Takehiro , Kitaiwa Taisuke , Nishizono Kosuke , Umahashi Minori , Miyaji Shunsuke , Agake Shin-ichiro , Kuwahara Kana , Yokoyama Tadashi , Maruyama-Nakashita Akiko , Sugiyama Ryosuke , Hirai Masami Yokota , Ohkama-Ohtsu Naoko
Published: November 2021

Organic sulfur is stored as glutathione (GSH) in plants. InArabidopsis, γ-glutamyl cyclotransferases (GGCT2;1, GGCT2;2, and GGCT2;3) degrade cytosolic GSH, but they do not fully explain the rapid GSH turnover. Here, we demonstrate that γ-glutamyl peptidases, GGP1 and GGP3, play a substantial role in degrading GSH in the cytosol.

We conducted yeast complementation assay and activity assay of recombinant proteins to identify the novel GSH degradation enzymes. The expression patterns were investigated by RT-qPCR. GSH concentrations in the mutants were also analyzed.

GGP1complemented the yeast phenotype. Recombinant GGP1 and GGP3 showed reasonableKmvalues considering cytosolic GSH concentration, and their activity was comparable to that of GGCTs. TheGGP1transcript was highly abundant in mature organs such as rosette leaves. The expression ofGGCT2;1was conspicuously enhanced under sulfur deficiency. GSH concentration was higher inggp1knockout mutants regardless of nutritional conditions; the concentration was higher inggct2;1knockout mutants under sulfur-deficient conditions.

We propose a model wherein cytosolic GSH is degraded fundamentally by GGP1. The degradation is accelerated by GGCT2;1 under sulfur deficiency. Given the energy cost throughout the reactions, GGPs could render a more efficient route for GSH degradation than GGCTs.
Where is the money? Dynamics in feedback processing and attention during spatial probabilistic learning
Authors: Pütz Celina , van den Berg Berry , Lorist Monicque M.
Published: November 2021

Learned feature-based stimulus-reward-associations can modulate behavior and the underlying neural processing of information. In our study, we investigated the neurocognitive mechanisms underlying learning ofspatialstimulus-reward-associations. Participants performed a probabilistic spatial reward-learning task that required participants, within 40 trials, to learn which out of four locations on a computer screen yielded the most gain-feedback when chosen. Our behavioral findings show that participants learned to choose which location was most rewarding. Those findings were paralleled by significant amplitude differences in event-related potentials (ERPs) elicited by the presentation of loss and gain feedback; the amplitude of the feedback-related negativity (FRN) was more negative in response to loss feedback compared to gain feedback, but showed no modulation by trial-number. On the other hand, the late positive component (LPC), became larger in response to losses as the learning-set progressed, but smaller in response to gains. Additionally, immediately following feedback presentation, brain activity in the visual cortex - read out through alpha frequency oscillations measured over occipital sites - was predictive of the amplitude of the N2pc ERP component, a marker of spatial attention orienting, observed on the next trial. Taken together, we elucidated neurocognitive dynamics underlying feedback processing in spatial reward learning, and the subsequent effects that spatial stimulus-reward association learning have on spatial attention.
Synchronization through uncorrelated noise in excitatory-inhibitory networks
Authors: Lucas Rebscher , Klaus Obermayer , Christoph Metzner
Published: November 2021

