bluuebunny/crossref_metadata_2025 huggingface dataset:
Curbing the AI-induced enthusiasm in diagnosing COVID-19 on chest X-Rays: the present and the near-future
Authors: Burlacu Alexandru , Crisan-Dabija Radu , Popa Iolanda Valentina , Artene Bogdan , Birzu Vasile , Pricop Mihai , Plesoianu Cristina , Generali Daniele
Published: May 2020

In the current context of COVID-19 pandemic, a rapid and accessible screening tool based on image processing of chest X-rays (CXRs) using machine learning (ML) approaches would be much needed. Initially, we intended to create and validate an ML software solution able to discriminate on the basis of the CXR between SARS-CoV-2-induced bronchopneumonia and other bronchopneumonia etiologies.

A systematic search of PubMed, Scopus and arXiv databases using the following search terms [“artificial intelligence” OR “deep learning” OR “neural networks”], AND [“COVID-19” OR “SARS-CoV-2”] AND [“chest X-ray” OR “CXR” OR “X-ray”] found 14 recent studies. Most of them declared to be able to confidently identify COVID-19 based on CXRs using deep neural networks. Firstly, weaknesses of artificial intelligence (AI) solutions were analyzed, tackling the issues with datasets (from both medical and technical points of view) and the vulnerability of used algorithms. Then, arguments were provided for why our study design is stronger and more realistic than the previously quoted papers, balancing the possible false expectations with facts.

The authors consider that the potential of AI use in COVID-19 diagnosis on CXR is real. However, scientific community should be careful in interpreting statements, results and conclusions regarding AI use in imaging. It is therefore necessary to adopt standards for research and publication of data, because it seems that in the recent months scientific reality suffered manipulations and distortions. Also, a call for responsible approaches to the imaging methods in COVID-19 is raised. It seems mandatory to follow some rigorous approaches in order to provide with adequate results in daily routine. In addition, the authors intended to raise public awareness about the quality of AI protocols and algorithms and to encourage public sharing of as many CXR images with common quality standards.
COVID-19 versus non-COVID-19 pneumonia: A retrospective cohort study in Chengdu, China
Authors: Li Xiao-Jin , Shuai Bing-Xing , Zhang Zhong-Wei , Kang Yan
Published: May 2020

Background and Objective

Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in Wuhan, Hubei Province, China, it has spread throughout the world and become a global public health emergency. It is important to distinguish COVID-19 from other viral pneumonias to properly screen and diagnose patients, reduce nosocomial infections, and complement the inadequacy of nucleic acid testing. In this study, we retrospectively analysed the clinical data of COVID-19 versus non-COVID-19 patients treated at our hospital between January 17 and February 27, 2020 to summarize our clinical experience in the differential diagnosis of COVID-19.

Methods

In this retrospective cohort study, 23 confirmed COVID-19 patients were consecutively enrolled from January 17 to February 27, 2020, and 29 confirmed non-COVID-19 patients were enrolled in the West China Hospital of Sichuan University. We collected baseline data, epidemiological data, clinical characteristics, imaging findings, viral nucleic acid test results, and survival data. SPSS v22.0 was used for the statistical analysis. Outcomes were followed-up until March 25.

Results

A total of 52 patients were included in this study, including 23 COVID-19 patients and 29 non-COVID-19 patients. No significant between-group differences were observed for age, sex, primary signs or symptoms, cellular immunity, or platelet count. Significant between-group differences were observed in clinical characteristics such as dry cough, contact with individuals from Wuhan, some underlying diseases, nucleated cell count, chest imaging findings, viral nucleic acid test results, 28-day mortality, and 28-day survival.

Conclusion

Epidemiological data, clinical symptoms, nucleic acid test results for COVID-19 and chest CT manifestation may help distinguish COVID-19 from non-COVID-19 cases, prevent imported cases and nosocomial infections.
Gap junction protein INNEXIN2 modulates the period of free-running rhythms inDrosophila melanogaster
Authors: Ramakrishnan Aishwarya , Sheeba Vasu
Published: May 2020

The circadian neuronal circuit ofDrosophila melanogasteris made up of about 150 neurons, distributed bilaterally and distinguished into 7 clusters. Multiple lines of evidence suggest that coherent rhythms in behaviour are brought about when these clusters function as a network. Although chemical modes of communication amongst circadian neurons have been well-studied, there has been no report of communication via electrical synapses made up of gap junctions. Here, we report for the first time that gap junction proteins – Innexins play crucial roles in determining the period of free-running activity rhythms in flies. Our experiments reveal the presence of gap junction protein INNEXIN2 in the ventral lateral neurons. RNA-interference based knockdown of its expression in circadian pacemakers slows down the speed of locomotor activity rhythm. Concomitantly, we find alterations in the oscillation of a core-clock protein PERIOD and in the output molecule Pigment Dispersing Factor in the circadian pacemaker neuron network.
Durable memories and efficient neural coding through mnemonic training using the method of loci
Authors: Wagner Isabella C. , Konrad Boris N. , Schuster Philipp , Weisig Sarah , Repantis Dimitris , Ohla Kathrin , Kühn Simone , Fernández Guillén , Steiger Axel , Lamm Claus , Czisch Michael , Dresler Martin
Published: May 2020

