bluuebunny/crossref_metadata_2025 huggingface dataset:
Transformer's frequency response analysis results interpretation using a novel cross entropy based methodology
Authors: Parkash Chander , Abbasi Ali Reza
Published: April 2023

Transformer defects can be identified by the FRA (frequency response analysis) that is a promising diagnostic technique. Despite the standardization in FRA measuring technique, its results interpretation is yet a research area. Because different faults types can be identified in various frequency bounds of the FRA signatures, it is necessary to identify the possible relationships between specific failures and frequency ranges in this contribution. For this purpose, a real transformer is used to conduct the essential tests, which include both healthy and faulted circumstances (axial displacement (AD), radial deformation (RD), and short-circuits (SC)). To identify efficient characteristics from the produced frequency response traces and improve interpretation accuracy of such traces, a new hyperbolic fuzzy cross entropy (FCE) measure is demonstrated and then utilized for the aim of discrimination and classification of transformer winding defects in pre-defined frequency ranges. After normalizing FRA results of the transformer under healthy and various fault circumstances the lower bounds from such responses have been extracted and then utilized to construct the desired form of the fuzzy sets of healthy and faulted circumstances. Then, a new hyperbolic FCE measure-based discrimination and classification of winding faults methodology is offered on the basis of highest and lowest FCE measure values. The highest FCE measure value between the fuzzy sets of healthy and faulted circumstances such as AD, RD and SC is designated to confirm the occurrence of winding faults in a suitable frequency range. The suggested methodology ensures smart interpretation of FRA signature and accurate classification of winding faults as it can effectively discriminate both healthy and faulted circumstances in the desired frequency ranges. The proposed approaches' performance is tested and compared by applying the experimental data after feature extraction.
A novel CT image de-noising and fusion based deep learning network to screen for disease (COVID-19)
Authors: Khan Sajid Ullah , Ullah Imdad , Ullah Najeeb , Shah Sajid , Affendi Mohammed El , Lee Bumshik
Published: April 2023

A COVID-19, caused by SARS-CoV-2, has been declared a global pandemic by WHO. It first appeared in China at the end of 2019 and quickly spread throughout the world. During the third layer, it became more critical. COVID-19 spread is extremely difficult to control, and a huge number of suspected cases must be screened for a cure as soon as possible. COVID-19 laboratory testing takes time and can result in significant false negatives. To combat COVID-19, reliable, accurate and fast methods are urgently needed. The commonly used Reverse Transcription Polymerase Chain Reaction has a low sensitivity of approximately 60% to 70%, and sometimes even produces negative results. Computer Tomography (CT) has been observed to be a subtle approach to detecting COVID-19, and it may be the best screening method. The scanned image's quality, which is impacted by motion-induced Poisson or Impulse noise, is vital. In order to improve the quality of the acquired image for post segmentation, a novel Impulse and Poisson noise reduction method employing boundary division max/min intensities elimination along with an adaptive window size mechanism is proposed. In the second phase, a number of CNN techniques are explored for detecting COVID-19 from CT images and an Assessment Fusion Based model is proposed to predict the result. The AFM combines the results for cutting-edge CNN architectures and generates a final prediction based on choices. The empirical results demonstrate that our proposed method performs extensively and is extremely useful in actual diagnostic situations.
Bars and boxy/peanut bulges in thin and thick discs
Authors: Ghosh Soumavo , Fragkoudi Francesca , Di Matteo Paola , Saha Kanak
Published: April 2023

