bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain imaging techniques and their application to bipolar disorder
Authors: Adler Caleb M.
Published: March 2022

Advances in medical imaging over the last half-century have impacted clinical care of neurological disorders and revolutionized our understanding of neuroanatomy and physiology. More, these advances have given investigators access to technologies allowing them to probe the brain much deeper and more fully than possible with the naked eye. The result has been an evolution in psychiatric research from an almost exclusive focus on behavioral change to more recent efforts to understand the neuropathology underlying psychiatric disorders. Arguably the research application of progressively available imaging techniques has had a particularly profound effect on studies of bipolar disorder, a condition with a level of symptomatic variability that has often complicated understanding. This increasing availability to investigators over recent decades of both structural and functional neuroimaging data has been instrumental in the development of newer, more evidence-based models of bipolar pathophysiology. In combination with advances in previously disparate fields such as genetics and epigenetics, as well as data analysis techniques such as machine learning, neuroimaging studies may revolutionize our understanding and treatment of bipolar disorder.
Structural brain abnormalities in bipolar disorder
Authors: Bellani Marcella , Zovetti Niccolò , Sanches Marsal , Matsuo Koji , Soares Jair C. , Brambilla Paolo
Published: March 2022

Bipolar disorder is a psychiatric condition associated with shifts in mood, energy, and activity levels severely altering the quality of life of affected individuals. Although widely accepted, the neurobiological bases of the disorder are still incompletely described. This chapter offers an in-depth description of the brain alterations characteristic of bipolar disorder from several perspectives; in the first part the chapter describes alterations of grey matter regions and volumetric differences of several neuronal networks and presents the alterations of key white matter bundles and demyelinization processes associated with bipolar disorder. In the second part the chapter describes current scientific findings about genetic vulnerabilities and presents specific brain differences associated with various clinical features (e.g., bipolar disorder subtype, length of illness, medication). To summarize, bipolar disorder is characterized by widespread reductions of grey matter volumes in the frontal gyrus, left anterior cingulate cortex, and right insula and alterations of white matter in the cingulate cortex, corpus callosum, and frontal regions.
Genetic techniques and applications to bipolar disorder
Authors: Zhang Yuhua , McInnis Melvin G. , Zöllner Sebastian
Published: March 2022

The methods and technologies behind the analyses of genetic data and information have advanced considerably since the identification and expansion of DNA sequence-based markers, genotypes, that map the human genome. The capacity for generating large numbers of genotypes have provided a base for developing innovative methods of analysis. The approach has shifted from family-based linkage analyses to population-based association analyses and emerging results have opened new directions for inquiry. In disorders with non-Mendelian inheritance, tens to hundreds of susceptibility loci have been identified, and methods adapted to assess a polygenic risk score are being tested. Methods for estimating epigenetic influences on gene expression are actively being developed and tested. The mitochondria are an exciting frontier in the search for causality. As current methods and technologies are considered, there is momentum and innovation driving the process. Emerging data and results demand new approaches, which create new data and results.
General genetics of bipolar disorder
Authors: Nurnberger John I.
Published: March 2022

It has been known for centuries that major mood disorders, including bipolar disorder, cluster in families. The heritability of bipolar disorder appears to be about 85%. Some of that heritability can now be assigned to specific common genetic variants identified in genome-wide association studies and specific rare variants identified in sequencing studies. Some key areas for ongoing investigation include calcium channel–related genes, variants related to synaptic transmission, and markers of neuronal growth and development. Genetic counseling is now based on empirical risk figures from family studies but may in the future be aided by genetic measures such as polygenic risk scores and/or screening for rare variants.
MiRNAs as predictors of bipolar disorder diagnosis and treatment response
Authors: Dwivedi Yogesh
Published: March 2022

Bipolar disorder is associated with substantial functional impairment, high health care costs, and premature mortality. The neurobiological mechanisms associated with bipolar disorder, however, are not well understood. In recent years, numerous studies about posttranscriptional regulation mechanisms have emerged in neuroscience. In this context, microRNAs (miRNAs), which belong to the noncoding RNA family and regulate gene expression via posttranscriptional mechanisms, have gained prominence. Their role in regulating the entire gene circuitry has provided a unique opportunity to characterize them at the genome-wide level and has stimulated investigators to scrutinize their involvement in disease pathogenesis and treatment response. Compared to other psychiatric illnesses, the studies of miRNAs in bipolar disorder are in the early stages; nevertheless, the results are quite encouraging and compel investigators to pursue more in-depth analyses using various approaches. The present chapter reviews miRNAs in the predictive validity of bipolar disorder pathogenesis, in the mechanisms of action of antimanic agents, and in their role as biomarkers of treatment response.
Mitochondrial genetics and bipolar disorder
Authors: Konradi Christine , Kato Tadafumi
Published: March 2022