Mnemonic techniques, such as the method of loci, can powerfully boost memory. Here, we compared memory athletes ranked among the world’s top 50 in memory sports to mnemonics-naïve controls. In a second study, participants completed a six-weeks memory training, working memory training, or no intervention. Behaviorally, memory training enhanced durable, longer-lasting memories. fMRI during encoding and recognition revealed task-based activation decreases in lateral prefrontal, as well as in parahippocampal and retrosplenial cortices in both memory athletes and participants after memory training, partly associated with better performance after four months. This was complemented by hippocampal-neocortical coupling during consolidation, which was stronger the more durable memories participants formed. Our findings are the first to demonstrate that mnemonic training boosts durable memory formation via decreased task-based activation and increased consolidation thereafter. This is in line with conceptual accounts of neural efficiency and highlights a complex interplay of neural processes critical for extraordinary memory.
Gene expression profiling reveals subgenome dominance duringBrassica napusseed development
Authors: Khan Deirdre , Ziegler Dylan J. , Kalichuk Jenna L. , Hoi Vanessa , Hyunh Nina , Hajihasani Abolfazl , Parkin Isobel A.P. , Robinson Stephen J. , Belmonte Mark F.
Published: May 2020

We profiled the gene regulatory landscape ofBrassica napusreproductive development using RNA sequencing. Comparative analysis of this nascent amphidiploid across the plant lifecycle revealed the contribution of each subgenome to plant reproduction. Global mRNA profiling revealed lower accumulation of Cnsubgenome transcripts relative to the Ansubgenome. Subgenome-specific transcriptional networks identified distinct transcription factor families enriched in each of the Anand Cnsubgenome early in seed development. Global gene expression profiling of laser-microdissected seed subregions further reveal subgenome expression dynamics in the embryo, endosperm, and seed coat of early stage seeds. Transcription factors predicted to be regulators encoded by the Ansubgenome are expressed primarily in the seed coat whereas regulators encoded by the Cnsubgenome were expressed primarily in the embryo. Data suggest subgenome bias are characteristic features of theB. napusseed throughout development, and that such bias might not be universal across the embryo, endosperm, and seed coat of the developing seed. Whole genome transcription factor networks identified BZIP11 as a transcriptional regulator of earlyB. napusseed development. Knockdown ofBZIP11using RNA interference resulted in a similar reduction in gene activity of predicted gene targets, and a reproductive-lethal phenotype. Taken together, transcriptional networks spanning both the Anand Cngenomes of theB. napusseed can identify valuable targets for seed development research and that-omics level approaches to studying gene regulation inB. napuscan benefit from both broad and high-resolution analyses.

One Sentence Summary

Global RNA sequencing coupled with laser microdissection provides a critical resource to study subgenome bias in whole seeds and specific tissues of polyploid plants.
Differential Effects of Two Early Life Stress Paradigms on Cerebellar-Dependent Delay Eyeblink Conditioning
Authors: Moussa-Tooks Alexandra B. , Hetrick William P. , Green John T.
Published: May 2020

Early life stress paradigms have become prominent in the animal literature to model atypical development. Currently, two models have prevailed within the literature: (1) limited bedding or nesting and (2) maternal separation or deprivation. Both models have produced aberrations spanning behavior and neural circuitry. Surprisingly, these two models have yet to be directly compared. The current study utilized delay eyeblink conditioning, an associative learning task with a well-defined cerebellar circuit, to compare the behavioral effects of standard limited bedding (postnatal day 2-9, n=15) and maternal separation (60 minutes per day during postnatal day 2-14, n=13) early life stress paradigms. Animals in all groups exhibited robust learning curves. Surprisingly, facilitated conditioning was observed in the maternal separation group. Rats that underwent limited bedding did not differ from the control or maternal separation groups on any conditioning measures. This study contributes to a clearer understanding of early life stress paradigms and the claims made about their mechanisms, which if better clarified can be properly leveraged to increase translational value.
The Spatial Scale of Synaptic Protein Allocation during Homeostatic Plasticity
Authors: Sun Chao , Nold Andreas , Tchumatchenko Tatjana , Heilemann Mike , Schuman Erin M.
Published: May 2020

An individual neuron hosts up to 10,000 individual synapses that can be made stronger or weaker by local and cell-wide plasticity mechanisms, both of which require protein synthesis. To address over what spatial scale a neuron allocates synaptic resources, we quantified the distribution of newly synthesized proteins after global homeostatic upscaling using metabolic labeling and single-molecule localization (DNA-PAINT). Following upscaling, we observed a global increase in locally synthesized nascent protein in synapses and at dendrites, with a high degree of variability between individual synapses. We determined the smallest spatial scale over which nascent proteins were evenly distributed and found that it is best described by synaptic neighborhoods (~ 10 microns in length)-smaller than a dendritic branch and larger than an individual synapse. Protein allocation at the level of neighborhoods thus represents a solution to the problem of protein allocation within a neuron that balances local autonomy and global homeostasis.
SARS-CoV-2 selectively mimics a cleavable peptide of human ENaC in a strategic hijack of host proteolytic machinery
Authors: Anand Praveen , Puranik Arjun , Aravamudan Murali , Venkatakrishnan AJ , Soundararajan Venky
Published: May 2020