The Milky Way and a majority of external galaxies possess a thick disc. However, the dynamical role of the (geometrically) thick disc in the bar formation and evolution is not fully understood. Here, we investigate the effect of thick discs in the formation and evolution of bars by means of a suite of N-body models of (kinematically cold) thin and (kinematically hot) thick discs. We systematically varied the mass fraction of the thick disc, the thin-to-thick disc scale length ratio, and the thick disc scale height to examine the bar formation under diverse dynamical scenarios. Bars form almost always in our models, even in the presence of a massive thick disc. The part of the bar that consists of the thick disc closely follows the overall growth and temporal evolution of the part of the bar that consists of the thin disc, but the part of the bar in the thick disc is weaker than the part of the bar in the thin disc. The formation of stronger bars is associated with a simultaneous greater loss of angular momentum and a more intense radial heating. In addition, we demonstrate a preferential loss of angular momentum and a preferential radial heating of disc stars in the azimuthal direction within the extent of the bar in both thin and thick disc stars. For purely thick-disc models (without any thin disc), the bar formation critically depends on the disc scale length and scale height. A larger scale length and/or a larger vertical scale height delays the bar formation time and/or suppresses the bar formation almost completely in thick-disc-only models. We find that the Ostriker-Peeble criterion predicts the bar instability scenarios in our models better than the Efstathiou-Lake-Negroponte criterion.
Investigation of a wearable piezoelectric-IMU multi-modal sensing system for real-time muscle force estimation
Authors: Lu Yun , Cao Yudong , Chen Yi , Li Hui , Li Weihua , Du Haiping , Zhang Shiwu , Sun Shuaishuai
Published: April 2023

Piezoelectric based ultrasonic transducer shows a promising application prospect in the wearable muscle force estimator by detecting the morphological-biochemical peculiarity of human motion. However, due to the nonlinearity of muscle contraction, muscle force estimation in a dynamic motion, such as leg lifting, is still a challenge. In this study, a wearable multi-sensory system was developed for muscle force estimation in the isometric contraction assessment and during the dynamic training. A customized wearable ultrasound system was adopted for real-time deformation measurement of muscle, and an inertial measurement unit sensor was utilized to detect the joint angle. Thus, the muscle force can be predicted by identifying the muscle deformation as well as considering the muscle thickness change caused by the joint angel variation. The robustness and efficiency of the system was investigated by evaluating the muscle force of the rectus femoris during the isometric contraction assessment and the knee’s dynamic exercise. The accuracy of muscle force prediction is over 90%. During the knee’s dynamic exercise, the predicted force output of the lower-limb agreed well with the measured value, demonstrating the promising application of the system in dynamic muscle force estimation. This approach can provide real-time muscle force information for the patients to improve the rehabilitative training effect when using an exoskeletal rehabilitation robot as well as evaluate their recovery situation.
Triangle mechanism in the decay process
*
Authors: Lu Jialiang , Luo Xuan , Song Mao , Li Gang
Published: April 2023

The role of the triangle mechanism in the decay processes

and

is probed. In these processes, the triangle singularity appears from the decay of

into

, and then, ϕ decays into

and

merged into

or

, which finally decay into

and

, respectively. We find that this mechanism leads to a triangle singularity around

and gives sizable branching fractions

and

. This investigation can help us obtain the information of the scalar meson

or

.
Ecological factors related to seed germination and early seedling establishment inUlmus minorMill., an endangered riparian tree species
Authors: López-Almansa Juan Carlos
Published: April 2023

Natural populations of Ulmus minor Mill., an outstanding component of European riparian forests, are endangered due to Dutch elm disease, which has led to the development of several breeding programs throughout Europe. However, the reproductive ecology of this species is scarcely known even though sexual regeneration is an essential factor that must be understood before implementing elm stand restoration. In this paper, the main ecological factors affecting seed germination and early seedling establishment in U. minor are studied through a factorial design with five different factors: Light (levels: Full-sun, Shade), Initial water (levels: Initially-flooded, Initially-irrigated), Subsequent water (levels: Semi-submerged, Later-irrigated), Soil cover (levels: Bare-soil, Litter) and Substrate (levels: Silty-clay, Sandy-loam). Seed germination and seedling survival were monitored for 7 weeks. All factors except Initial water and Substrate turned out to be highly significant. Shade increased seed germination and seedling survival. Response to Initial water fluctuated, with an early higher percentage of germinated seeds in Initially-flooded but a higher seedling survival in Initially-irrigated. Subsequent water did not affect seedling establishment and survival, but Semi-submerged treatments increased seed germination. Bare-soilincreased seed germination too, whereas, in the medium term, Litter affected positively seedling survival. Sandy-loam substrates favoured seed germination, but Silty-claysubstrates favoured seedling survival. Together, these results suggest that the most favourable scenario for U. minor sexual regeneration may be a combination of a not-too-severe late-winter or early-spring flood followed by a wet spring and summer, probably with a higher establishment in heavy-textured substrates located in small gaps and forest edges where the overstorey provides some protection against strong sunlight.
quEHRy: a question answering system to query electronic health records
Authors: Soni Sarvesh , Datta Surabhi , Roberts Kirk
Published: April 2023

