bluuebunny/crossref_metadata_2025 huggingface dataset:
Can’t decide how much to EAT? Effort variability for reward is associated with cognitive restraint
Authors: van den Hoek Ostende Mechteld M. , Neuser Monja P. , Teckentrup Vanessa , Svaldi Jennifer , Kroemer Nils B.
Published: May 2020

Food intake is inherently variable and often characterized by episodical restraint or overeating (uncontrolled eating). Such heightened variability in intake has been associated with higher variability in the brain response to food reward, but it is an open issue whether comparable associations with elevated variability in reward seeking exist. Here, we assessed whether restraint and uncontrolled eating as markers of trait-like variability in eating are associated with higher intra-individual variability in reward seeking as captured by a cost-benefit paradigm. To test this hypothesis, 81 healthy, overnight-fasting participants (MBMI= 23.0 kg/m2± 2.95) completed an effort allocation task (EAT) twice. In the EAT, participants had to exert physical effort to earn monetary and food rewards and indicated levels of wanting through visual analog scales (VAS). As predicted, we found that greater trial-by-trial effort variability was associated with lower scores on cognitive restraint,rp(78) = −.28,p= .011 (controlled for average effort). In line with previous findings, higher wanting variability was associated with higher BMI,rp(78) = .25,p= .026 (controlled for average effort). Collectively, our results support the idea that higher variability in reward seeking is a potential risk factor for eating beyond homeostatic need. Since associations with variability measures of reward exceeded associations with average reward seeking, our findings may indicate that variability in the representation of the reward value could be a crucial aspect driving fluctuations in food intake.
Reactivation of single-episode pain patterns in the hippocampus and decision making
Authors: Wimmer G. Elliott , Büchel Christian
Published: May 2020

Aversive and rewarding experiences can exert a strong influence on subsequent behavior. While decisions are often supported by the value of single past episodes, most research has focused on the role of well-learned value associations. Recent studies have begun to investigate the influence of reward-associated episodes, but it is unclear if these results generalize to negative experiences such as pain. To investigate whether and how the value of previous aversive experiences modulates behavior and brain activity, in our experiments female and male human participants experienced episodes of high or low pain in conjunction with incidental, trial-unique neutral pictures. In an incentive-compatible surprise test phase, we found that participants avoided pain-paired objects. In a separate fMRI experiment, at test, participants exhibited significant pain value memory. Neurally, when participants were re-exposed to pain-paired objects, we found no evidence for reactivation of pain-related patterns in pain-responsive regions such as the anterior insula. Critically, however, we found significant reactivation of pain-related patterns of activity in the hippocampus, such that activity significantly discriminated high versus low pain episodes. Further, stronger reactivation in the anterior hippocampus was related to improved pain value memory performance. Our results demonstrate that single incidental aversive experiences can build memories that affect decision making and that this influence may be supported by the hippocampus.

Significance Statement

Aversive and rewarding experiences can exert a strong influence on our subsequent behavior. While decisions are often supported by single past negative or positive episodes, most research has focused on the role of well-learned value associations. In experiments using aversive heat pain in conjunction with incidental objects, we found that participant’s choices were biased by the level of pain associated with the objects. Further, when participants saw the objects again, pain-related neural patterns in the hippocampus were re-expressed and this was related to pain value memory performance. These results suggest a mechanism by which even single negative experiences can guide our later decisions.
Shape-centered representations of bounded regions of space mediate the transformation of retinotopic representations into conscious perception of objects
Authors: Vannuscorps G. , Galaburda A. , Caramazza A.
Published: May 2020

The primary visual cortex represents the retinotopic orientation of visual primitives (edges, blobs, bars), but our conscious perception is of orientated objects (e.g., dogs, forks) in the environment. How this transformation operates remains unknown. We report here the study of a young woman presenting with an extraordinarily clear and informative visual disorder that affects highly specific aspects of object perception allowing precise inferences about the type and properties of visual representations that mediate this transformation. Davida perceives sharp-edged 2D bounded regions of space of medium to high contrast as if they were plane-rotated by 90, 180 or 270 degrees around their center, mirrored across their own axes, or both. In contrast, her perception of strongly blurred or very low contrast shapes, and of compound shapes emerging from a collection of bounded elements, is intact. The nature of her errors implies that visual perception is mediated by a representation of each bounded region of space in a shape-centered coordinate system aligned on either the shape’s most elongated part or on the shape’s axis of symmetry and centered either at the midpoint of the shape’s most elongated part or at the shape’s centroid. The selectivity of her disorder to sharp-edged medium to high-contrast stimuli additionally suggests that duplicate shape-centered representations are computed in parallel from information derived from the parvocellular and magnocellular subcortical channels and integrated precisely at the level at which shape representations must be mapped onto a behaviorally relevant frame of reference.
Interleukin-10 and Small Molecule SHIP1 Allosteric Regulators Trigger Anti-Inflammatory Effects Through SHIP1/STAT3 Complexes
Authors: Chamberlain Thomas C. , Cheung Sylvia T. , Yoon Jeff S.J. , Ming-Lum Andrew , Gardill Bernd R. , Shakibakho Soroush , Dzananovic Edis , Ban Fuqiang , Samiea Abrar , Jawanda Kamaldeep , Priatel John , Krystal Gerald , Ong Christopher J. , Cherkasov Artem , Andersen Raymond J. , McKenna Sean A. , Van Petegem Filip , Mui Alice L-F
Published: May 2020