Mitochondria play a central role in brain energy metabolism and brain health. Because the brain is uniquely dependent on mitochondria for its energy requirements, minor disruptions in mitochondrial function can lead to selective disturbances in affective networks. A number of observations have led to the insight that mitochondria play a role in mood disorders in at least a subset of individuals. Bona fide mitochondrial diseases have a high prevalence of mood disturbances and psychiatric conditions; mitochondria-related functions are abnormal in bipolar disorder; some mitochondrial DNA variants are associated with bipolar disorder; mitochondria-related gene expression is altered in bipolar disorder; and mood stabilizers also stabilize mitochondrial function. This chapter will delve into the intricacies of mitochondria and their function in the brain, and detail the various experimental conditions and findings that show the association of mitochondria and energy metabolism with bipolar and mood disorders.
Integration and consolidation
Authors: Strakowski Stephen M. , Malhi Gin S.
Published: March 2022

In this book, leading experts have provided comprehensive and current reviews of the current state of knowledge regarding how genomics and brain imaging are defining the etiology and expression of bipolar disorder. Taken together, this state of knowledge begins to define a model of illness that is discussed in this chapter. As a starting point, the symptoms of bipolar disorder suggest that the disruption in brain systems that manage emotional homeostasis and reward processing (i.e., behavioral activation) must be represented in any proposed models of illness. Moreover, the typical onset in youth and progressive course of illness suggest a developmental component that persists until a recurrent mood disorder is established. Supporting these assumptions, neuroimaging research has steadily defined disruption in key ventral prefrontal-striatal-thalamic networks that may define the functional neuroanatomy of this condition. Differences from typical neurodevelopment in the formation of these networks, perhaps due to underlying multigenetic causes, likely establishes this disruption. The specific genetic basis has remained elusive, although studies of genes, gene combinations, and epigenetic events, including mitochondrial control, appear to be contributing components. These models offer an opportunity for focused, hypothesis-driven testing to drive future investigations, hopefully identifying the causes of bipolar disorder and ultimately providing specific targets for improved treatments.
Hypomorphism of a novel long ERα isoform causes severe reproductive dysfunctions in female mice
Authors: Saito Kenji , Dickey Jacob E. , Rodeghiero Samuel R. , Toth Brandon A. , Kelly Matthew J. , Deng Yue , Singh Uday , Deng Guorui , Jiang Jingwei , Cui Huxing
Published: March 2022

Estrogen receptor alpha (ERα)-mediated estrogen signaling play a pivotal role in both reproductive and non-reproductive functions. Transcriptional regulation of ERα gene is highly complex, with multiple transcript variants being differentially produced across the tissues. However, tissue-specific variation and physiological specificity of the ERα variants are not yet fully understood. In an attempt to generate a Cre-dependently restorable ERα-null mice for functional investigation of the genetic sufficiency, we unexpectedly produced ERα hypomorphic mice with biased downregulation of a previously unappreciated long ERα isoform that is enriched in the female reproductive organs (uterus and ovaries) and the pituitary but minimally expressed in the brain. Female homozygous mutant mice were capable of pregnancy but displayed irregular estrus cycle and rarely maintained alive newborns without significant morphological and pathological changes in reproductive system and the disruption of body weight homeostasis, indicating the vital role of this long isoform in female reproductive function. Collectively, our results define a tissue-specifically enriched long ERα isoform and its preferential role in female reproductive function over body weight homeostasis.
Service-user experiences of an integrated psychological intervention for depression or anxiety and tobacco smoking in IAPT: A qualitative investigation into mechanisms of change in quitting smoking
Authors: Fredman Stein Kim , Sawyer Katherine , Daryan Shadi , Allen Jennifer L , Taylor Gemma
Published: March 2022

Background

High smoking prevalence leads to increased morbidity and mortality in individuals with depression/anxiety. Integrated interventions targeting both smoking and mood have been found to be more effective than those targeting smoking alone, but the mechanisms of change of these integrated interventions have not been investigated.

Aims

This qualitative study aimed to investigate participants’ subjective experiences of the mechanisms underlying change in smoking behaviour following an integrated CBT-based intervention for smoking cessation and depression/anxiety.

Methods

This study was embedded within an ongoing randomised controlled acceptability and feasibility trial (http://www.isrctn.com/ISRCTN99531779). Semi-structured interviews were conducted with 15 IAPT service users and data were analysed using thematic analysis.

Results

Five themes were identified: (1) acquiring an increased awareness of smoking patterns, (2) developing individualised strategies, (3) practitioner style as “supportive but not lecture-y” (4) importance of regular sessions, and (5) having the opportunity to access intervention at “the right time”.

Conclusions

These findings further our understanding of the mechanisms of change towards smoking cessation in this integrated intervention and highlight the need to emphasise and embed these components in manualised interventions to optimise therapeutic benefits and reduce smoking prevalence in people with depression/anxiety.