Molecular mimicry of host proteins is an evolutionary strategy adopted by viruses to evade immune surveillance and exploit host cell systems. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide. Single cell RNA-seq from 65 studies shows significant overlap between the expression of ENaC-α and ACE2, the putative receptor for the virus, in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular fingerprint with amino acid cleavage signatures of 178 human proteases shows the potential for tissue-specific proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. We extrapolate that the evolution of SARS-CoV-2 into a global coronavirus pandemic may be in part due to its targeted mimicry of human ENaC and hijack of the associated host proteolytic network.
Longitudinal Quantification of Metabolites and Macromolecules Reveals Age- and Sex-Related Changes in the Healthy Fischer 344 Rat Brain
Authors: Fowler Caitlin F. , Madularu Dan , Dehghani Masoumeh , Devenyi Gabriel A. , Near Jamie
Published: May 2020

Normal aging is associated with numerous biological changes including altered brain metabolism and tissue chemistry.In vivocharacterization of the neurochemical profile during aging is possible using magnetic resonance spectroscopy, a powerful non-invasive technique capable of quantifying brain metabolites involved in physiological processes that become impaired with age. A prominent macromolecular signal underlies those of brain metabolites and is particularly visible at high fields; parameterization of this signal into components improves quantification and expands the number of biomarkers comprising the neurochemical profile. The present study reports, for the first time, the simultaneous absolute quantification of brain metabolites and individual macromolecules in aging male and female Fischer 344 rats, measured longitudinally using proton magnetic resonance spectroscopy at 7T. We identified age- and sex-related changes in neurochemistry, with prominent differences in metabolites implicated in anaerobic energy metabolism, antioxidant capacity, and neuroprotection, as well as numerous macromolecule changes. These findings contribute to our understanding of the neurobiological processes associated with healthy aging, critical for the proper identification and management of pathological aging trajectories.

HIGHLIGHTS

→ Magnetic resonance spectroscopy reveals altered chemistry in the aging rat brain

→ Age- and sex-dependent differences in metabolites and macromolecules are present

→ Metabolites and macromolecules are markers of processes involved in healthy aging

→ This study clarifies normative progression of brain chemistry and metabolismin vivo

→ Improved understanding will inform future studies in pathological aging
Longevity, clonal relationship and transcriptional program of celiac disease-specific plasma cells
Authors: Lindeman Ida , Zhou Chunyan , Eggesbø Linn M. , Miao Zhichao , Polak Justyna , Lundin Knut E. A. , Jahnsen Jørgen , Qiao Shuo-Wang , Iversen Rasmus , Sollid Ludvig M.
Published: May 2020

Disease-specific plasma cells (PCs) reactive with transglutaminase 2 (TG2) or deamidated gluten peptides (DGP) are abundant in celiac disease (CeD) gut lesions. Their contribution toward CeD pathogenesis is unclear. We assessed expression of markers associated with PC longevity in 15 untreated and 26 treated CeD patients in addition to 13 non-CeD controls, and performed RNA-sequencing with clonal inference and transcriptomic analysis of 3251 single PCs. We observed antigen-dependent V-gene selection and stereotypic antibodies. Generation of recombinant DGP-specific antibodies revealed a key role of a heavy-chain residue that displays polymorphism, suggesting that immunoglobulin gene polymorphisms may influence CeD-specific antibody responses. We identified transcriptional differences between CeD-specific vs non-disease-specific PCs and between short-lived vs long-lived PCs. The short-lived CD19+CD45+phenotype dominated in untreated and short-term-treated CeD, in particular among disease-specific PCs but also in the general PC population. Thus, the disease lesion of untreated CeD is characterized by massive accumulation of short-lived PCs that are not only directed against disease-specific antigens.
A machine learning approach to optimizing cell-free DNA sequencing panels: with an application to prostate cancer
Authors: Cario Clinton L. , Chen Emmalyn , Leong Lancelote , Emami Nima C. , Lopez Karen , Tenggara Imelda , Simko Jeffry P. , Friedlander Terence W. , Li Patricia S. , Paris Pamela L. , Carroll Peter R. , Witte John S.
Published: May 2020

Background

Cell-free DNA’s (cfDNA) use as a biomarker in cancer is challenging due to genetic heterogeneity of malignancies and rarity of tumor-derived molecules. Here we describe and demonstrate a novel machine-learning guided panel design strategy for improving the detection of tumor variants in cfDNA. Using this approach, we first generated a model to classify and score candidate variants for inclusion on a prostate cancer targeted sequencing panel. We then used this panel to screen tumor variants from prostate cancer patients with localized disease in bothin silicoand hybrid capture settings.