The anti-inflammatory actions of interleukin-10 (IL10) are thought to be mediated primarily by the STAT3 transcription factor, but pro-inflammatory cytokines such as interleukin-6 (IL6) also act through STAT3. We now report that IL10, but not IL6 signaling, induces formation of a complex between STAT3 and the inositol polyphosphate-5-phosphatase SHIP1 in macrophages. Both SHIP1 and STAT3 translocate to the nucleus in macrophages. Remarkably, sesquiterpenes of the Pelorol family we previously described as allosteric activators of SHIP1 phosphatase activity, could induce SHIP1/STAT3 complex formation in cells, and mimic the anti-inflammatory action of IL10 in a mouse model of colitis. Using crystallography and docking studies we identified a drug-binding pocket in SHIP1. Our studies reveal new mechanisms of action for both STAT3 and SHIP1, and provide a rationale for use of allosteric SHIP1-activating compounds which mimic the beneficial anti-inflammatory actions of IL10.
Two new immature and dysfunctional neutrophil cell subsets define a predictive signature of sepsis useable in clinical practice
Authors: Meghraoui-Kheddar Aïda , Chousterman Benjamin G. , Guillou Noëlline , Barone Sierra M. , Granjeaud Samuel , Vallet Helene , Corneau Aurélien , Guessous Karim , Boissonnas Alexandre , Irish Jonathan M. , Combadière Christophe
Published: May 2020

Sepsis is the leading cause of death in adult intensive care units. At present, sepsis diagnosis relies on non-specific clinical features. It could transform clinical care to have objective immune cell biomarkers that could predict sepsis diagnosis and guide treatment. For decades, neutrophil phenotypes have been studied in sepsis, but a diagnostic cell subset has yet to be identified. Here, high dimensional mass cytometry was used to reveal for the first time a specific neutrophil signature of sepsis severity that does not overlap with other inflammatory biomarkers, and that distinguishes patients with sepsis from those with non-infectious inflammatory syndrome. Unsupervised analysis of 42-dimesional mass cytometry data characterized previously unappreciated heterogeneity within the CD64+immature neutrophils and revealed two new subsets distinguished by CD123 and PD-L1 expression. These immature neutrophils exhibited diminished activation and phagocytosis functions. The proportion of CD123-expressing neutrophils also correlated with clinical severity. Critically, this study showed that these two new neutrophil subsets were specific to sepsis and detectable by routine flow cytometry using seven markers. The demonstration here that a simple blood test distinguishes sepsis from other inflammatory conditions represents a key biological milestone that can be immediately translated into improvements in patient care.

One Sentence Summary

CD123+and/or PD-L1+immature and dysfunctional neutrophil subsets identified by mass cytometry, define an early human blood signature of sepsis
The mevalonate pathway contributes to monoterpene production in peppermint
Authors: Koley Somnath , Grafahrend-Belau Eva , Raorane Manish L. , Junker Björn H.
Published: May 2020

Peppermint produces monoterpenes which are of great commercial value in different traditional and modern pharmaceutical and cosmetic industries. In the classical view, monoterpenes are synthesized via the plastidic 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway, while the cytosolic mevalonate (MVA) pathway produces sesquiterpenes. Interactions between both pathways have been documented in several other plant species, however, a quantitative understanding of the metabolic network involved in monoterpene biosynthesis is still lacking. Isotopic tracer analysis, steady state13C metabolic flux analysis (MFA) and pathway inhibition studies were applied in this study to quantify metabolic fluxes of primary and isoprenoid metabolism of peppermint glandular trichomes (GT). Our results offer new insights into peppermint GT metabolism by confirming and quantifying the crosstalk between the two isoprenoid pathways towards monoterpene biosynthesis. In addition, a quantitative description of precursor pathways involved in isoprenoid metabolism is given. While glycolysis was shown to provide precursors for the MVA pathway, the oxidative bypass of glycolysis fueled the MEP pathway, indicating prominent roles for the oxidative branch of the pentose phosphate pathway and RuBisCO. This study reveals the potential of13C-MFA to ascertain previously unquantified metabolic routes of the trichomes and thus advancing insights on metabolic engineering of this organ.
Brachyury controlsCionanotochord fate as part of a feedforward network and not as a unitary master regulator
Authors: Reeves Wendy M. , Shimai Kotaro , Winkley Konner M. , Veeman Michael T.
Published: May 2020

The notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordateCiona. Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes are unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators and find that combinatorial cocktails are more effective at reprograming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a and other components of the notochord gene regulatory network and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically-defined master regulator.
Pupil-linked arousal biases evidence accumulation towards desirable percepts during perceptual decision-making
Authors: Leong Yuan Chang , Dziembaj Roma , D’Esposito Mark
Published: May 2020