Relevance statement

This study qualitatively investigated mechanisms underlying change in smoking behaviour following an integrated intervention for depression/anxiety and smoking cessation. Research shows interventions integrating smoking cessation and mood management are more effective than smoking cessation interventions alone; however further investigation is needed to understand mechanisms of change for integrated interventions. The current results identified key factors that were important for participants in the integrated intervention to reduce smoking. An improved understanding of mechanisms underlying change in smoking behaviour helps to identify therapist characteristics and treatment components that improve therapeutic outcomes which future research could investigate using a randomised controlled trial design.
Unearthing the global impact of mining construction minerals on biodiversity
Authors: Torres Aurora , zu Ermgassen Sophus O.S.E. , Ferri-Yanez Francisco , Navarro Laetitia M. , Rosa Isabel M.D. , Teixeira Fernanda Z. , Wittkopp Constanze , Liu Jianguo
Published: March 2022

Construction minerals – sand, gravel, limestone – are the most extracted solid raw materials1and account for most of the world’s anthropogenic mass, which as of 2020 outweighed all of Earth’s living biomass2. However, knowledge about the magnitude, geography, and profile of this widespread threat to biodiversity remains scarce and scattered3–6. Combining long-term data from the IUCN Red List and new species descriptions we provide the first systematic evaluation of species threatened by mining of construction minerals globally. We found 1,047 species in the Red List impacted by this type of mining, of which 58.5% are threatened with extinction and four species already went extinct. We also identified 234 new species descriptions in 20 biodiversity hotspots reporting impacts from mining. Temporal trends in the assessments highlight the increased saliency of this threat to biodiversity, whose full extent may well reach over 24,000 animal and plant species. While rock quarrying mostly threatens karst biodiversity and narrow-ranged species, sand and gravel extraction is a more prominent threat to freshwater and coastal systems. This study provides the first evidence base to support a global strategy to limit the biodiversity impacts of construction mineral extraction.
Inter-brain coupling reflects disciplinary differences in real-world classroom learning
Authors: Chen Jingjing , Qian Penghao , Gao Xinqiao , Li Baosong , Zhang Yu , Zhang Dan
Published: March 2022

Classroom is the primary site for learning. One important feature of classroom learning is its organization into different disciplines. While disciplinary differences could substantially influence students’ learning processes, little is known about the neural mechanism underlying successful disciplinary learning. In the present study, wearable EEG devices were used to record a group of high school students during their classes of a soft (Chinese) and a hard (Math) discipline throughout one semester. The students with higher learning outcomes in Chinese were found to have better inter-brain neural couplings with their excellent peers, whereas the students with higher Math outcomes were found to have better couplings with the class average. Moreover, the inter-brain couplings showed distinct dominant frequencies for the two disciplines. Our results illustrate disciplinary differences in successful learning from an inter-brain perspective and suggest the neural activities of excellent peers and class average as exemplars for soft and hard disciplines.

Teaser

Successful classroom learning is associated with distinct inter-brain coupling patterns for soft and hard disciplines
In silicoInvestigation of Molecular Networks Linking Gastrointestinal Diseases, Malnutrition, and Sarcopenia
Authors: Hoch Matti , Ehlers Luise , Bannert Karen , Stanke Christina , Brauer David , Caton Vanessa , Lamprecht Georg , Wolkenhauer Olaf , Jaster Robert , Wolfien Markus
Published: March 2022

Malnutrition is a common primary or secondary complication in gastrointestinal diseases. The patient’s nutritional status also influences muscle mass and function, which can be impaired up to the degree of sarcopenia. The molecular interactions in diseases leading to sarcopenia are complex and multifaceted, affecting muscle physiology, the intestine (nutrition), and the liver at different levels. Although extensive knowledge of individual molecular factors is available, their regulatory interplay is not yet fully understood. A comprehensive overall picture of pathological mechanisms and resulting phenotypes is lacking.In silicoapproaches that convert existing knowledge into computationally readable formats can help to unravel such complex systems. We compiled available experimental evidence for molecular interactions involved in the development of sarcopenia into a knowledge base, referred to as the Sarcopenia Map. By including specific diseases, namely liver cirrhosis, and intestinal dysfunction, and considering their effects on nutritional status and blood secretome, we investigated their contribution to the development of sarcopenia. The Sarcopenia Map is publicly available as an open-source, interactive online resource, providing tools that allow users to explore the information on the map and performin silicoperturbation experiments.
Keratose sponges in ancient carbonates – a problem of interpretation
Authors: Neuweiler Fritz , Kershaw Stephen , Boulvain Frédéric , Matysik Michał , Sendino Consuelo , McMenamin Mark , Wood Rachel
Published: March 2022