Methods

Whole Genome Sequence (WGS) data from 550 prostate tumors was analyzed to build a targeted sequencing panel of single point and small (<200bp) indel mutations, which was subsequently screenedin silicoagainst prostate tumor sequences from 5 patients to assess performance against commonly used alternative panel designs. The panel’s ability to detect tumor-derived cfDNA variants was then assessed using prospectively collected cfDNA and tumor foci from a test set 18 prostate cancer patients with localized disease undergoing radical proctectomy.

Results

The panel generated from this approach identified as top candidates mutations in known driver genes (e.g. HRAS) and prostate cancer related transcription factor binding sites (e.g. MYC, AR). It outperformed two commonly used designs in detecting somatic mutations found in the cfDNA of 5 prostate cancer patients when analyzed in anin silicosetting. Additionally, hybrid capture and 2,500X sequencing of cfDNA molecules using the panel resulted in detection of tumor variants in all 18 patients of a test set, where 15 of the 18 patients had detected variants found in multiple foci.

Conclusion

Machine learning-prioritized targeted sequencing panels may prove useful for broad and sensitive variant detection in the cfDNA of heterogeneous diseases. This strategy has implications for disease detection and monitoring when applied to the cfDNA isolated from prostate cancer patients.
A biomimetic liver model recapitulating bio-physical properties and tumour stroma interactions in hepatocellular carcinoma
Authors: Calitz C. , Pavlovic N. , Rosenquist J. , Zagami C. , Samanta A. , Heindryckx F.
Published: May 2020

Hepatocellular carcinoma (HCC) is a primary liver tumor developing in the wake of chronic liver disease. Chronic liver disease and inflammation leads to a fibrotic environment actively supporting and driving hepatocarcinogenesis. Insight into hepatocarcinogenesis in terms of the interplay between the tumor stroma micro-environment and tumor cells is thus of considerable importance. Three-dimensional (3D) cell culture models are proposed as the missing link between currentin vitro2D cell culture models andin vivoanimal models. Our aim was to design a novel 3D biomimetic HCC model with accompanying fibrotic stromal compartment and vasculature. Physiologically relevant hydrogels such as collagen and fibrinogen were incorporated to mimicking the bio-physical properties of the tumor ECM. In our model LX2 and HepG2 cells embedded in a hydrogel matrix were seeded onto the inverted insert membrane of a Transwell™ system. HUVEC cells were then seeded onto the opposite side of the membrane. Three formulations consisting of ECM-hydrogels embedded with cells were prepared and the bio-physical properties determined by rheology. Cell viability was determined by the AlamarBlue®assay over 21-days. The effect of the chemotherapeutic drug doxorubicin was evaluated in both a 2D co-culture and our 3D model for a period of 72h. We show that this model is viable for 25-days and gives rise to metastatic tumor nodules after 17 days in culture. Rheology results show that bio-physical properties of a fibrotic, cirrhotic and HCC liver can be successfully mimicked. Overall, results indicate that this 3D model is more representative of thein vivosituation compared to traditional 2D cultures. Our 3D tumor model showed a decreased response to chemotherapeutics, mimicking drug resistance typically seen in HCC patients. This model could in future provide a valuable new platform to study multifocal HCC or to identify mechanisms that contribute to early stages of metastasis.

A protocol for a novel 3D biomimetic HCC model with accompanying fibrotic stromal compartment and vasculature, to study endocrine and paracrine signaling in liver cancer. The model uses physiological relevant hydrogels in ratios mimicking the bio-physical properties of the stromal extracellular matrix, which is an active mediator of cellular interactions, tumor growth and metastasis.
Earlier springs enable High-Arctic wolf spiders to produce a second clutch
Authors: Høye Toke T. , Kresse Jean-Claude , Koltz Amanda M. , Bowden Joseph J.
Published: May 2020

Spiders at southern latitudes commonly produce multiple clutches, but this has not been observed at high latitudes where activity seasons are much shorter. Yet the timing of snowmelt is advancing in the Arctic, and may allow some species to produce an additional clutch. To determine if this is already happening, we used specimens of the wolf spiderPardosa glacialiscaught by pitfall traps from the long-term (1996-2014) monitoring program at Zackenberg, Northeast Greenland. We dissected individual egg sacs and counted the number of eggs and partially developed juveniles, and measured carapace width of the mothers. Upon discovery of a bimodal frequency distribution of clutch sizes, as is typical for wolf spiders at lower latitudes producing a second clutch, we assigned egg sacs to being a first or second clutch depending on clutch size. We tested whether the median capture date differed among first and second clutches, whether clutch size was correlated to female size, and whether the proportion of second clutches produced within a season was related to climate. We found that assigned second clutches appeared significantly later in the season than first clutches. In years with earlier snowmelt, first clutches occurred earlier and the proportion of second clutches produced was larger. This result, likely a result of female spiders producing first clutches earlier in those years, which allowed time for another clutch. Clutch size for first clutches was correlated to female size, while this was not the case for second clutches. Our results provide the first evidence for Arctic invertebrates producing additional clutches in response to warming. This could be a common but overlooked phenomenon due to the challenges associated with long-term collection of life history data in the Arctic. Moreover, given that wolf spiders are a widely distributed, important tundra predator, we may expect to see population and food web consequences of their increased reproductive rates.
The evolution of extreme fertility defied ancestral gonadotropin mediated brain-reproduction tradeoff
Authors: Shpigler Hagai Y , Herb Brian , Drnevich Jenny , Band Mark , Robinson Gene E , Bloch Guy
Published: May 2020