Objective

We propose a system, quEHRy, to retrieve precise, interpretable answers to natural language questions from structured data in electronic health records (EHRs).

Materials and Methods

We develop/synthesize the main components of quEHRy: concept normalization (MetaMap), time frame classification (new), semantic parsing (existing), visualization with question understanding (new), and query module for FHIR mapping/processing (new). We evaluate quEHRy on 2 clinical question answering (QA) datasets. We evaluate each component separately as well as holistically to gain deeper insights. We also conduct a thorough error analysis for a crucial subcomponent, medical concept normalization.

Results

Using gold concepts, the precision of quEHRy is 98.33% and 90.91% for the 2 datasets, while the overall accuracy was 97.41% and 87.75%. Precision was 94.03% and 87.79% even after employing an automated medical concept extraction system (MetaMap). Most incorrectly predicted medical concepts were broader in nature than gold-annotated concepts (representative of the ones present in EHRs), eg, Diabetes versus Diabetes Mellitus, Non-Insulin-Dependent.

Discussion

The primary performance barrier to deployment of the system is due to errors in medical concept extraction (a component not studied in this article), which affects the downstream generation of correct logical structures. This indicates the need to build QA-specific clinical concept normalizers that understand EHR context to extract the “relevant” medical concepts from questions.

Conclusion

We present an end-to-end QA system that allows information access from EHRs using natural language and returns an exact, verifiable answer. Our proposed system is high-precision and interpretable, checking off the requirements for clinical use.
Weakly supervised spatial relation extraction from radiology reports
Authors: Datta Surabhi , Roberts Kirk
Published: April 2023

Objective

Weak supervision holds significant promise to improve clinical natural language processing by leveraging domain resources and expertise instead of large manually annotated datasets alone. Here, our objective is to evaluate a weak supervision approach to extract spatial information from radiology reports.

Materials and Methods

Our weak supervision approach is based on data programming that uses rules (or labeling functions) relying on domain-specific dictionaries and radiology language characteristics to generate weak labels. The labels correspond to different spatial relations that are critical to understanding radiology reports. These weak labels are then used to fine-tune a pretrained Bidirectional Encoder Representations from Transformers (BERT) model.

Results

Our weakly supervised BERT model provided satisfactory results in extracting spatial relations without manual annotations for training (spatial trigger F1: 72.89, relation F1: 52.47). When this model is further fine-tuned on manual annotations (relation F1: 68.76), performance surpasses the fully supervised state-of-the-art.

Discussion

To our knowledge, this is the first work to automatically create detailed weak labels corresponding to radiological information of clinical significance. Our data programming approach is (1) adaptable as the labeling functions can be updated with relatively little manual effort to incorporate more variations in radiology language reporting formats and (2) generalizable as these functions can be applied across multiple radiology subdomains in most cases.

Conclusions

We demonstrate a weakly supervision model performs sufficiently well in identifying a variety of relations from radiology text without manual annotations, while exceeding state-of-the-art results when annotated data are available.
Metrics in action: how social media metrics shape news production on Facebook
Authors: Mukerjee Subhayan , Yang Tian , Peng Yilang
Published: April 2023

Social media metrics allow media outlets to get a granular, real-time understanding of audience preferences, and may therefore be used to decide what content to prioritize in the future. We test this mechanism in the context of Facebook, by using topic modeling and longitudinal data analysis on a large dataset comprising all posts published by major media outlets used by American citizens (N≈2.23M, 2015–2019). We find that while the overall effect of audience engagement on future news coverage is significant, there is substantial heterogeneity in how individual outlets respond to different kinds of topics. A handful of right-wing media outlets are more likely to respond to audience engagement metrics than other outlets, but with partisan politics topics and not with entertainment-oriented content. Our research sheds new light on how social media platforms have shaped journalistic practices and has implications for the future health of journalism in the United States.
Families of choice with no choice: remarks concerning the situation of families of choice in Polish law
Authors: Drapalska-Grochowicz Marlena
Published: April 2023