Increasing current interest in sponge fossils includes numerous reports of diverse vermicular and peloidal structures interpreted as keratose sponges in Neoproterozoic to Mesozoic carbonates and in various open marine to peritidal and restricted settings. Reports of their occurrence are fundamental and far-reaching for understanding microfacies and diagenesis where they occur; and fossil biotic assemblages, as well as wider aspects of origins of animals, sponge evolution/ecology and the systemic recovery from mass extinctions. Keratose sponges: 1) have elaborate spongin skeletons but no spicules, thus lack mineral parts and therefore have poor preservation potential so that determining their presence in rocks requires interpretation; and 2) are presented in publications as interpreted fossil structures almost entirely in two-dimensional (thin section) studies, where structures claimed as sponges comprise diverse layered, network, particulate and amalgamated fabrics involving calcite sparite in a micritic groundmass. There is no verification of sponges in these cases and almost all of them can be otherwise explained; some are certainly not correctly identified. The diversity of structures seen in thin sections may be reinterpreted to include: a) meiofaunal activity; b) layered, possibly microbial (spongiostromate) accretion; c) sedimentary peloidal to clotted micrites; d) fluid escape and capture resulting in birdseye to vuggy porosities; and e) molds of siliceous sponge spicules. Without confirmation of keratose sponges in ancient carbonates, interpretations of their role in ancient carbonate systems, including facies directly after mass extinctions, are unsafe, and alternative explanations for such structures should be considered. This study calls for greater critical appraisal of evidence, to seek confirmation or not, of keratose sponge presence. (259/300 max, for Sedimentology)
Multifactorial remodeling of the cancer immunopeptidome by interferon gamma
Authors: Newey Alice , Yu Lu , Barber Louise J , Choudhary Jyoti S. , Bassani-Sternberg Michal , Gerlinger Marco
Published: March 2022

IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We performed proteomic analyses of untreated and IFNγ-treated colorectal cancer patient-derived organoids (PDOs) and combined this with transcriptomic and HLA-I immunopeptidomics data to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNγ. IFNγ-induced changes in the abundance of source proteins, switching from the constitutive- to the immunoproteasome, and differential upregulation of different HLA alleles explained some, but not all, observed peptide abundance changes. By selecting for peptides which increased or decreased the most in abundance, but originated from proteins with limited abundance changes, we discovered that the amino acid composition of presented peptides also influences whether a peptide is up- or downregulated on HLA-I through IFNγ. The presence of proline within the peptide core was most strongly associated with peptide downregulation. This was validated in an independent dataset. Proline substitution in relevant core positions did not influence the predicted HLA-I binding affinity or stability, indicating that proline effects on peptide processing may be most relevant. Understanding the multiple factors that influence the abundance of peptides presented on HLA-I in the absence or presence of IFNγ is important to identify the best targets for antigen-specific cancer immunotherapies such as vaccines or T-cell receptor engineered therapeutics.
GASOTRANSMITTER MODULATION OF HYPOGLOSSAL MOTONEURON ACTIVITY
Authors: Browe Brigitte , Peng Ying-Jie , Nanduri Jayasri , Prabhakar Nanduri R. , Garcia Alfredo J.
Published: March 2022

Obstructive sleep apnea (OSA) is characterized by sporadic collapse of the upper airway leading to periodic disruptions in breathing. Upper airway patency governed by genioglossal nerve activity originates from the hypoglossal motor nucleus. Mice with targeted deletion of the gene Hmox2, encoding the carbon monoxide (CO) producing enzyme, heme oxygenase-2 (HO-2), exhibit severe OSA, yet the contribution of central HO-2 dysregulation to the phenomenon is unknown. Using the rhythmic brainstem slice preparation, which contains the preBötzinger complex (preBötC) and the hypoglossal nucleus, we tested the hypothesis that central HO-2 dysregulation weakens hypoglossal motoneuron output. Disrupting HO-2 activity increased transmission failure as determined by the intermittent inability of the preBötC rhythm to trigger output from the hypoglossal nucleus. Failed transmission was associated with a reduced input-output relationship between the preBötC and the motor nucleus. These network phenomena were related to smaller inspiratory drive currents and reduced intrinsic excitability among hypoglossal neurons. In addition to HO-2, hypoglossal neurons also expressed the CO-regulated H2S producing enzyme cystathionine □-lyase (CSE). H2S abundance was higher in hypoglossal neurons of HO-2 null mice than wild-type controls. Disrupting CSE function normalized transmission in HO-2 null mice and an H2S donor mimicked the effects of HO-2 dysregulation. These findings demonstrate a hitherto uncharacterized modulation of hypoglossal activity through the interaction of HO-2 and CSE-derived H2S, and supports the perspective that centrally derived HO-2 activity plays an important role regulating upper airway control.
PPML-Omics: a Privacy-Preserving federated Machine Learning method protects patients’ privacy in omic data
Authors: Zhou Juexiao , Chen Siyuan , Wu Yulian , Li Haoyang , Zhang Bin , Zhou Longxi , Hu Yan , Xiang Zihang , Li Zhongxiao , Chen Ningning , Han Wenkai , Wang Di , Gao Xin
Published: March 2022