Gonadotropic hormones coordinate processes in diverse tissues regulating animal reproductive physiology and behavior. Juvenile hormone (JH) is the ancient and most common gonadotropin in insects, but not in advanced eusocial honey bees and ants. To probe the evolutionary basis of this change, we combined endocrine manipulations, transcriptomics, and behavioral analyses to study JH regulated processes in a bumble bee showing an intermediate level of sociliality. We found that in the fat body, more JH-regulated genes were upregulated and enriched for metabolic and biosynthetic pathways. This transcriptomic pattern is consistent with earlier evidence that JH is the major gonadotropin in the bumble bee. In the brain, most JH-regulated genes were downregulated and enriched for protein turnover pathways. Brain ribosomal protein gene expression was similarly downregulated in dominant workers, which naturally have high JH titers. In other species, similar downregulation of protein turnover is found in aging brains or under stress, and is associated with compromised long-term memory and health. These findings suggest a previously unknown gonadotropin-mediated tradeoff. We did not find a similar downregulation of protein turnover pathways in the brain of honey bees in which JH is not a gonadotropin but rather regulates division of labor. These differences between JH effets in the bumble bee and in the advanced eusocial honey bee suggest that the evolution of advanced eusociality was associated with modifications in hormonal signaling supporting extended and extremely high fertility while reducing the ancient costs of high gonadotropin titers to the brain.
The Role of Conjunctive Representations in Regulating Actions
Authors: Kikumoto Atsushi , Mayr Ulrich
Published: May 2020

Action selection appears to rely on conjunctive representations that nonlinearly integrate task-relevant features (Kikumoto & Mayr, 2020). We test here the corollary hypothesis that such representations are also intricately involved during attempts to stop an action—a key aspect of action regulation. We tracked both conjunctive representations and those of constituent rule, stimulus, or response features through trial-by-trial representational similarity analysis of the EEG signal in a combined, rule-selection and stop-signal paradigm. Across two experiments with student participants (N= 57), we found (a) that the strength of decoded conjunctive representations prior to the stop signal uniquely predicted trial-by-trial stopping success (Exp. 1) and (b) that these representations were selectively suppressed following the onset of the stop signal (Exp. 1 and 2). We conclude that conjunctive representations are key to successful action execution and therefore need to be suppressed when an intended action is no longer appropriate.

Statement of Relevance

Some theorists have posited that as a necessary step during action selection, action-relevant features need to be combined within a conjunctive representation that is more than the sum if its basic features. Consequently, such representations should also play a critical role when trying to stop an intended action—a key aspect of self-regulation. However direct evidence of conjunctive representations has been elusive. Using a method for tracking both conjunctive and basic-feature representations on a trial-by-trial basis in the EEG signal, we show that the stronger the conjunctive representations, the harder it was to stop the intended action. Furthermore, the stopping process also selectively reduced the strength of conjunctive representations. These results further our knowledge about action regulation by showing that conjunctive representations are a necessary precursor for carrying out actions successfully and for that reason also need to be the target of self-regulatory stopping attempts.
A functional screening platform for engineering chimeric antigen receptors with reduced on-target, off-tumour activation
Authors: Di Roberto Raphaël B. , Rueda Rocío Castellanos , Frey Samara , Egli David , Vazquez-Lombardi Rodrigo , Reddy Sai T.
Published: May 2020

Chimeric antigen receptor (CAR) T cell therapies have advanced substantially in the clinic for cancer immunotherapy. However, challenges related to safety persist; one major concern is when CARs respond to antigen present on healthy cells (on-target, off-tumour response). A strategy to ameliorate this consists in engineering the affinity of CARs such that they are only activated by tumor cells expressing high antigen levels. Here, we developed a CAR T cell display platform for functional screening based on cell signaling. Starting with a CAR with high affinity towards its target antigen, we used CRISPR-Cas9 genome editing to generate a library of antigen-binding domain variants. Following multiple rounds of functional screening and deep sequencing-guided selection, CAR variants were identified that were discriminatively activated by tumor cells based on antigen expression levels. Our platform demonstrates how directed evolution based on functional screening can be used to enhance the selectivity and safety of CARs.
Determination of primary microRNA processing in clinical samples by targeted pri-miR-sequencing
Authors: Conrad Thomas , Ntini Evgenia , Lang Benjamin , Cozzuto Luca , Andersen Jesper B , Marquardt Jens U , Ponomarenko Julia , Tartaglia Gian Gaetano , Ørom Ulf A V
Published: May 2020

MicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in disease such as cancer. The processing of primary microRNA transcripts is an important regulatory step in microRNA biogenesis. Due to low expression level and association with chromatin primary microRNAs are challenging to study in clinical samples where input material is limited.

Here, we present a high-sensitivity targeted method to determine processing efficiency of several hundred primary microRNAs from total RNA using as little as 500 thousand Illumina HiSeq sequencing reads. We validate the method using RNA from HeLa cells and show the applicability to clinical samples by analyzing RNA from normal liver and hepatocellular carcinoma.