People are biased towards seeing outcomes they are motivated to see. The arousal system coordinates the body’s response to motivationally significant events, and is well positioned to regulate motivational effects on sensory perception. However, it remains unclear whether arousal would enhance or reduce motivational biases. Here we measured pupil dilation as a measure of arousal while participants performed a visual categorization task. We used monetary bonuses to motivate participants to see one category over another. Even though the reward-maximizing strategy was to perform the task accurately, participants were more likely to report seeing the motivationally desirable category. Furthermore, higher arousal levels were associated with making motivationally biased responses. Analyses using computational models suggest that arousal enhanced motivational effects by biasing evidence accumulation in favor of motivationally desirable percepts. These results suggest heightened arousal biases people towards what they want to see and away from an objective representation of the environment.

Statement of Relevance

When confronted with an event of motivational significance (e.g., an opportunity to earn a huge reward), people often experience a strong arousal response that includes increased sweating, faster heart-rate and larger pupils. Does this arousal response help individuals make more accurate decisions, or does it instead bias and impair decision-making? This work examines the effects of arousal on how people decide what they see when they are motivated to see a particular outcome. We found that heightened arousal, as measured by larger pupils, was associated with a bias in how participants accumulated sensory evidence to make their decisions. As a result, participants became more likely to report seeing an ambiguous visual image as the interpretation they were motivated to see. Our results suggest that arousal biases perceptual judgments towards desirable percepts, and that modulating arousal levels could be a promising approach in reducing motivational biases in decision-making.
NIMBus: a Negative Binomial Regression based Integrative Method for Mutation Burden Analysis
Authors: Zhang Jing , Liu Jason , McGillivray Patrick , Yi Caroline , Lochovsky Lucas , Lee Donghoon , Gerstein Mark
Published: May 2020

Background

Identifying frequently mutated regions is a key approach to discover DNA elements influencing cancer progression. However, it is challenging to identify these burdened regions due to mutation rate heterogeneity across the genome and across different individuals. Moreover, it is known that this heterogeneity partially stems from genomic confounding factors, such as replication timing and chromatin organization. The increasing availability of cancer whole genome sequences and functional genomics data from the Encyclopedia of DNA Elements (ENCODE) may help address these issues.

Results

We developed a Negative binomial regression-based Integrative Method for mutation Burden analysiS (NIMBus). Our approach addresses the over-dispersion of mutation count statistics by (1) using a Gamma-Poisson mixture model to capture the mutation-rate heterogeneity across different individuals and (2) estimating regional background mutation rates by regressing the varying local mutation counts against genomic features extracted from ENCODE.

We applied NIMBus to whole-genome cancer sequences from the PanCancer Analysis of Whole Genomes project (PCAWG) and other cohorts. It successfully identified well-known coding and noncoding drivers, such as TP53 and the TERT promoter. To further characterize the burdening of non-coding regions, we used NIMBus to screen transcription factor binding sites in promoter regions that intersect DNase I hypersensitive sites (DHSs). This analysis identified mutational hotspots that potentially disrupt gene regulatory networks in cancer. We also compare this method to other mutation burden analysis methods.

Conclusion

NIMBus is a powerful tool to identify mutational hotspots. The NIMBus software and results are available as an online resource at github.gersteinlab.org/nimbus.
Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1
Authors: Dave Zankruti , Blanářová Olga Vondálová , Čada Štěpán , Janovská Pavlína , Zezula Nikodém , Běhal Martin , Hanáková Kateřina , Ganji Sri Ranjani , Krejci Pavel , Gömöryová Kristína , Peschelová Helena , Šmída Michael , Zdráhal Zbyněk , Pavlová Šárka , Kotašková Jana , Pospíšilová Šárka , Bryja Vítězslav
Published: May 2020

Chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) are malignancies characterized by the dependence on B-cell receptor (BCR) signaling and by the high expression of the cell surface receptor ROR1. Both, BCR and ROR1 are therapeutic targets in these diseases and the understanding of their mutual cross talk is thus of direct therapeutic relevance. In this study we analyzed the role of Lyn, a kinase from the Src family, as a mediator of the BCR-ROR1 crosstalk. We confirm the functional interaction between Lyn and ROR1 and demonstrate that Lyn kinase efficiently phosphorylates ROR1 in its kinase domain and aids the recruitment of an E3 ligase c-CBL. The absence of Lyn in Lyn KO Maver-1 cells produced by CRISPR-Cas9 resulted in the increased ROR1 cell surface levels and deregulated migratory properties. Similar correlations between ROR1 surface dynamics, levels of active Lyn and chemotactic properties were confirmed in primary CLL samples. Our data establish Lyn-mediated phosphorylation of ROR1 as a point of crosstalk between BCR and ROR1 signaling pathways.
Cellular plasticity balances the metabolic and proliferation dynamics of a regenerating liver
Authors: Chembazhi Ullas V. , Bangru Sushant , Hernaez Mikel , Kalsotra Auinash
Published: May 2020