This article focuses on the situation of families of choice in Polish law. The first research objective was to determine whether and how parenting in families of choice is regulated by law. To achieve this goal, the author analysed appropriate statute and case law, taking into account the sociological and psychological background of family relationships. The second objective was to find legal and non-legal factors affecting the current situation of families of choice in Polish law. Then it was assessed whether it is possible to provide court protection to the families of choice in the process of applying current regulations. This article shows that although the Polish legislator considers family life an important value, it is restricted to a specific understanding of family. Neither the Polish legislator nor the legal discourse recognize the needs of the families of choice, and the chances of changing the current situation are small.
A new approach for the construction of historical databases—NoSQL Document-oriented databases: the example ofAtlantoCracies
Authors: Diaz-Ordoñez Manuel , Rodríguez Baena Domingo Savio , Yun-Casalilla Bartolomé
Published: April 2023

This article proposes, and justifies, the use of the Document-oriented databases as a flexible, easy to use, and powerful digital tool in the field of historical research. First, the reasons that have made relational databases the predominant instrument among historians are studied, while detailing the problems involved in their use. Next, the way in which historians have tried to face these problems by using other digital tools is explained, as well as the limitations that such use entails. Through a case study—that of European aristocratic networks in early modern times—it is shown, however, that Document-oriented databases, present notable advantages and have greater explanatory power for the historian’s work. Thanks to their flexibility, they are better adapted to the often-unpredictable nature of historical sources without diminishing their ease of use or their analytical potential.
Proverbs as indicators of proficiency for art-generating AI
Authors: Tosina Fernández Luis J
Published: April 2023

Art generated by Artificial Intelligence (AI) is currently having great repercussion online. The reason for this is the fact that it allows people without creative talent to produce outstanding works by just typing in the description of what they want to illustrate. However, the appearance of this technology has also caused some discomfort among artists and graphic designers, who see their craft threatened by a service that is available to anyone free of charge. In this article, the capability of some of these platforms to process figurative language will be assessed with the help of five well-known proverbs found in almost identical terms across a number of Western languages. These proverbs were used as the prompts on five of the most popular AI art generators accessible at present. After analyzing the results, our experiment concludes that AI evidences significant deficiencies in the processing of proverbs and, therefore, of figurative language. Consequently, AI does not seem able to substitute human agency completely in artistic creation yet. This exposes an aspect that needs improvement not just for the creative applications of AI but for other applications that it may have in the future. To achieve this, disciplines such as psycholinguistics should be integrated into the teams that develop AI.
Structural adjustment and the political economy of capital flight
Authors: Nosrati Elias , Kern Andreas , Reinsberg Bernhard , Sevinc Dilek
Published: April 2023

The financial haemorrhaging of lower income countries in the form of capital flight is a leading cause of global economic inequality. On an annual basis, trillions of dollars bypass the already starved fiscal spaces of nations mired in poverty, making their way instead to lucrative offshore bank accounts governed by secrecy jurisdictions. The present article relates this phenomenon to the institutional architecture of the global financial system and provides causal evidence that structural adjustment programmes implemented at the behest of international financial organizations amplify such capital flight. In particular, by isolating exogenous variation in policy conditionalities through the use of instrumental variables, we find that trade liberalization, financial sector reforms and privatization measures mandated by the International Monetary Fund in developing contexts substantially increase financial outflows occurring via current and capital account transactions. Our findings thus document the contribution that structural adjustment makes to an underappreciated facet of contemporary global inequality.
Molecular subtypes of respiratory Adenovirus infection outbreak in children in Northern Vietnam and risk factors of more severe cases
Authors: Nguyen Dinh-Dung , Phung Lan Tuyet , Thanh Tran Huyen Thi , Thanh Ly Ha Thi , Mai Vo Anh Hang , Dinh Nhung Phuong , Doan Phuong Mai , Nguyen Anh Thi , Dang Luc Danh , Doan Thia Thi , Pham Khuong Thi , Pham Huong Lan , Xuan Dai Hoang , Nguyen Thao Phuong , Tran Bao Thai , Thuc Tran Trang Thi , Minh Le Huong Thi , Pham An Nhat , Antoniou Antony , Ho Nhan Thi
Published: April 2023