We identify 24 primary microRNAs with significant changes in processing efficiency from normal liver to hepatocellular carcinoma, among those the highly expressed miRNA-122 and miRNA-21, demonstrating that differential processing of primary microRNAs is occurring and could be involved in disease. With our method presented here we provide means to study pri-miRNA processing in disease from clinical samples.
Conservative and liberal attitudes drive polarized neural responses to political content
Authors: Leong Yuan Chang , Chen Janice , Willer Robb , Zaki Jamil
Published: May 2020

People tend to interpret political information in a manner that confirms their prior beliefs, a cognitive bias that contributes to rising political polarization. In this study, we combined functional magnetic resonance imaging with semantic content analyses to investigate the neural mechanisms that underlie the biased processing of real-world political content. We scanned American participants with conservative-leaning or liberal-leaning immigration attitudes while they watched news clips, campaign ads, and public speeches related to immigration policy. We searched for evidence of “neural polarization”: activity in the brain that diverges between people who hold liberal versus conservative political attitudes. Neural polarization was observed in the dorsomedial prefrontal cortex (DMPFC), a brain region associated with the interpretation of narrative content. Neural polarization in the DMPFC intensified during moments in the videos that included risk-related and moral-emotional language, highlighting content features most likely to drive divergent interpretations between conservatives and liberals. Finally, participants whose DMPFC activity closely matched that of the average conservative or the average liberal participant were more likely to change their attitudes in the direction of that group’s position. Our work introduces a novel multi-method approach to study the neural basis of political cognition in naturalistic settings. Using this approach, we characterize how political attitudes biased information processing in the brain, the language most likely to drive polarized neural responses, and the consequences of biased processing for attitude change. Together, these results shed light on the psychological and neural underpinnings of how identical information is interpreted differently by conservatives and liberals.

Significance Statement

Partisan biases in processing political information contribute to rising divisions in society. How do such biases arise in the brain? We measured the neural activity of participants watching videos related to immigration policy. Despite watching the same videos, conservative and liberal participants exhibited divergent neural responses. This “neural polarization” between groups occurred in a brain area associated with the interpretation of narrative content, and intensified in response to language associated with risk, emotion, and morality. Furthermore, polarized neural responses predicted attitude change in response to the videos. These findings suggest that biased processing in the brain drives divergent interpretations of political information and subsequent attitude polarization.
Computational Electrostatics Predict Variations in SARS-CoV-2 Spike and Human ACE2 Interactions
Authors: Morton Scott P. , Phillips Joshua L.
Published: May 2020

SARS-CoV-2 is a novel virus that is presumed to have emerged from bats to crossover into humans in late 2019. As the global pandemic ensues, scientist are working to evaluate the virus and develop a vaccine to counteract the deadly disease that has impacted lives across the entire globe. We perform computational electrostatic simulations on multiple variants of SARS-CoV-2 spike protein s1 in complex with human angiotensin-converting enzyme 2 (ACE2) variants to examine differences in electrostatic interactions across the various complexes. Calculations are performed across the physiological pH range to also examine the impact of pH on these interactions. Two of six spike protein s1 variations having greater electric forces at pH levels consistent with nasal secretions and significant variations in force across all five variants of ACE2. Five out of six spike protein s1 variations have relatively consistent forces at pH levels of the lung, and one spike protein s1 variant that has low potential across a wide range of pH. These predictions indicate that variants of SARS-CoV-2 spike proteins and human ACE2 in certain combinations could potentially play a role in increased binding efficacy of SARS-CoV-2 in vivo.
Developmental co-emergence of cardiac and gut tissues modeled by human iPSC-derived organoids
Authors: Silva A.C. , Matthys O.B. , Joy D.A. , Kauss M.A. , Natarajan V. , Lai M.H. , Turaga D. , Blair A.P. , Alexanian M. , Bruneau B.G. , McDevitt T.C.
Published: May 2020

During embryogenesis, paracrine signaling between tissues in close proximity contributes to the determination of their respective cell fate(s) and development into functional organs. Organoids arein vitromodels that mimic organ formation and cellular heterogeneity, but lack the paracrine input of surrounding tissues. Here, we describe a human multilineage iPSC-derived organoid that recapitulates cooperative cardiac and gut development and displays extensive cellular and structural complexity of both tissues. We demonstrate that the presence of endoderm tissue (gut/intestine) in multilineage organoids contributed to the development of the cardiac tissue, specifically cardiomyocyte expansion, compartmentalization, enrichment of atrial/nodal cells, myocardial compaction and functional fetal-like maturation. Overall, this study demonstrates the ability to generate specific cooperative tissues originating from different germ lineages within a single organoid model, an advance that will further the examination of multi-tissue interactions during development and disease.
Pazopanib induces dramatic but transient contraction of myeloid suppression compartment in favor of adaptive immunity
Authors: Rinchai Darawan , Verzoni Elena , Huber Veronica , Cova Agata , Squarcina Paola , De Cecco Loris , de Braud Filippo , Ratta Raffaele , Dugo Matteo , Lalli Luca , Vallacchi Viviana , Rodolfo Monica , Roelands Jessica , Castelli Chiara , Chaussabel Damien , Procopio Giuseppe , Bedognetti Davide , Rivoltini Licia
Published: May 2020