The adult liver has exceptional ability to regenerate, but how it sustains normal metabolic activities during regeneration remains unclear. Here, we use partial hepatectomy (PHx) in tandem with single-cell transcriptomics to track cellular transitions and heterogeneities of ~22,000 liver cells through the initiation, progression, and termination phases of mouse liver regeneration. Our results reveal that following PHx, a subset of hepatocytes transiently reactivates an early-postnatal-like gene expression program to proliferate, while a distinct population of metabolically hyperactive cells appears to compensate for any temporary deficits in liver function. Importantly, through combined analysis of gene regulatory networks and cell-cell interaction maps, we find that regenerating hepatocytes redeploy key developmental gene regulons, which are guided by extensive ligand–receptor mediated signaling events between hepatocytes and non-parenchymal cells. Altogether, our study offers a detailed blueprint of the intercellular crosstalk and cellular reprogramming that balances the metabolic and proliferation requirements of a regenerating liver.
What is an adaptive pattern of brain network coupling for a child? It depends on their environment
Authors: Ellwood-Lowe Monica E. , Whitfield-Gabrieli Susan , Bunge Silvia A.
Published: May 2020

Prior research indicates that lower resting-state functional coupling between two brain networks, lateral frontoparietal network (LFPN) and default mode network (DMN), relates to better cognitive test performance. However, most study samples skew towards wealthier individuals—and what is adaptive for one population may not be for another. In a pre-registered study, we analyzed resting-state fMRI from 6839 children ages 9-10 years. For children above poverty, we replicated the prior finding: better cognitive performance correlated with weaker LFPN-DMN coupling. For children in poverty, the slope of the relation was instead positive. This significant interaction related to several features of a child’s environment. Future research should investigate the possibility that leveraging internally guided cognition is a mechanism of resilience for children in poverty. In sum, “optimal” brain function depends in part on the external pressures children face, highlighting the need for more diverse samples in research on the human brain and behavior.
Distinct signalling routes mediates intercellular and intracellular rhizobial infection in Lotus japonicus
Authors: Montiel Jesús , Reid Dugald , Grønbæk Thomas H. , Benfeldt Caroline M. , James Euan K. , Ott Thomas , Ditengou Franck A. , Nadzieja Marcin , Kelly Simon , Stougaard Jens
Published: May 2020

Rhizobial infection of legume roots during development of nitrogen fixing root nodules occurs either intracellularly though plant derived infection threads traversing the epidermal and cortical cell layers to deliver the bacteria or intercellularly via bacterial entry between epidermal plant cells. Although, around 25% of all legume genera are postulated to be intercellularly infected, the pathways and mechanisms supporting this process has remained virtually unexplored due to lack of genetically amenable legumes that have this infection mode. In this study, we report that the model legume Lotus japonicus is infected intercellularly by Rhizobium sp. IRBG74 and demonstrate that the resources available in Lotus enable insight into the genetic requirements and the fine-tuning of the pathway governing intercellular infection. Inoculation of Lotus mutants shows that Ern1 and RinRK1 are dispensable for intercellular infection in contrast to intracellular infection. Other symbiotic genes, including Nfr5, SymRK, CCaMK, Epr3, Cyclops, Nin, Nsp1, Nsp2, Cbs and Vpy1 are equally important for both entry modes. Comparative RNAseq analysis of roots inoculated with IRBG74 revealed a distinctive transcriptome response compared to intracellular colonization. In particular, a number of cytokinin-related genes were differentially regulated. Corroborating this observation cyp735A and ipt4 cytokinin biosynthesis mutants were significantly affected in their nodulation with IRBG74 while lhk1 cytokinin receptor mutants did not form any nodules. These results indicate that a differential requirement for cytokinin signalling conditions intercellular rhizobial entry and highlight the distinct modalities of the inter- and intra-cellular infection mechanisms.
Elephant Genomes Elucidate Disease Defenses and Other Traits
Authors: Tollis Marc , Ferris Elliott , Campbell Michael S. , Harris Valerie K. , Rupp Shawn M. , Harrison Tara M. , Kiso Wendy K. , Schmitt Dennis L. , Garner Michael M. , Aktipis C. Athena , Maley Carlo C. , Boddy Amy M. , Yandell Mark , Gregg Christopher , Schiffman Joshua D. , Abegglen Lisa M.
Published: May 2020

Disease susceptibility and resistance comprise important factors in conservation, particularly in elephants. To determine genetic mechanisms underlying disease resistance and other unique elephant traits, we estimated 862 and 1,017 potential regulatory elements in Asian and African elephants, respectively. These elements are significantly enriched in both species with differentially expressed genes involved in immunity pathways, including tumor-necrosis factor which plays a role in the response to elephant endotheliotropic herpesvirus (EEHV). Population genomics analyses indicate that amplifiedTP53retrogenes are maintained by purifying selection and may contribute to cancer resistance in elephants, including less malignancies in African vs. Asian elephants. Positive selection scans across elephant genomes revealed genes that may control iconic elephant traits such as tusk development, memory, and somatic maintenance. Our study supports the hypothesis that interspecies variation in gene regulation contributes to differential inflammatory responses leading to increased infectious disease and cancer susceptibility in Asian versus African elephants. Genomics can inform functional immunological studies which may improve both conservation for elephants and human therapies.
Adaptive Efficient Coding: A Variational Auto-encoder Approach
Authors: Aridor Guy , Grechi Francesco , Woodford Michael
Published: May 2020