Background

Under the pressure of the outbreak of respiratory Human Adenovirus (HAdV) infections in children in Northern Vietnam in the end of 2022, this study was initiated to identify the HAdV subtype(s) responsible for the outbreak in relation to the clinical features of the patients and examine the risk factors of more severe cases.

Methods

The study was conducted on pediatric patients tested positive with HAdV using multiplex real- time PCR between October and November 2022. Nasal swab samples were used for sequencing to identify HAdV subtypes and clinical data were collected retrospectively.

Results

Among 97 successfully sequenced samples, the predominant subtypes were HAdV-B3 (83%), HAdV-B7 (16%) and HAdV-C2 (1%). Lower respiratory manifestations were found in 25% of patients (5% with severe pneumonia). There was no significant association between HAdV type and clinical features except that those infected with HAdV type 3 exhibited higher WBC and neutrophil % (p<0.001). Co- infection of HAdV with ≥1 other respiratory viruses or bacteria was found in 70.8% of those with lower respiratory illnesses (OR (95%CI); p-value vs. those without =5.21 (1.60, 19.36); 0.0084 after adjusting for age at hospital visit, sex, birth delivery method, day of disease at hospital visit), and in 100% of those with severe pneumonia vs. 33% of those without (p=0.005).

Conclusion

HAdV-B3 and HAdV-B7 were predominant in the outbreak. Co-infection of HAdV together with other respiratory viruses or bacteria was a strong risk factor for lower respiratory tract illnesses and severe pneumonia. The findings advocate the advantages of multi-factor microbial panels for the diagnosis and prognosis of respiratory infections in children.
Transgenic female mice producingtrans10,cis12-conjugated linoleic acid present excessive prostaglandin E2, adrenaline, corticosterone, glucagon, and FGF21
Authors: Rao Yu , Liang Lu-Wen , Li Mei-Juan , Wang Yang-Yang , Wang Bao-Zhu , Gou Ke-Mian
Published: April 2023

Dietarytrans10,cis12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.
Interplay of two small RNAs fine-tunes hierarchical flagellar gene expression in the foodborne pathogenCampylobacter jejuni
Authors: König Fabian , Svensson Sarah L. , Sharma Cynthia M.
Published: April 2023

Like for many enteric bacteria, flagella are a crucial virulence factor for the foodborne pathogenCampylobacter jejuni, allowing the bacteria to move through the viscous mucus of the human intestine. Assembly of the complex flagellar machinery and filament requires hierarchical regulation via transcriptional control of each component. InC. jejuni, class I genes are transcribed from σ70-dependent promoters and class II/III genes with the help of the alternative sigma factors RpoN (σ54) and FliA (σ28). In contrast to transcriptional control, less is known about post-transcriptional regulation of flagellar biosynthesis cascades via small regulatory RNAs (sRNAs). Here, we characterized two sRNAs with opposing effects on the cascade that fine-tuneC. jejuniflagellar filament assembly and thereby impact motility. We demonstrate that the highly conservedCampylobactersRNA CJnc230 (FlmE, flagellar length andmotilityenhancer), encoded downstream of the flagellar hook structural protein FlgE, is dependent on RpoN and that RNase III processes CJnc230 from theflgEmRNA, while RNase Y and PNPase mature its 3’ end. We identify mRNAs encoding a regulator of flagella-flagella interactions and the anti-σ28factor FlgM as direct targets of CJnc230 repression. Overexpression of CJnc230 de-represses FliA activity and upregulates class III flagellar genes, such as the major flagellinflaA, culminating in longer flagella and increased motility. In contrast, overexpression of the FliA-dependent sRNA CJnc170 (FlmR, flagellar length andmotilityrepressor) reduces flagellar length and motility. Overall, our study demonstrates sRNA-mediated post-transcriptional regulation fine-tunesC. jejuniflagellar biosynthesis through balancing of the hierarchically expressed components.
A mobile CRISPRi collection enables genetic interaction studies for the essential genes ofEscherichia coli
Authors: Rachwalski Kenneth , Tu Megan M , Madden Sean J , Hansen Drew M , Brown Eric D
Published: April 2023