Gamma rhythms play a major role in many different processes in the brain, such as attention, working memory and sensory processing. While typically considered detrimental, counterintuitively noise can sometimes have beneficial effects on communication and information transfer. Recently, Meng and Riecke showed that synchronization of interacting networks of inhibitory neurons in the gamma band increases while synchronization within these networks decreases when neurons are subject to uncorrelated noise. However, experimental and modeling studies point towards an important role of the pyramidal-interneuronal network gamma (PING) mechanism in the cortex. Therefore, we investigated the effect of uncorrelated noise on the communication between excitatory-inhibitory networks producing gamma oscillations via a PING mechanism. Our results suggest that synaptic noise can have a supporting role in facilitating inter-regional communication and that noise-induced synchronization between networks is generated via a different mechanism than when synchronization is mediated by strong synaptic coupling. Noise-induced synchronization is achieved by lowering synchronization within networks which allows the respective other network to impose its own gamma rhythm resulting in synchronization between networks.
Overdominant and partially dominant mutations drive short-term adaptation in diploid yeast
Authors: Aggeli Dimitra , Marad Daniel A. , Liu Xianan , Buskirk Sean W. , Levy Sasha F. , Lang Gregory I.
Published: November 2021

Identification of adaptive targets in experimental evolution typically relies on extensive replication and allele reconstructions. An alternative approach is to directly assay all mutations in an evolved clone by generating pools of segregants that contain random combinations of the evolved mutations. Here, we apply this method to 6 clones isolated from 4 diploid populations that were clonally evolved for 2,000 generations in rich glucose medium. Each clone contains ∼20-25 mutations relative to the ancestor. We derived intermediate genotypes between the founder and the evolved clones by bulk mating sporulated cultures of each evolved clone to a barcoded haploid version of the founder. We competed the barcoded segregants en masse and quantified the fitness of each barcode. We estimated average fitness effects of evolved mutations using barcode fitness and whole genome sequencing for a subset of segregants or time-course whole population whole genome sequencing. In contrast to our previous work in haploid populations, we find that diploids carry fewer evolved mutations with a detectable fitness effect (6%), contributing a modest fitness advantage (up to 5.4%). In agreement with theoretical expectations, reconstruction experiments show that all adaptive mutations manifest some degree of dominance over the ancestral allele, and most are overdominant. Competition assays under conditions that deviated from the evolutionary environment show that adaptive mutations are often pleiotropic.
Improving Mathematical Models of Cancer through Game-Theoretic Modelling: A Study in Non-Small Cell Lung Cancer
Authors: Ardévol Martínez Virginia , Salvioli Monica , Laleh Narmin Ghaffari , Thuijsman Frank , Brown Joel S. , Cavill Rachel , Kather Jakob Nikolas , Staňková Kateřina
Published: November 2021

We examined a dataset of 590 Non-Small Cell Lung Cancer patients treated with either chemotherapy or immunotherapy using a game-theoretic model that includes both the evolution of therapy resistance and a cost of resistance. We tested whether the game-theoretic model provides a better fit than classical mathematical models of population growth (exponential, logistic, classic Bertalanffy, general Bertalanffy, Gompertz, general Gompertz). To our knowledge, this is the first time a large clinical patient cohort (as opposed to only in-vitro data) has been used to apply a game-theoretic cancer model. The game-theoretic model provided a better fit to the tumor dynamics of the 590 Non-Small Cell Lung Cancer patients than any of the non-evolutionary population growth models. This was not simply due to having more parameters in the game-theoretic model. The game-theoretic model was seemingly able to fit more accurately patients whose tumor burden exhibit a U-shaped trajectory over time. We explained how this game-theoretic model provides predictions of future tumor growth based on just a few initial measurements. Using the estimates for treatment-specific parameters, we then explored alternative treatment protocols and their expected impact on tumor growth and patient outcome. As such, the model could possibly be used to suggest patient-specific optimal treatment regimens with the goal of minimizing final tumor burden. Therapeutic protocols based on game-theoretic modeling can help to predict tumor growth, and could potentially improve patient outcome in the future. The model invites evolutionary therapies that anticipate and steer the evolution of therapy resistance.
Sub-Cluster Identification through Semi-Supervised Optimization of Rare-cell Silhouettes (SCISSORS) in Single-Cell Sequencing
Authors: Leary Jack , Xu Yi , Morrison Ashley , Jin Chong , Shen Emily C. , Su Ye , Rashid Naim , Yeh Jen Jen , Peng Xianlu L.
Published: November 2021