We study a model of neural coding with the structure of a variational auto-encoder. The model posits that the encoding of individual stimulus values is optimally adjusted for a finite training sample of stimuli retained in memory. We demonstrate that this model can rationalize existing experimental evidence on both perceptual discrimination thresholds and neural tuning curve widths in multiple sensory domains. Finally, since our model implies that encoding is optimized for a sample from the environment, it also provides predictions about the adaptation of neural coding as the environmental frequency distribution changes.
25 Years of Pathway Figures
Authors: Hanspers Kristina , Riutta Anders , Kutmon Martina , Pico Alexander R
Published: May 2020

Background: Pathway diagrams are fundamental tools for describing biological processes in all aspects of science, including training, generating hypotheses, describing new knowledge and ultimately as communication tools in published work. Thousands of pathway diagrams are published each year as figures in papers. But as static images the pathway knowledge represented in figures is not accessible to researchers for computational queries and analyses. In this study, we aimed to identify pathway figures published in the past 25 years, to characterize the human gene content in figures by optical character recognition, and to describe their utility as a resource for pathway knowledge. Approach: To identify pathway figures representing 25 years of published research, we trained a machine learning service on manually-classified figures and applied it to 235,081 image query results from PubMed Central. Our previously described pipeline was utilized to extract human genes from the pathway figure images. These figures were characterized in terms of their parent papers, human gene content and enriched disease terms. Diverse use cases were explored for this newly accessible pathway resource. Results: We identified 64,643 pathway figures published between 1995 and 2019, depicting 1,112,551 instances of human genes (13,464 unique NCBI Genes) in various interactions and contexts. This represents more genes than found in the text of the same papers, as well as genes not found in any pathway database. We developed an interactive web tool to explore the results from the 65k set of figures, and used this tool to explore the history of scientific discovery of the Hippo Signaling pathway. We also defined a filtered set of 32k pathway figures useful for enrichment analysis.
RNA secondary structure packages evaluated and improved by high-throughput experiments
Authors: Wayment-Steele Hannah K. , Kladwang Wipapat , Strom Alexandra I. , Lee Jeehyung , Treuille Adrien ,   Eterna Participants, Das Rhiju
Published: May 2020

The computer-aided study and design of RNA molecules is increasingly prevalent across a range of disciplines, yet little is known about the accuracy of commonly used structure modeling packages in tasks sensitive to ensemble properties of RNA. Here, we demonstrate that the EternaBench dataset, a set of over 20,000 synthetic RNA constructs designed in iterative cycles on the RNA design platform Eterna, provides incisive discriminative power in evaluating current packages in ensemble-oriented structure prediction tasks. We find that CONTRAfold and RNAsoft, packages with parameters derived through statistical learning, achieve consistently higher accuracy than more widely used packages in their standard settings, which derive parameters primarily from thermodynamic experiments. Motivated by these results, we develop a multitask-learning-based model, EternaFold, which demonstrates improved performance that generalizes to diverse external datasets, including complete mRNAs and viral genomes probed in human cells and synthetic designs modeling mRNA vaccines.
Retina-specific targeting of pericytes reveals structural diversity and enables control of capillary blood flow
Authors: Ivanova Elena , Corona Carlo , Eleftheriou Cyril G. , Bianchimano Paola , Sagdullaev Botir T.
Published: May 2020

Pericytes are a unique class of mural cells essential for angiogenesis, maintenance of the vasculature and are key players in microvascular pathology. However, their diversity and specific roles are poorly understood, limiting our insight into vascular physiology and the ability to develop effective therapies. Here, in the mouse retina, a tractable model of the CNS, we evaluated distinct classes of mural cells along the vascular tree for both structural characterization and physiological manipulation of blood flow. To accomplish this, we first tested three inducible mural cell-specific mouse lines using a sensitive Ai14 reporter and tamoxifen application either by a systemic injection, or by local administration in the form of eye drops. Across three lines, under either the PDGFRb or NG2 promoter, the specificity and pattern of Cre activation varied significantly. In particular, a mouse line with Cre under the NG2 promoter resulted in sparse TdTomato labeling of mural cells, allowing for an unambiguous characterization of anatomical features of individual sphincter cells and capillary pericytes. Furthermore, in one PDGFRb line, we found that focal eye drop application of tamoxifen led to an exclusive Cre-activation in pericytes, without affecting arterial mural cells. We then used this approach to boost capillary blood flow by selective expression of Halorhodopsin, a highly precise hyperpolarizing optogenetic actuator. The ability to exclusively target capillary pericytes may prove a precise and potentially powerful tool to treat microcirculation deficit, a common pathology in numerous diseases.
Predicting subsurface sonar observations with satellite-derived ocean surface data in the California Current Ecosystem
Authors: Gadeken Kellie R. , Joseph Maxwell B. , McGlinchy Joseph , Karnauskas Kristopher B. , Wall Carrie C.
Published: May 2020