Ordered collections of precise gene deletions inE. coliand other model microbes have proven to be invaluable resources to study the dispensability of the non-essential genome in different environmental and genetic contexts. The dispensability of canonically essential genes, however, has been largely unstudied in such contexts. Advances in gene editing, in particular CRISPR interference (CRISPRi), have enabled depletion of essential cellular machinery to study the downstream effects on bacterial physiology. Here, we describe the construction of an orderedE. coliCRISPRi collection, designed to knock down the expression of 356 essential genes with the induction of a catalytically inactive Cas9, harbored on the conjugative plasmid pFD152, that also encodes for expression of specific guide RNA scaffolds. This mobile CRISPRi library can be conjugated into other ordered genetic libraries, to assess combined effects of essential gene knockdowns with non-essential gene deletions. As proof of concept, we probed cell envelope synthesis with two crosses. First, we crossed a deletion in the genelppwith the entire CRISPRi library. Similarly, we crossed the CRISPRi knockdown oflolAwith ∼4,000 deletion strains of the Keio collection. These experiments revealed a number of notable genetic interactions for the essential phenotype probed and, in particular, showed supressing interactions for the loci in question.
Chemical stimuli override a temperature-dependent morphological program by reprogramming the transcriptome of a fungal pathogen
Authors: Assa Dror , Voorhies Mark , Sil Anita
Published: April 2023

The human fungal pathogenHistoplasmachanges its morphology in response to temperature. At 37°C it grows as a budding yeast whereas at room temperature it transitions to hyphal growth. Prior work has demonstrated that 15-20% of transcripts are temperature-regulated, and that transcription factors Ryp1-4 are necessary to establish yeast growth. However, little is known about transcriptional regulators of the hyphal program. To identify TFs that regulate filamentation, we utilize chemical inducers of hyphal growth. We show that addition of cAMP analogs or an inhibitor of cAMP breakdown overrides yeast morphology, yielding inappropriate hyphal growth at 37°C. Additionally, butyrate supplementation triggers hyphal growth at 37°C. Transcriptional profiling of cultures filamenting in response to cAMP or butyrate reveals that a limited set of genes respond to cAMP while butyrate dysregulates a larger set. Comparison of these profiles to previous temperature- or morphology-regulated gene sets identifies a small set of morphology-specific transcripts. This set contains 9 TFs of which we characterized three,STU1,FBC1, andPAC2, whose orthologs regulate development in other fungi. We found that each of these TFs is individually dispensable for room-temperature (RT) induced filamentation but each is required for other aspects of RT development.FBC1andPAC2, but notSTU1, are necessary for filamentation in response to cAMP at 37°C. Ectopic expression of each of these TFs is sufficient to induce filamentation at 37°C. Finally,PAC2induction of filamentation at 37°C is dependent onSTU1, suggesting these TFs form a regulatory circuit that, when activated at RT, promotes the hyphal program.

Importance

Fungal illnesses pose a significant disease burden. However, the regulatory circuits that govern the development and virulence of fungi remain largely unknown. This study utilizes chemicals that can override the normal growth morphology of the human pathogenHistoplasma. Using transcriptomic approaches, we identify novel regulators of hyphal morphology and refine our understanding of the transcriptional circuits governing morphology inHistoplasma.
Transcriptional dissection of symptomatic profiles across the brain of men and women with depression
Authors: Mansouri Samaneh , Pessoni André M , Rivera Arturo M , Tamminga Carol A. , Parise Eric , Turecki Gustavo , Nestler Eric J. , Chen Ting-Huei , Labonté Benoit
Published: April 2023