Modern machine learning models towards various tasks with omic data analysis give rise to threats of privacy leakage of patients involved in those datasets. Despite the advances in different privacy technologies, existing methods tend to introduce too much computational cost (e.g. cryptographic methods) or noise (e.g. differential privacy), which hampers either model usefulness or accuracy in protecting privacy in biological data. Here, we proposed a secure and privacy-preserving machine learning method (PPML-Omics) by designing a decentralized version of the differential private federated learning algorithm. We applied PPML-Omics to analyze data from three sequencing technologies, and addressed the privacy concern in three major tasks of omic data, namely cancer classification with bulk RNA-seq, clustering with single-cell RNA-seq, and the integration of spatial gene expression and tumour morphology with spatial transcriptomics, under three representative deep learning models. We also examined privacy breaches in depth through privacy attack experiments and demonstrated that PPML-Omics could protect patients’ privacy. In each of these applications, PPML-Omics was able to outperform methods of comparison under the same level of privacy guarantee, demonstrating the versatility of the method in simultaneously balancing the privacy-preserving capability and utility in practical omic data analysis. Furthermore, we gave the theoretical proof of the privacy-preserving capability of PPML-Omics, suggesting the first mathematically guaranteed method with robust and generalizable empirical performance in protecting patients’ privacy in omic data.
HALO: A software tool for real-time head alignment in the MR scanner
Authors: Zhao Zhiying , Galiana Gigi , Zillo Cristofer , Camarro Terry , Qiu Maolin , Papademetris Xenophon , Hampson Michelle
Published: March 2022

Magnetic resonance imaging (MRI) studies in human subjects often require multiple scanning sessions/visits. Changes in a subject’s head position across sessions result in different alignment between brain tissues and the magnetic field which leads to changes in magnetic susceptibility. These changes can have considerable impacts on acquired signals. Therefore, we developed the Head Alignment Optimization (HALO) tool. HALO provides real-time visual feedback of a subject’s current head position relative to the position in a previous session. We verified that HALO enabled subjects to actively align their head positions to the desired position of their initial sessions. Our pilot sample of healthy subjects were able to improve their head alignment significantly using HALO and achieved good alignment with their first session meeting stringent criteria similar to that used for within-run head motion (less than 2mm translation or 2 degrees rotation in any direction from the desired position). Utilization of HALO in longitudinal studies will reduce the noise across sessions related to changes in magnetic susceptibility. HALO has been made publicly available.
EPHierStats: a statistical tool to model the hierarchical relationships in electrophysiological data
Authors: Kolpakova Jenya , Marvel-Zuccola Jonathan D. , Futai Kensuke , Martin Gilles E. , van der Vinne Vincent
Published: March 2022

Electrophysiological datasets are typically analyzed under the assumption that repeated measurements of the same unit of analysis (i.e. neuron or animal) can be treated as statistically independent. Recently, this assumption has been questioned and our data confirms and quantifies this skepticism using ex vivo slice recordings of synaptic currents in D1R+ medium spiny neurons in the nucleus accumbens. We therefore present EPHierStats as a statistical framework to analyze electrophysiological datasets with large numbers of measurements (>100) per unit of analysis. This novel analysis framework enables encoding of the full hierarchical relationships between measurements in a mixed-effects general linear model while also analyzing the distribution of values in assessed variables. Our method can easily be adapted to analyze a wide range of repeated-measures electrophysiological experiments. Implementation of the EPHierStats tool will aid the adaption of modern statistical approaches that prevent pseudoreplication and its associated false discovery rate while enabling statistical assessments of the complex relationships inherent to the field of neuroscience.
Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea
Authors: Watanabe Hitoshi , Du Wen , Son Jinsook , Sui Lina , Asahara Shun-ichiro , Kurland Irwin J , Kuo Taiyi , Kitamoto Takumi , Miyachi Yasutaka , de Cabo Rafael , Accili Domenico
Published: March 2022

Sulfonylureas (SU) are effective and affordable anti-diabetic drugs. But chronic use leads to secondary failure, limiting their utilization. The mechanism of secondary failure is unknown. Here we identify Cyb5r3 downregulation as a mechanism of SU failure and successfully reverse it. Chronic exposure to SU impairs Cyb5r3 levels and reduces islet glucose utilization with a metabolomics signature characterized by low acetyl-CoA and amino acid levels. Cyb5r3 engages in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Accordingly, activating Gck mutations in patients with hyperinsulinemia reduce Cyb5r3 binding, whereas inactivating MODY mutations increase it, providing evidence for a role of Cyb5r3 in determining flux through Gck. The Cyb5r3 activator tetrahydroindenoindole (THII) rescues secondary failure to SU in an animal model of chronic SU treatment and restores insulin secretion from ex vivo islets. We conclude that Cyb5r3 loss-of-function is a key factor in the secondary failure to SU and a potential target for its prevention, which may lead to a rehabilitation of SU use in diabetes.
L-GIREMI uncovers RNA editing sites in long-read RNA-seq
Authors: Liu Zhiheng , Quinones-Valdez Giovanni , Fu Ting , Choudhury Mudra , Reese Fairlie , Mortazavi Ali , Xiao Xinshu
Published: March 2022