Anti-angiogenic tyrosine-kinase inhibitors (TKIs) and immune checkpoint blockade (ICB) constitute the backbone of metastatic renal cell carcinoma (mRCC) treatment. The development of the optimal combinatorial or sequential approach is hindered by the lack of comprehensive data regarding TKI-induced immunomodulation and its kinetics. Through the use of orthogonal transcriptomic and phenotyping platforms combined with functional analytic pipelines, we demonstrated that the anti-angiogenic TKI pazopanib induces a dramatic and coherent reshaping of systemic immunity in mRCC patients, downsizing the myeloid-derived suppressor cell (MDSC) compartment in favor of a strong enhancement of cytotoxic T and Natural Killer (NK) cell effector functions. The intratumoral expression level of a MDSC signature here generated was strongly associated with poor prognosis in mRCC patients. The marked but transient nature of this immunomodulation, peaking at the 3rdmonth of treatment, provides the rationale for the use of TKIs as a preconditioning strategy to improve the efficacy of ICB.
Signal-to-Signal Neural Networks for Improved Spike Estimation from Calcium Imaging Data
Authors: Sebastian Jilt , Sur Mriganka , Murthy Hema A. , Magimai.-Doss Mathew
Published: May 2020

Spiking information of individual neurons is essential for functional and behavioral analysis in neuroscience research. Calcium imaging techniques are generally employed to obtain activities of neuronal populations. However, these techniques result in slowly-varying fluorescence signals with low temporal resolution. Estimating the temporal positions of the neuronal action potentials from these signals is a challenging problem. In the literature, several generative model-based and data-driven algorithms have been studied with varied levels of success. This article proposes a neural network-based signal-to-signal conversion approach, where it takes as input raw-fluorescence signal and learns to estimate the spike information in an end-to-end fashion. Theoretically, the proposed approach formulates the spike estimation as a single channel source separation problem with unknown mixing conditions. The source corresponding to the action potentials at a lower resolution is estimated at the output. Experimental studies on the spikefinder challenge dataset show that the proposed signal-to-signal conversion approach significantly outperforms state-of-the-art-methods in terms of Pearson’s correlation coefficient and Spearman’s rank correlation coefficient and yields comparable performance for the area under the receiver operating characteristics measure. We also show that the resulting system: (a) has low complexity with respect to existing supervised approaches and is reproducible; (b) is layer-wise interpretable; and (c) has the capability to generalize across different calcium indicators.

Author summary

Information processing by a population of neurons is studied using two-photon calcium imaging techniques. A neuronal spike results in an increased intracellular calcium concentration. Fluorescent calcium indicators change their brightness upon a change in the calcium concentration, and this change is captured in the imaging technique. The task of estimating the actual spike positions from the brightness variations is formally referred to as spike estimation. Several signal processing and machine learning-based algorithms have been proposed in the past to solve this problem. However, the task is still far from being solved. Here we present a novel neural network-based data-driven algorithm for spike estimation. Our method takes the fluorescence recording as the input and synthesizes the spike information signal, which is well-correlated with the actual spike positions. Our method outperforms state-of-the-art methods on standard evaluation framework. We further analyze different components of the model and discuss its benefits.
DAnkrd49 and Bdbt act via Casein Kinase Iε to regulate planar polarity inDrosophila
Authors: Strutt Helen , Strutt David
Published: May 2020

The core planar polarity proteins are essential mediators of tissue morphogenesis, controlling both the polarised production of cellular structures and polarised tissue movements. During development the core proteins promote planar polarisation by becoming asymmetrically localised to opposite cell edges within epithelial tissues, forming intercellular protein complexes that coordinate polarity between adjacent cells. Here we describe a novel protein complex that regulates the asymmetric localisation of the core proteins in theDrosophilapupal wing. DAnkrd49 (an ankyrin repeat protein) and Bride of Doubletime (Bdbt, a non-canonical FK506 binding protein family member) physically interact, and regulate each other’s levelsin vivo. Loss of either protein results in a reduction in core protein asymmetry and disruption of the placement of trichomes at the distal edge of pupal wing cells. Post-translational modifications are thought to be important for the regulation of core protein behaviour and their sorting to opposite cell edges. Consistent with this, we find that loss of DAnkrd49 or Bdbt leads to reduced phosphorylation of the core protein Dishevelled and to decreased Dishevelled levels both at cell junctions and in the cytoplasm. Bdbt has previously been shown to regulate activity of the kinase Discs Overgrown (Dco, also known as Doubletime or Casein Kinase Iε), and Dco itself has been implicated in regulating planar polarity by phosphorylating Dsh as well as the core protein Strabismus. We demonstrate that DAnkrd49 and Bdbt act as dominant suppressors of Dco activity. These findings support a model whereby Bdbt and DAnkrd49 act together to modulate the activity of Dco during planar polarity establishment.