Single-cell RNA-sequencing (scRNA-seq) has enabled the molecular profiling of thousands to millions of cells simultaneously in biologically heterogenous samples. Currently, common practice in scRNA-seq is to determine cell type labels through unsupervised clustering and the examination of cluster-specific genes. However, even small differences in analysis and parameter choice can greatly alter clustering solutions and thus impose great influence on which cell types are identified. Existing methods largely focus on determining the optimal number of robust clusters, which is not favorable for identifying cells of extremely low abundance due to their subtle contributions towards overall patterns of gene expression. Here we present a carefully designed framework, SCISSORS, which accurately profiles subclusters within major cluster(s) for the identification of rare cell types in scRNA-seq data. SCISSORS employs silhouette scoring for the estimation of heterogeneity of clusters and reveals rare cells in heterogenous clusters by implementing a multi-step, semi-supervised reclustering process. Additionally, SCISSORS provides a method for the identification of marker genes of rare cells, which may be used for further study. SCISSORS is wrapped around the popular Seurat R package and can be easily integrated into existing Seurat pipelines. SCISSORS, including source code and vignettes for two example datasets, is freely available athttps://github.com/jrleary/SCISSORS.
Invariant neural subspaces maintained by feedback modulation
Authors: Naumann Laura Bella , Keijser Joram , Sprekeler Henning
Published: November 2021

Sensory systems reliably process incoming stimuli in spite of changes in context. Most recent models accredit this context invariance to an extraction of increasingly complex sensory features in hierarchical feedforward networks. Here, we study how context-invariant representations can be established by feedback rather than feedforward processing. We show that feedforward neural networks modulated by feedback can dynamically generate invariant sensory representations. The required feedback can be implemented as a slow and spatially diffuse gain modulation. The invariance is not present on the level of individual neurons, but emerges only on the population level. Mechanistically, the feedback modulation dynamically reorients the manifold of neural activity and thereby maintains an invariant neural subspace in spite of contextual variations. Our results highlight the importance of population-level analyses for understanding the role of feedback in flexible sensory processing.
Dry Powders for Inhalation Containing Monoclonal Antibodies Made by Thin-Film Freeze-Drying
Authors: Hufnagel Stephanie , Xu Haiyue , Sahakijpijarn Sawittree , Moon Chaeho , Chow Laura Q.M. , Williams Robert O. , Cui Zhengrong
Published: November 2021

Thin-film freeze-drying (TFFD) is a rapid freezing and then drying technique used to prepare inhalable dry powders from the liquid form for drug delivery to the lungs. We report the preparation of aerosolizable dry powders of monoclonal antibodies (mAbs) by TFFD. We first formulated IgG with lactose/leucine (60:40 w/w) or trehalose/leucine (75:25). IgG 1% (w/w) formulated with lactose/leucine (60:40 w/w) in phosphate buffered saline (PBS) (IgG-1-LL-PBS) and processed by TFFD was found to produce the powder with the most desirable aerosol properties. We then replaced IgG with a specific antibody, anti-programmed cell death protein (anti-PD-1 mAb), to prepare a dry powder (anti-PD1-1-LL-PBS), which performed similarly to the IgG-1-LL-PBS powder. The aerosol properties of anti-PD1-1-LL-PBS were significantly better when TFFD was used to prepare the powder as compared to conventional shelf freeze-drying (shelf FD). The dry powder had a porous structure with nanoaggregates. The dry powder had a Tg value between 39-50 °C. When stored at room temperature, the anti-PD-1 mAb in the TFFD powder was more stable than that of the same formulation stored as a liquid. The addition of polyvinylpyrrolidone (PVP) K40 in the formulation was able to raise the Tg to 152 °C, which is expected to further increase the storage stability of the mAbs. The PD-1 binding activities of the anti-PD-1 mAbs before and after TFFD were not different. While protein loss, likely due to protein binding to glass or plastic vials and the TFF apparatus, was identified, we were able to minimize the loss by increasing mAb content in the powders. Lastly, we show that another mAb, anti-TNF-α, can also be converted to a dry powder with a similar composition by TFFD. We conclude that TFFD can be applied to produce stable aerosolizable dry powders of mAbs for pulmonary delivery.
A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
Authors: Charlebois Edouard , Fillebeen Carine , Katsarou Angeliki , Rabinovich Aleksandr , Wisniewski Kazimierz , Venkataramani Vivek , Michalke Bernhard , Velentza Anastasia , Pantopoulos Kostas
Published: November 2021