Major depressive disorder (MDD) is one of the most important causes of disability worldwide. While recent work provides insights into the molecular alterations in the brain of patients with MDD, whether these molecular signatures can be associated with the expression of specific symptom domains in males and females remains unclear. Here, we identified sex-specific gene modules associated with the expression of MDD, combining differential gene expression and co-expression network analyses in six cortical and subcortical brain regions. Our results show varying levels of network homology between males and females across brain regions, although the association between these structures and the expression of MDD remains highly sex-specific. We refined these associations to several symptom domains and identified transcriptional signatures associated with distinct functional pathways, including GABAergic and glutamatergic neurotransmission, metabolic processes, and intracellular signal transduction, across brain regions associated with distinct symptomatic profiles in a sex-specific fashion. In most cases, these associations were specific to males or to females with MDD, although a subset of gene modules associated with common symptomatic features in both sexes was also identified. Together, our findings suggest that the expression of distinct MDD symptom domains is associated with sex-specific transcriptional structures across brain regions.
Structure of a dimeric ABC transporter
Authors: Bickers Sarah C. , Benlekbir Samir , Rubinstein John L. , Kanelis Voula
Published: April 2023

ATP binding cassette (ABC) proteins generally couple ATP hydrolysis to the active transport of solutes across cellular membranes. All ABC proteins contain a core structure of two transmembrane domains (TMD1, TMD2) and two nucleotide binding domains (NBD1, NBD2), and many ABC proteins contain additional domains. Some members of the C subfamily of ABC (ABCC) proteins, such as the multidrug resistant protein 1 (MRP1), contain an N-terminal transmembrane domain (TMD0) and L0 linker that regulate transport activity and cellular trafficking, and mediate interactions with other proteins. Regulation can also be imparted by phosphorylation, proteolytic processing, and/or oligomerization of the proteins. Here we present the structure of yeast cadmium factor 1 (Ycf1p), a homologue of MRP1, in its mature form following cleavage by the yeast protease Pep4p. Remarkably, proteolytically cleaved Ycf1p forms a well-ordered dimer, with some monomeric particles also present in solution. Numerous other ABC proteins have been proposed to form dimers but no high-resolution structures have been reported. The monomeric and dimeric Ycf1p species are differentially phosphorylated at the intrinsically disordered regulatory (R) region, which links NBD1 to TMD2, and possess different ATPase activities indicating that dimerization affects the function of the protein. Protein-protein interactions involving TMD0, the L0 linker, and the R region mediate contacts between Ycf1p protomers in the dimer. In addition, cryo-EM density is observed for lipids at the interface between protomers, which suggests that lipids stabilize the dimer. The Ycf1p dimer structure is consistent with proposed dimerization interfaces of other ABCC dimers, such as MRP1.
Dietary phenolics and their microbial metabolites are poor inhibitors of trimethylamine oxidation to trimethylamine N-oxide by hepatic flavin monooxygenase 3
Authors: Iglesias-Carres Lisard , Chadwick-Corbin Sydney A. , Sweet Michael G. , Neilson Andrew P.
Published: April 2023