Vessel-based sonar systems that focus on the water column provide valuable information on the distribution of underwater marine organisms, but such data are expensive to collect and limited in their spatiotemporal coverage. Satellite data, however, are widely available across large regions and provide information on surface ocean conditions. If satellite data can be linked to subsurface sonar measurements, it may be possible to predict marine life over broader spatial regions with higher frequency using satellite observations. Here, we use random forest models to evaluate the potential for predicting a sonar-derived proxy for subsurface biomass as a function of satellite imagery in the California Current Ecosystem. We find that satellite data may be useful for prediction under some circumstances, but across a range of sonar frequencies and depths, overall predictive performance was low. Performance in spatial interpolation tasks exceeded performance in spatial and temporal extrapolation, suggesting that this approach is not yet reliable for forecasting or spatial extrapolation. We conclude with some potential limitations and extensions of this work.
Preferential Pharmacological Inhibition of Nav1.6, but not Nav1.1, Abolishes Epileptiform Activity Induced by 4-AP in Mouse Cortical Slices
Authors: Patel Reesha R. , Ping Xingjie , Patel Shaun R. , McDermott Jeff S. , Krajewski Jeffrey L. , Chi Xian Xuan , Nisenbaum Eric S. , Jin Xiaoming , Cummins Theodore R.
Published: May 2020

Brain isoforms of voltage-gated sodium channels (VGSCs) have distinct cellular and subcellular expression patterns as well as functional roles that are critical for normal physiology as aberrations in their expression or activity lead to pathophysiological conditions. In this study, we asked how inhibition of select isoforms of VGSCs alters epileptiform activity to further parse out the roles of VGSCs in the brain. We first determined the relative selectivity of recently discovered small molecule, aryl sulfonamide, inhibitors (ICA-121431 and Compound 801) against Nav1.1, Nav1.2, and Nav1.6 activity using whole-cell patch clamp recordings obtained from HEK293 cells. To test the effects of these inhibitors on epileptiform activity, we obtained multielectrode array (MEA) recordings from mouse cortical slices in the presence of 4-aminopyridine (4-AP) to induce epileptiform activity. We found that the ICA-121431 and Compound 801 compounds are relatively selective for Nav1.1 and Nav1.6, respectively. From the MEA recordings, we found that inhibition of Nav1.6 and Nav1.2 with 500nM of the Compound 801 compound completely abolishes ictal local field potentials induced by 4-AP, whereas inhibition of Nav1.1 with 500nM of the ICA-121431 compound had minimal effect on epileptiform activity induced by 4-AP. Due to the prominent expression of Nav1.1 in inhibitory neurons, we asked whether inhibition of Nav1.1 alone alters activity. We found that, indeed, inhibition of Nav1.1 with the ICA-121431 compound increased basal activity in the absence of 4-AP. These findings expand our current understanding of the roles of VGSC isoforms in the brain and suggest that selective targeting of Nav1.6 may be a more efficacious treatment strategy for epileptic syndromes.
Adaptive optics two-photon endomicroscopy enables deep brain imaging at synaptic resolution over large volumes
Authors: Qin Zhongya , Chen Congping , He Sicong , Wang Ye , Tam Kam Fai , Ip Nancy Y. , Qu Jianan Y.
Published: May 2020

Optical deep brain imaging in vivo at high resolution has remained a great challenge over the decades. Two-photon endomicroscopy provides a minimally invasive approach to image buried brain structures, once it is integrated with a gradient refractive index (GRIN) lens embedded in the brain. However, its imaging resolution and field of view are compromised by the intrinsic aberrations of the GRIN lens. Here, we develop a two-photon endomicroscopy by adding adaptive optics based on the direct wavefront sensing, which enables recovery of diffraction-limited resolution in deep brain imaging. A new precompensation strategy plays a critical role to correct aberrations over large volumes and achieve rapid random-access multiplane imaging. We investigate the neuronal plasticity in the hippocampus, a critical deep brain structure, and reveal the relationship between the somatic and dendritic activity of pyramidal neurons.
CellMeSH: Probabilistic Cell-Type Identification Using Indexed Literature
Authors: Mao Shunfu , Zhang Yue , Seelig Georg , Kannan Sreeram
Published: May 2020

Single-cell RNA sequencing (scRNA-seq) is widely used for analyzing gene expression in multi-cellular systems and provides unprecedented access to cellular heterogeneity. scRNA-seq experiments aim to identify and quantify all cell types present in a sample. Measured single-cell transcriptomes are grouped by similarity and the resulting clusters are mapped to cell types based on cluster-specific gene expression patterns. While the process of generating clusters has become largely automated, annotation remains a laborious ad-hoc effort that requires expert biological knowledge. Here, we introduce CellMeSH - a new automated approach to identifying cell types based on prior literature. CellMeSH combines a database of gene-cell type associations with a probabilistic method for database querying. The database is constructed by automatically linking gene and cell type information from millions of publications using existing indexed literature resources. Compared to manually constructed databases, CellMeSH is more comprehensive and scales automatically. The probabilistic query method enables reliable information retrieval even though the gene-cell type associations extracted from the literature are necessarily noisy. CellMeSH achieves up to 60% top-1 accuracy and 90% top-3 accuracy in annotating the cell types on a human dataset, and up to 58.8% top-1 accuracy and 88.2% top-3 accuracy on three mouse datasets, which is consistently better than existing approaches.