Using third-generation sequencers, long-read RNA-seq is increasingly applied in transcriptomic studies given its major advantage in characterizing full-length transcripts. A number of methods have been developed to analyze this new type of data for transcript isoforms and their abundance. Another application, which is significantly under-explored, is to identify and analyze single nucleotide variants (SNVs) in the RNA. Identification of SNVs, such as genetic mutations or RNA editing sites, is fundamental to many biomedical questions. In long-read RNA-seq, SNV analysis presents significant challenges, due to the well-known relatively high error rates of the third-generation sequencers. Here, we present the first study to detect and analyze RNA editing sites in long-read RNA-seq. Our new method, L-GIREMI, effectively handles sequencing errors and biases in the reads, and uses a model-based approach to score RNA editing sites. Applied to PacBio long-read RNA-seq data, L-GIREMI affords a high accuracy in RNA editing identification. In addition, the unique advantage of long reads allowed us to uncover novel insights about RNA editing occurrences in single molecules and double-stranded RNA (dsRNA) structures. L-GIREMI provides a valuable means to study RNA nucleotide variants in long-read RNA-seq.
At-home blood collection and stabilization in high temperature climates using homeRNA
Authors: Brown Lauren G. , Haack Amanda J. , Kennedy Dakota S. , Adams Karen N. , Stolarczuk Jennifer E. , Takezawa Meg G. , Berthier Erwin , Thongpang Sanitta , Lim Fang Yun , Chaussabel Damien , Garand Mathieu , Theberge Ashleigh B.
Published: March 2022

Expanding whole blood sample collection for transcriptome analysis beyond traditional phlebotomy clinics will open new frontiers for remote immune research and telemedicine. Determining the stability of RNA in blood samples exposed to high ambient temperatures (>30°C) is necessary for deploying home-sampling in settings with elevated temperatures (e.g., studying physiological response to natural disasters that occur in warm locations or in the summer). Recently, we have developed homeRNA, a technology that allows for self-blood sampling and RNA stabilization remotely. homeRNA consists of a lancet-based blood collection device, the Tasso-SST™ which collects up to 0.5 mL of blood from the upper arm, and a custom-built stabilization transfer tube containing RNAlater™. In this study, we investigated the robustness of our homeRNA kit in high temperature settings via two small pilot studies in Doha, Qatar (no. participants = 8), and the Western and South Central USA during the summer of 2021, which included a heatwave of unusually high temperatures in some locations (no. participants = 11). Samples collected from participants in Doha were subjected to rapid external temperature fluctuations from being moved to and from air-conditioned areas and extreme heat environments (up to 41°C external temperature during brief temperature spikes). In the USA pilot study, regions varied in outdoor temperature highs (between 25°C and 43.4°C). All samples that returned a RNA integrity number (RIN) value from the Doha, Qatar group had a RIN ≥7.0, a typical integrity threshold for downstream transcriptomics analysis. RIN values for the Western and South Central USA samples (n=12 samples) ranged from 6.9-8.7 with 9 out of 12 samples reporting RINs ≥7.0. Overall, our pilot data suggest that homeRNA can be used in some regions that experience elevated temperatures, opening up new geographical frontiers in disseminated transcriptome analysis for applications critical to telemedicine, global health, and expanded clinical research. Further studies, including our ongoing work in Qatar, USA, and Thailand, will continue to test the robustness of homeRNA.
bpRNA-align: Improved RNA Secondary Structure Global Alignment for Comparing and Clustering RNA Structures
Authors: Lasher Brittany , Hendrix David A.
Published: March 2022

Ribonucleic acid (RNA) is a polymeric molecule that is fundamental to biological processes, with structure being more highly conserved than primary sequence and often key to its function. Advances in RNA structure characterization have resulted in an increase in the number of accurate secondary structures. The task of uncovering common RNA structural motifs with a collective function through structural comparison remains challenging and could be used to discover new RNA families. In this work, we present a novel secondary structure alignment and clustering method, bpRNA-align. bpRNA-align is a customized global structural alignment method, utilizing an inverted (gap extend costs more than gap open) context-specific affine gap penalty and a structural, feature-specific substitution matrix to provide similarity scores. We evaluate our similarity scores in comparison to other methods, using affinity propagation clustering, applied to a benchmarking data set of known structure types.
StrainXpress: strain aware metagenome assembly from short reads
Authors: Kang Xiongbin , Luo Xiao , Schönhuth Alexander
Published: March 2022

Next-generation sequencing based metagenomics has enabled to identify microorganisms in characteristic habitats without the need for lengthy cultivation. Importantly, clinically relevant phenomena such as resistance to medication, virulence or interactions with the environment can vary already within species. Therefore, a major current challenge is to reconstruct individual genomes from the sequencing reads at the level of strains, and not just the level of species. However, strains of one species can differ only by minor amounts of variants, which makes it difficult to distinguish them. Despite considerable recent progress, related approaches have remained fragmentary so far. Here, we present StrainXpress, as a comprehensive solution to the problem of strain aware metagenome assembly from next-generation sequencing reads. In experiments, StrainXpress reconstructs strain-specific genomes from metagenomes that involve up to more than 1000 strains, and proves to successfully deal with poorly covered strains. The amount of reconstructed strain-specific sequence exceeds that of the current state-of-the-art approaches by on average 26.75% across all data sets (first quartile: 18.51%, median: 26.60%, third quartile: 35.05%).
Effective holistic characterization of small molecule effects using heterogeneous biological networks
Authors: Mangione William , Falls Zackary , Samudrala Ram
Published: March 2022