The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in LPS-treated wt mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/-mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wt animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/-mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen, to stimulate ferroportin mRNA translation. Prolonged LPS treatment eliminating ferroportin mRNA permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient combined with iron depletion.
Intragenomic variation in mutation biases causes underestimation of selection on synonymous codon usage
Authors: Cope Alexander L. , Shah Premal
Published: November 2021

Patterns of non-uniform usage of synonymous codons (codon bias) varies across genes in an organism and across species from all domains of life. The bias in codon usage is due to a combination of both non-adaptive (e.g. mutation biases) and adaptive (e.g. natural selection for translation efficiency/accuracy) evolutionary forces. Most population genetics models quantify the effects of mutation bias and selection on shaping codon usage patterns assuming a uniform mutation bias across the genome. However, mutation biases can vary both along and across chromosomes due to processes such as biased gene conversion, potentially obfuscating signals of translational selection. Moreover, estimates of variation in genomic mutation biases are often lacking for non-model organisms. Here, we combine an unsupervised learning method with a population genetics model of synonymous codon bias evolution to assess the impact of intragenomic variation in mutation bias on the strength and direction of natural selection on synonymous codon usage across 49 Saccharomycotina budding yeasts. We find that in the absence of a priori information, unsupervised learning approaches can be used to identify regions evolving under different mutation biases. We find that the impact of intragenomic variation in mutation bias varies widely, even among closely-related species. We show that the overall strength and direction of selection on codon usage can be underestimated by failing to account for intragenomic variation in mutation biases. Interestingly, genes falling into clusters identified by machine learning are also often physically clustered across chromosomes, consistent with processes such as biased gene conversion. Our results indicate the need for more nuanced models of sequence evolution that systematically incorporate the effects of variable mutation biases on codon frequencies.
Cycles of transcription and local translation support molecular long-term memory in the hippocampus
Authors: Das Sulagna , Lituma Pablo J. , Castillo Pablo E. , Singer Robert H.
Published: November 2021

Long-term memory requires transcription and translation of activity-regulated genes. Many of these are immediate early genes (IEGs) with short-lived mRNAs and proteins, decaying rapidly after stimulation. It remains unknown how an IEG with rapid mRNA and protein turnover can impact long-lasting changes at the synapses. Using fluorescently tagged endogenous Arc, an IEG important for memory consolidation, we performed high-resolution imaging of transcription and translation in individual neurons to identify the long-term gene dynamics after stimulation. Unexpectedly, once induced, Arc underwent transcriptional reactivation often at the same allele. Cycles of transcription were coordinated with localized translation. This cyclical regulation of an IEG, dependent on protein synthesis, reactivates subsequent transcription for maintaining mRNA supply to dendrites. The ensuing Arc mRNAs were preferentially localized at sites marked by previous Arc protein, thereby consolidating local “hubs” of dendritic Arc. These findings revealed the spatio-temporal dynamics of transcription-translation coupling of an IEG and provide a mechanism by which short-lived synaptic proteins can be sustained over the long-time scales of memory consolidation.
Fragmented Spatial Maps from Surprisal: State Abstraction and Efficient Planning
Authors: Klukas Mirko , Sharma Sugandha , Du YiLun , Lozano-Perez Tomas , Kaelbling Leslie , Fiete Ila
Published: November 2021