Author summary

In many animal tissues, sheets of cells are polarised in the plane of the tissue, which is evident by the production of polarised structures, such as hairs on the fly wing that point in the same direction or cilia that beat in the same direction. One group of proteins controlling this coordinated polarity are the core planar polarity proteins, which localise asymmetrically within cells such that some core proteins localise to one cell end and others to the opposite cell end. It is thought that modifications such as phosphorylation may locally regulate core protein stability, and this promotes sorting of proteins to different cell ends. We identify two proteins, DAnkrd49 and Bdbt, that form a complex and regulate core protein asymmetry. Loss of either protein causes a reduction in overall levels of the core protein Dishevelled (Dsh), and a reduction in its phosphorylation. We provide evidence that the effect on core protein asymmetry is mediated via regulation of the kinase activity of Discs overgrown (Dco, also known as Doubletime/Casein Kinase Iε) by DAnkrd49 and Bdbt. We propose that modulation of Dco activity by DAnkrd49 and Bdbt is a key step in the sorting of core proteins to opposite cell ends.
TheO-GlcNAc transferase OGT is a conserved and essential regulator of the cellular and organismal response to hypertonic stress
Authors: Urso Sarel J. , Comly Marcella , Hanover John A. , Lamitina Todd
Published: May 2020

The conservedO-GlcNAc transferase OGTO-GlcNAcylates serine and threonine residues of intracellular proteins to regulate their function. OGT is required for viability in mammalian cells, but its specific roles in cellular physiology are poorly understood. Here we describe a conserved requirement for OGT in an essential aspect of cell physiology: the hypertonic stress response. Through a forward genetic screen inCaenorhabditis elegans, we discovered OGT is acutely required for osmoprotective protein expression and adaptation to hypertonic stress. Gene expression analysis shows thatogt-1functions through a post-transcriptional mechanism. Human OGT partially rescues theC. elegansphenotypes, suggesting that the osmoregulatory functions of OGT are ancient. Intriguingly, mutations that ablateO-GlcNAcylation activity in either human orC. elegansOGT rescue the hypertonic stress response phenotype. Our findings are among the first to demonstrate a specific physiological role for OGT at the organismal level and demonstrate that OGT engages in important molecular functions outside of its well described roles in post-translational O-GlcNAcylation of intracellular proteins.

Author Summary

The ability to sense and adapt to changes in the environment is an essential feature of cellular life. Changes in environmental salt and water concentrations can rapidly cause cell volume swelling or shrinkage and, if left unchecked, will lead to cell and organismal death. All organisms have developed similar physiological strategies for maintaining cell volume. However, the molecular mechanisms that control these physiological outputs are not well understood in animals. Using unbiased genetic screening inC. elegans, we discovered that a highly conserved enzyme called O-GlcNAc transferase (OGT) is essential for regulating physiological responses to increased environmental solute levels. A human form of OGT can functionally substitute for worm OGT, showing that this role is conserved across evolution. Surprisingly, the only known enzymatic activity of OGT was not required for this role, suggesting this enzyme has important undescribed molecular functions. Our studies reveal a new animal-specific role for OGT in the response to osmotic stress and show thatC. elegansis an important model for defining the conserved molecular mechanisms that respond to alterations in cell volume.
GCN sensitive protein translation in yeast
Authors: Barr William A. , Sheth Ruchi B. , Kwon Jack , Cho Jungwoo , Glickman Jacob W. , Hart Felix , Chatterji Om K. , Scopino Kristen , Voelkel-Meiman Karen , Krizanc Daniel , Thayer Kelly M. , Weir Michael P.
Published: May 2020

Levels of protein translation by ribosomes are governed both by features of the translation machinery as well as sequence properties of the mRNAs themselves. We focus here on a striking three-nucleotide periodicity, characterized by overrepresentation of GCN codons and underrepresentation of G at the second position of codons, that is observed in Open Reading Frames (ORFs) of mRNAs. Our examination of mRNA sequences inSaccharomyces cerevisiaerevealed that this periodicity is particularly pronounced in the initial codons--the ramp region--of ORFs of genes with high protein expression. It is also found in mRNA sequences immediately following non-standard AUG start sites, located upstream or downstream of the standard annotated start sites of genes. To explore the possible influences of the ramp GCN periodicity on translation efficiency, we tested edited ramps with accentuated or depressed periodicity in two test genes,SKN7andHMT1. Greater conformance to (GCN)nwas found to significantly depress translation, whereas disrupting conformance had neutral or positive effects on translation. Our recent Molecular Dynamics analysis of a subsystem of translocating ribosomes in yeast revealed an interaction surface that H-bonds to the +1 codon that is about to enter the ribosome decoding center A site. The surface, comprised of 16S/18S rRNA C1054 and A1196 (E. colinumbering) and R146 of ribosomal protein Rps3, preferentially interacts with GCN codons, and we hypothesize that modulation of this mRNA-ribosome interaction may underlie GCN-mediated regulation of protein translation. Integration of our expression studies with large-scale reporter studies of ramp sequence variants suggests a model in which theC1054-A1196-R146 (CAR) interaction surface can act as both an accelerator and braking system for ribosome translation.