The two most common reasons for attrition in therapeutic clinical trials are efficacy and safety. We integrated heterogeneous data to create a human interactome network that was used to comprehensively describe drug behavior in biological systems, with the goal of accurate therapeutic candidate generation. The Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multiscale therapeutic discovery, repurposing, and design was enhanced by integrating drug side effects, protein pathways, protein-protein interactions, protein-disease associations, and the Gene Ontology, complemented with its existing drug/compound, protein, and indication libraries. These integrated networks were reduced to a “multiscale interactomic signature” for each compound that describe its functional behavior as vectors of real values. These signatures are then used for relating compounds to each other with the hypothesis that similar signatures yield similar behavior. Our results indicated that there is significant biological information captured within our networks (particularly via side effects) which enhance the performance of our platform, as evaluated by performing all-against-all leave-one-out drug-indication association benchmarking. Further, drug impacts on pathways derived from computed compound-protein interaction scores served as the features for a random forest machine learning model trained to predict drug-indication associations, with applications to mental disorders and cancer metastasis highlighted. This interactomic pipeline highlights the ability of CANDO to accurately relate drugs in a multitarget and multiscale context, and paves the way for predicting novel putative drug candidates using the information gleaned from indirect data such as side effect profiles and protein pathway information.
SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping
Authors: Ghoddousi Ramin Ali Marandi , Magalong Valerie M. , Kamitakahara Anna K. , Levitt Pat
Published: March 2022

Spatial gene expression, achieved classically through in situ hybridization, is a fundamental tool for topographic phenotyping of cell types in the nervous system. Newly developed techniques allow for the visualization of multiple mRNAs at single-cell resolution, greatly expanding the ability to link gene expression to tissue topography. Yet, methods for efficient and accurate quantification and analysis of high dimensional in situ hybridization are limited. To this end, the Single-Cell Automated Multiplex Pipeline for RNA (SCAMPR) was developed, facilitating rapid and accurate segmentation of neuronal cell bodies using a dual immunohistochemistry-RNAscope protocol and quantification of low and high abundance mRNA signals using open-source image processing and automated segmentation tools. Proof of principle using SCAMPR focused on spatial mapping of gene expression by peripheral (vagal nodose) and central (visual cortex) neurons. The analytical effectiveness of SCAMPR is demonstrated by identifying the impact of early life stress on differential gene expression by vagal neuron subtypes.

Motivation

Quantitative analysis of spatial mRNA expression in neurons can lack accuracy and be both computationally and time intensive. Existing methods that rely on nuclear labeling (DAPI) to distinguish adjoining cells lack the precision to detect mRNA expression in the cytoplasm. In addition, quantification methods that rely on puncta counts can generate large, variable datasets that potentially undercount highly expressed mRNAs. To overcome these methodological barriers, we developed the SCAMPR pipeline that allows for fast, accurate segmentation of neuronal cell body boundaries, topographic gene expression mapping, and high dimensional quantification and analysis of mRNA expression in tissue sections.
A Spinal Circuit That Transmits Innocuous Cool Sensations
Authors: Horwitz Lorraine R , Lee Hankyu , Hor Chia Chun , Shen Fred Y , Cai Wei , Li Chen , Pai Emily Ling-Lin , Fung Tin Long Rex , Rovcanin Ilma , Pipe Kevin P , Xu X.Z. Shawn , Cai Dawen , Duan Bo
Published: March 2022

Temperature information is precisely processed in the nervous system. While progress has been made in identifying molecular thermosensors in the periphery, the neural circuits that process temperature information in the central nervous system remain unknown. Here we have identified an essential node in the neural circuitry for innocuous cool sensations. We found that a population of excitatory interneurons co-expressing Calbindin1 and Lbx1 (Calb1Lbx1) in the dorsal horn of the spinal cord is activated by innocuous cool temperatures. Genetic ablation or silencing of spinal Calb1Lbx1 neurons causes loss of innocuous cool but not noxious cold sensations. Further Brainbow labeling with expansion microscopy and electrophysiology showed that a small cluster of spinal Calb1Lbx1 interneurons in lamina I and the outer layer of lamina II represents the cooling-transmission neurons. These neurons receive monosynaptic connections from TRPM8+ primary sensory neurons and amplify the activity of cool-sensitive spinoparabrachial projection neurons. Our findings reveal a microcircuit in the dorsal spinal cord that specifically transmits innocuous cool sensations.
Polytypy and systematics: diversification ofPapilioswallowtail butterflies in the biogeographically complex Indo-Australian Region
Authors: Joshi Jahnavi , Kunte Krushnamegh
Published: March 2022