Availability

Web server:https://uncurl.cs.washington.edu/db_queryand API:https://github.com/shunfumao/cellmesh
Validation and Performance Comparison of Three SARS-CoV-2 Antibody Assays
Authors: Paiva Kimberly J , Grisson Ricky D , Chan Philip A , Lonks John R. , King Ewa , Huard Richard C , Pytel-Parenteau Diane L , Nam Ga Hie , Yakirevich Evgeny , Lu Shaolei
Published: May 2020

Serology testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is increasingly being used during the current pandemic of Coronavirus Disease 2019 (COVID-19). The clinical and epidemiologic utilities of antibody-based SARS-CoV-2 testing are under debate. Characterizing these assays helps to understand the disease and provides scientific basis for deciding how to best use these assays. The study assessed one chemiluminescent assay (Abbott COVID-2 IgG) and two lateral flow assays (STANDARD Q [SQ] IgM/IgG Duo and Wondfo Total Antibody Test). Validation included 113 blood samples from 71 PCR-confirmed COVID-19 patients and 1182 samples from negative controls with potential interferences/cross-reactions, including 1063 pre-pandemic samples. IgM antibodies against SARS-CoV-2 were detected as early as post-symptom onset days 3-4. IgG antibodies were first detected post-onset days 5-6 by SQ assays. The detection rates increased gradually, and SQ IgG, Abbott IgG and Wondfo Total detected antibodies from all the PCR-confirmed patients 14 days after symptom onset. Overall agreements between SQ IgM/IgG and Wondfo Total was 88.5% and between SQ IgG and Abbott IgG was 94.6% (Kappa = 0.75, 0.89). No cross-reaction with other endemic coronavirus infections were identified. Viral hepatitis and autoimmune samples were the main cross-reactions observed. However, the interferences/cross-reactions were low. The specificities were 100% for SQ IgG and Wondfo Total and 99.62% for Abbott IgG and 98.87% for SQ IgM. These findings demonstrate high sensitivity and specificity of appropriately validated antibody-based SARS-CoV-2 assays with implications for clinical use and epidemiological seroprevalence studies.
Structural neuroplastic responses preserve functional connectivity and neurobehavioural outcomes in children born without corpus callosum
Authors: Siffredi Vanessa , Preti Maria G. , Kebets Valeria , Obertino Silvia , Leventer Richard J. , McIlroy Alissandra , Wood Amanda G. , Anderson Vicki , Spencer-Smith Megan M. , Van De Ville Dimitri
Published: May 2020

Background

The corpus callosum is the largest white matter pathway in the brain connecting the left and the right hemispheres. Developmental absence of the corpus callosum is a model disease for exploring disrupted connectivity and in turn understanding plasticity of the human brain, with atypically developing structure and function resulting in a highly heterogeneous clinical and cognitive profile. A proposed candidate for neuroplastic response in the context of this brain malformation is strengthening of intra-hemispheric pathways.

Methods

To test this hypothesis, we assessed structural and functional connectivity at the whole-brain and regional level in a uniquely large cohort of children with agenesis of the corpus callosum (AgCC, n = 20) compared with typically developing controls (TDC, n = 29), and then examined associations with neurobehavioural outcomes using a multivariate data-driven approach.

Results

For structural connectivity, children with AgCC showed a significant increase in intrahemispheric connectivity in addition to a significant decrease in inter-hemispheric connectivity compared with TDC. In contrast, for functional connectivity, children with AgCC and TDC showed a similar pattern of intra-hemispheric and inter-hemispheric connectivity. In AgCC, structural strengthening of the intra-hemispheric pathway was uniquely associated with verbal learning and memory, attention and executive measures.

Conclusions

We observed structural strengthening of intra-hemispheric pathways in children born without corpus callosum, which seems to allow for functional connectivity comparable to a typically developing brain, and were relevant to explain neurobehavioural outcomes in this population. This neuroplasticity might be relevant to other disorders of axonal guidance, and developmental disorders in which corpus callosum alteration is observed.
SARS-CoV-2 PCR and antibody testing for an entire rural community: methods and feasibility of high-throughput testing procedures
Authors: Appa Ayesha , Chamie Gabriel , Sawyer Aenor , Baltzell Kimberly , Dippell Kathryn , Ribeiro Salu , Duarte Elias , Vinden Joanna ,   Cliahub Consortium, Kramer-Feldman Jonathan , Rahdar Shahryar , MacIntosh Doug , Nicholson Katherine , Im Jonathan , Havlir Diane , Greenhouse Bryan
Published: May 2020