When animals explore spatial environments, their representations often fragment into multiple maps. What determines these map fragmentations, and can we predict where they will occur with simple principles? We pose the problem of fragmentation of an environment as one of (online) spatial clustering. Taking inspiration from the notion of acontiguous regionin robotics, we develop a theory in which fragmentation decisions are driven by surprisal. When this criterion is implemented with boundary, grid, and place cells in various environments, it produces map fragmentations from the first exploration of each space. Augmented with a long-term spatial memory and a rule similar to the distance-dependent Chinese Restaurant Process for selecting among relevant memories, the theory predicts the reuse of map fragments in environments with repeating substructures. Our model provides a simple rule for generating spatial state abstractions and predicts map fragmentations observed in electrophysiological recordings. It further predicts that there should be “fragmentation decision” or “fracture” cells, which in multicompartment environments could be called “doorway” cells. Finally, we show that the resulting abstractions can lead to large (orders of magnitude) improvements in the ability to plan and navigate through complex environments.
Development of a QSAR model to predict molecular inhibition of human STAT3
Authors: Patterson Joshua M. , Milligan Kimberly , Winstead Cherese
Published: November 2021

Herein is described a method to develop a QSAR model to predict the molecular inhibition of human STAT3. The model was built using machine learning using Python 3.3. A random forest machine learning algorithm was deployed. The model produced a R2 value of 0.86, indicating that our QSAR model is effective at predicting inhibitory compounds of STAT3.
Sex and Estrous Cycle in Memory for Sequences of Events in Rats
Authors: Jayachandran M. , Langius P. , Pazos Rego F. , Vertes R. P. , Allen T. A.
Published: November 2021

The ability to remember sequences of events is fundamental to episodic memory. While rodent studies have examined sex and estrous cycle in episodic-like spatial memory tasks, little is known about these biological variables in memory for sequences of events that depend on representations of temporal context. We investigated the role of sex and estrous cycle in rats during all training and testing stages of a cross-species validated sequence memory task (Jayachandran et al., 2019). Rats were trained on a task composed of two sequences, each with four unique odors delivered on opposite ends of a linear track. Training occurred in six successive stages starting with learning to poke in a nose port for ≥1.2s; eventually demonstrating sequence memory by holding their nose in the port for ≥1s for in-sequence odors and <1s for out-of-sequence odors in order to receive a water reward. Performance was analyzed across sex and estrous cycle (proestrus, estrus, metestrus, and diestrus), the latter being determined by the cellular composition of a daily vaginal lavage. We found no evidence of sex differences in asymptotic sequence memory performance, similar to published data in humans performing the analogous task (Reeders et al., 2021). Likewise, we found no differences in performance across the estrous cycle. One minor difference was that female rats tended to have slightly longer poke times, while males had slightly more short poke times but this did not affect their decisions. These results suggest sex and estrous cycle are not major factors in sequence memory capacities.
Serial invasions can disrupt the time course of ecosystem recovery
Authors: Karatayev Vadim A. , Rudstam Lars G. , Karatayev Alexander Y. , Burlakova Lyubov E. , Adamovich Boris V. , Zhukava Hanna A. , Holeck Kristen T. , Hetherington Amy Lee , Jackson James R. , Hotaling Christopher W. , Zhukova Tatyana V. , Mikheyeva Tamara M. , Kovalevskaya Raisa Z. , Makarevich Oleg A. , Kruk Darya V.
Published: November 2021