A long-standing problem in evolutionary biology and systematics is defining patterns of diversification and speciation, which is compounded by allopatric distributions of polytypic taxa in biogeographically fragmented landscapes. In this paper we revisit this enduring systematic challenge using Mormon swallowtail butterflies (PapiliosubgenusMenelaides)—an evolutionary and genetic model system.Menelaidesis speciose and intensively sampled, with nearly 260 years of systematic study complicated by polytypy resulting from discontinuous morphological variation. This variation is structured by the mainland-island matrix of the geologically complex Indo-Australian Region, where drawing species boundaries has been difficult. We sampled variation across the biogeographic range ofMenelaides, covering 97% of currently recognized species and nearly half of all subspecies. We generated a well-supported mito-nuclear phylogeny, on which we delineated species based on two species delimitation methods (GMYC and mPTP) and strongly supported reciprocal monophyly. These analyses showed that the true species diversity in this group may be up to 25% greater than traditional taxonomy suggests, and prompts extensive taxonomic restructuring. Biogeographic analyses showed thatMenelaideshave diversified largely in allopatry in Indo-Australian subregions by repeated dispersals across key biogeographic barriers. These results provide critical insights into the diversification process in this morphologically diverse and taxonomically complicated model group. These results will also be informative in future studies on systematics, biogeography, speciation and morphological diversification in the Indo-Australian Region—arguably the most complex geological land/seascape in the world.
Ecological diversity exceeds evolutionary diversity in model ecosystems
Authors: Rubin Ilan , Ispolatov Yaroslav , Doebeli Michael
Published: March 2022

Understanding community saturation is fundamental to ecological theory. While investigations of the diversity of evolutionary stable states (ESSs) are widespread, the diversity of communities that have yet to reach an evolutionary endpoint is poorly understood. We use Lotka-Volterra dynamics and trait-based competition to compare the diversity of randomly assembled communities to the diversity of the ESS. We show that, with a large enough founding diversity (whether assembled at once or through sequential invasions), the number of long-time surviving species exceeds that of the ESS. However, the excessive founding diversity required to assemble a saturated community increases rapidly with the dimension of phenotype space. Additionally, traits present in communities resulting from random assembly are more clustered in phenotype space compared to random, though still markedly less ordered than the ESS. By combining theories of random assembly and ESSs we bring a new viewpoint to both the saturation and random assembly literature.
Extended longevity geometrically-inverted proximal tubule organoids for protein uptake studies
Authors: Parigoris Eric , Lee Ji-Hoon , Liu Amy Yunfan , Zhao Xueying , Takayama Shuichi
Published: March 2022

While some in vitro platforms have been adapted to study proteinuric kidney disease, organoids have been challenging to study the disease. This is because apical access is historically difficult, and this is the surface on which megalin (LRP2), an endocytic receptor responsible for tubular reabsorption of filtered plasma proteins, resides. Based on our previous geometrically-inverted organoids, this study established high-throughput basal-in and apical-out proximal tubule organoids to study proteinuric kidney disease in a more physiologically consistent manner. Organoids successfully formed around a minimal Matrigel scaffold, and were maintained in culture for 90+ days, the longest reported hanging drop culture to date. The proximal tubule organoids exhibited good polarization, showed upregulation of maturity markers, such as aquaporin-1 and megalin, and experienced less epithelial-to-mesenchymal (EMT) transition compared to 2D cells. To assess protein uptake, fluorescent albumin was placed in the surrounding media, facing the apical surface, and organoids demonstrated functional protein uptake even at 90 days. To mimic proteinuric conditions, organoids were exposed to human serum albumin and released kidney injury molecule-1 (KIM-1), a common biomarker for kidney injury, in both dose- and time-dependent manners. While this study focuses on applications for modeling proteinuric kidney disease conditions, these organoids are envisioned to have broad utility where apical proximal tubule cell access is required.
A global high-density chromatin interaction network reveals functional long-range and trans-chromosomal relationships
Authors: Lohia Ruchi , Fox Nathan , Gillis Jesse
Published: March 2022

Chromatin contacts are essential for gene-expression regulation, however, obtaining a high-resolution genome-wide chromatin contact map is still prohibitively expensive owing to large genome sizes and the quadratic scale of pairwise data. Chromosome conformation capture (3C) based methods such as Hi-C have been extensively used to obtain chromatin contacts. However, since the sparsity of these maps increases with an increase in genomic distance between contacts, long-range or trans chromatin contacts are especially challenging to sample.

Here, we created a high density reference genome-wide chromatin contact map using a meta-analytic approach. We integrate 3600 Human, 6700 Mouse, and 500 Fly 3C experiments to create species-specific meta-3C contact maps with 304 billion, 193 billion, and 19 billion contacts in respective species. We validate that meta-3C are uniquely powered to capture functional chromatin contacts in both cis and trans. Unlike individual experiments, meta-3C gene contacts predict gene coexpression for long-range and trans chromatin contacts. Similarly, for long-range cis-regulatory interactions, meta-3C contacts outperform all individual experiments, providing an improvement over the conventionally used linear genomic distance-based association. Assessing between species, we find patterns of chromatin contacts conservation in both cis and trans and strong associations with coexpression even in species for which 3C data is lacking.

We have generated an integrated chromatin interaction network which complements a large number of methodological and analytic approaches focused on improved specificity or interpretation. This high-depth “super-experiment” is surprisingly powerful in capturing long-range functional relationships of chromatin interactions, which are now able to predict coexpression, expression quantitative trait loci (eQTL), and cross-species relationships.