High-volume, community-wide ascertainment of SARS-CoV-2 prevalence by PCR and antibody testing was successfully performed using a community-led, drive-through model with strong operational support, well-trained testing units, and an effective technical platform
When to relax a lockdown? A modelling-based study of testing-led strategies coupled with sero-surveillance against SARS-CoV-2 infection in India
Authors: Mandal Sandip , Das Hemanshu , Deo Sarang , Arinaminpathy Nimalan
Published: May 2020

India's lockdown against SARS-CoV-2, if lifted without any other mitigations in place, could risk a second wave of infection. A test-and-isolate strategy, using PCR diagnostic tests, could help to minimise the impact of this second wave. Meanwhile, population-level serological surveillance can provide valuable insights into the level of immunity in the population. Using a mathematical model, consistent with an Indian megacity, we examined how seroprevalence data could guide a test-and-isolate strategy, for lifting a lockdown. For example, if seroprevalence is 20% of the population, we show that a testing strategy needs to identify symptomatic cases within 5 - 8 days of symptom onset, in order to prevent a resurgent wave from overwhelming hospital capacity in the city. This estimate is robust to uncertainty in the effectiveness of the lockdown, as well as in immune protection against reinfection. To set these results in their economic context, we estimate that the weekly cost of such a PCR-based testing programme would be less than 2.1% of the weekly economic loss due to the lockdown. Our results illustrate how PCR-based testing and serological surveillance can be combined to design evidence-based policies, for lifting lockdowns in Indian cities and elsewhere.
Use of community-based intervention to promote Family Planning use among Pastoralist women in Ethiopia: Cluster randomized controlled trial
Authors: Alemayehu Mussie , Medhanyie Araya Abrha , Reed Elizabeth , Bezabih Afework Mulugeta
Published: May 2020

Objective

We assessed the effect of a community-based intervention for promoting FP use and intention among pastoralist communities of Afar region state, Ethiopia.

Methods

The design was parallel, cluster randomized controlled trial (CRT) recruiting married women. It had three arms: 1) women’s FP education, 2) male involvement and 3) control with one to one ratio. A total of 33 kebeles were randomized and allocated. Data were collected through an open data kit. Women’s FP education and male involvement in FP service were the interventions. It was implemented with the assistance of a faema leader using a separate group meeting for males and women and disseminates video recorded messages on FP. The intervention was given for a total of 9 months. FP use and intentions were measured. Cluster level summaries considering a cluster effect analysis was performed. The result was presented with adjusted risks and 95% CI. A p-value < 0.05 was used to declare statistically significant.

Results

There was a positive change in the proportion of married women who use FP in the women’s FP education arm, absolute risk (AR) of 0.13(95% CI,0.08,0.17) and male involvement arm with AR of 0.29 (95% CI, 0.23,0.34) as compared to the control arm. In the control arm, the proportion of FP use was 4.3%, whereas it was 17.5% with women who receive FP education and 34% in the male involvement arm. Furthermore, the proportion of married women who had high intention to use FP was high in arms of women’s FP education and male involvement with AR = 3.4(95% CI: 2.48,4.91) and AR = 2.1 (95% CI: 1.5,2.95), respectively as compared with the control arm.

Conclusion

The community-based intervention (male involvement and women’s education about FP use) brings a significant change in increasing FP users and promotes the intention to use FP.
Alpha globin gene deletions in amelioration of clinical severity in beta haemoglobinopathy subjects with the β0/β+ genotype
Authors: Saha Dipankar , Chowdhury Prosanto Kumar , Panja Amrita , Pal Debashis , Chakraborty Sharmistha , Nayek Kaustav , Chakraborty Gispati , Sharma Prashant , Das Reena , Basu Surupa , Chatterjee Raghunath , Basu Anupam
Published: May 2020

Thalassemia is the commonest inherited hemoglobinopathy worldwide. Variation of clinical symptoms entail differences in disease-onset and transfusion requirements. Our objective was to investigate the role of alpha gene deletions in modulating the clinical heterogeneity of thalassemia syndromes. A total of 214 individuals with diagnosed beta-thalassemia major/intermedia were included in the study. Beta globin mutations were determined and categorized as β+ and β0. Eight common alpha globin gene deletions were detected by multiplex GAP-PCR. Out of the 17 individuals with β+/β+, 16 did not harbour alpha deletions (αα/αα), and most of them were non-severe. On the other hand, out of 46 individuals with β0/β0, 30 did not reveal alpha deletions, whereas 16 possessed one or more alpha deletion(s). Accordingly, most of them presented as clinically severe. Out of the 151 β0/β+ individuals, 119 were negative for alpha deletion, whereas 32 possessed alpha deletions. It was observed that, only in this last category, alpha deletions made a significant contribution (P< 0.0001) in modulation of clinical non severity in this genotype. In conclusion, alpha globin gene deletions play a role to help in ameliorating the phenotype in the β+/β0 genotype. However, they may have only minor/no role in patients with β+/β+ or β0/β0 genotype.