The impacts of species invasions can subside or amplify over time as ecosystems “adapt” or additional invaders arrive. These long-term changes provide important insights into ecosystem dynamics. Yet studies of long-term dynamics are rare and often confound species impacts with coincident environmental change. We synthesize many-decade time-series across ecosystems to resolve shared changes in seven key features following invasion by quagga and zebra mussels, two widespread congeners that re-engineer and increasingly co-invade freshwaters. Six polymictic shallow lakes with long-term data sets reveal remarkably similar trends, with the strongest ecosystem impacts occurring within 5-10 years of zebra mussel invasion. Surprisingly, plankton communities then exhibited a partial, significant recovery. This recovery was absent, and impacts of initial invasion amplified, in lakes where quagga mussels outcompeted zebra mussels and more completely depleted phytoplankton. Thus, invasion impacts subside over time but can amplify with serial introductions of competing, even closely similar, taxa.
Asparagine metabolism in tumors is linked to poor survival in females with colorectal cancer: A cohort study
Authors: Shen Xinyi , Cai Yuping , Lu Lingeng , Huang Huang , Yan Hong , Paty Philip B. , Muca Engjel , Ahuja Nita , Zhang Yawei , Johnson Caroline H. , Khan Sajid A.
Published: November 2021

Background or Purpose

The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study aims to examine the link between tumor metabolome and prognosis by sex for CRC patients.

Methods

Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N=95 females, N=102 males) after surgical colectomy for stage I-III CRC. Cox Proportional Hazards (PH) regression models were applied to estimate the associations between tumor metabolome and 5-year overall survival (OS) and 5-year recurrence-free survival (RFS), and their interactions with sex.

Results

Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS (Pinteraction < .05). The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, sex-specific differences were found in the associations between prognosis and metabolic pathways. Notably, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (hazard ratio [HR] = 6.39, 95% confidence interval [CI] = 1.78-22.91, P = .004) and RFS (HR = 4.36, 95% CI = 1.39-13.68, P = .01) for female patients only (Pinteraction, OS = .02, Pinteraction, RFS = .003). Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis.

Discussion or Conclusions

Unique metabolite profiles indicated increased asparagine synthesis was associated with poorer prognosis for females only, providing insights into precision medicine for CRC treatment stratified by sex.
MFN2Influences Amyotrophic Lateral Sclerosis Pathology
Authors: Russell Kristi L. , Downie Jonathan M. , Gibson Summer B. , Figueroa Karla P. , Steely Cody J. , Bromberg Mark B. , Murtaugh L. Charles , Jorde Lynn B. , Pulst Stefan M.
Published: November 2021

Objective

To better understand the pathology of amyotrophic lateral sclerosis, we used sequence data from patients seen at the University of Utah to identify novel disease-associated loci. We utilized bothin vitroandin vivostudies to determine the biological effect of patient mutations inMFN2.

Method

Sequence data for a total of 140 patients were run through VAAST and Phevor to determine genes that were more burdened with rare, nonsynonymous variants compared to control longevity cohort. Variants identified in MFN2 were expressed inMfn2knockout cells to determine if mutant MFN2 could rescue mitochondrial morphology defects. We identified additional rare, nonsynonymous variants in MFN2 in ALSdb that were expressed in knockout mouse embryonic fibroblasts (MEFs). Membrane potential was measured to quantify mitochondrial health upon mutant MFN2 expression.mfn2knockout zebrafish were used to examine movement compared to wildtype and protein aggregation in brain.

Results

MFN2mutations identified in ALS patients from our University of Utah cohort and ALSdb were defective in rescuing morphological defects inMfn2knockout MEFs. Selected mutants showed decreased membrane potential compared to wildtype MFN2 expression. Zebrafish heterozygous and homozygous for loss ofmfn2showed increased TDP-43 levels in their hindbrain and cerebellum.

Conclusion

In total, 21 rare, deleterious mutations inMFN2were tested inMfn2knockout MEFs. Mutant MFN2 expression was not able to rescue the knockout phenotype, though at differing degrees of severity. Decreased membrane potential also argues for inhibited mitochondrial function. Increased TDP-43 levels in mutant zebrafish illustrates MFN2’s function in ALS pathology. MFN2 variants influence ALS pathology and highlight the importance of mitochondria in neurodegeneration.