High circulating levels of trimethylamine N-oxide (TMAO) have been associated with cardiovascular disease risk. TMAO is formed through a microbiome-host pathway utilizing primarily dietary choline as a substrate. Specific gut microbiota transform choline into trimethylamine (TMA), and, when absorbed, host hepatic flavin-containing monooxygenase 3 (FMO3) oxidizes TMA into TMAO. Chlorogenic acid and its metabolites reduce microbial TMA productionin vitro. However, little is known regarding the potential for chlorogenic acid and its bioavailable metabolites to inhibit the last step: hepatic conversion of TMA to TMAO. We developed a screening methodology to study FMO3-catalyzed production of TMAO from TMA. HepG2 cells were unable to oxidize TMA into TMAO due to their lack of FMO3 expression. Although Hepa-1 cells did express FMO3 when pre-treated with TMA and NADPH, they lacked enzymatic activity to produce TMAO. Rat hepatic microsomes contained active FMO3. Optimal reaction conditions were: 50 µM TMA, 0.2 mM NADPH and 33 µL microsomes/mL reaction. Methimazole (a known FMO3 competitive substrate) at 200 µM effectively reduced FMO3-catalyzed conversion of TMA to TMAO. However, bioavailable chlorogenic acid metabolites did not generally inhibit FMO3 at physiological (1 µM) nor supra-physiological (50 µM) doses. Thus, the effects of chlorogenic acid in regulating TMAO levelsin vivoare unlikely to occur through direct FMO3 enzyme inhibition. Potential effects on FMO3 expression remain unknown. Intestinal inhibition of TMA production and/or absorption are thus likely their primary mechanisms of action.
Association of inflammation and tissue damage induced biological processes in masseter muscle with the resolution of chronic myalgia
Authors: Lindquist Karen A. , Shein Sergey A. , Hovhannisyan Anahit H. , Mecklenburg Jennifer , Zou Yi , Lai Zhao , Tumanov Alexei V. , Akopian Armen N.
Published: April 2023

Biological processes linked to intramuscular inflammation during myogenous temporomandibular disorder (TMDM) are largely unknown. We mimicked this inflammation by intra-masseteric muscle (MM) injections of complete Freund’s adjuvant (CFA) or collagenase type 2 (Col), which emulates tissue damage. CFA triggered mechanical hypersensitivity at 1d post-injection was mainly linked to processes controlling chemotactic activity of monocytes and neutrophils. At 5d post-CFA, when hypersensitivity was resolved, there was minimal inflammation whereas tissue repair processes were pronounced. Low dose Col (0.2U) also produced acute orofacial hypersensitivity that was linked to tissue repair, but not inflammatory processes. High dose Col (10U) triggered prolonged orofacial hypersensitivity with inflammatory processes dominating at 1d post-injection. At pre-resolution time point (6d), tissue repair processes were underway and a significant increase in pro-inflammatory gene expressions compared to 1d post-injection were detected. RNA-seq and flow cytometry showed that immune processes in MM were linked to accumulation of macrophages, natural killer and natural killer T cells, dendritic cells and T-cells. Altogether, CFA and Col treatments induced different immune processes in MM. Importantly, orofacial hypersensitivity resolution was preceded with repairs of muscle cell and extracellular matrix, an elevation in immune system gene expression and accumulation of distinct immune cells in MM.
High prevalence of antibiotic resistance in traditionally fermented foods as a critical risk factor for host gut antibiotic resistome
Authors: Li Yutong , Fu Siying , Klein Matthias S. , Wang Hua
Published: April 2023

Disrupted gut microbiota as a critical risk factor for many noncommunicable diseases is largely driven by gut microbiota-impacting drugs, especially orally administrated as well as biliary excreted antibiotics. Fermented food consumption has been encouraged to replenish disrupted gut microbiota, but its overall impact on host gut health remains to be elucidated. This study examined retail traditionally fermented foods and gut microbiota of consumers of fermented foods for antibiotic resistome. Dietary intervention by fermented foods was found leading to a surge of the antibiotic resistome in gut microbiota of most human subjects. Antibiotic resistome was further illustrated in traditionally fermented food samples, and viable antibiotic resistant (AR) bacteria were recovered and highly prevalent in retail kimchi and artisan cheeses assessed in this pilot screening. Identified AR isolates included pathogens of importance in nosocomial infections such asKlebsiella pneumoniae,Enterococcus, etc., as well as commensals and lactic acid bacteria, some exhibited extremely high minimum inhibitory concentration (MIC) against antibiotics of clinical significance. Exposing fermented food microbiota to representative antibiotics further led to a boost of the corresponding antibiotic and multidrug-resistance gene pools and disturbed microbiota. These results revealed an underestimated public health risk associated with fermented foods intervention, particularly to susceptible population with gastrointestinal tract symptoms and compromised immune functions seeking gut microbiota rescue. The findings call for more comprehensive investigation and investment on the benefits and potential safety challenges associated with traditionally fermented foods, productive intervention of foodborne antibiotic resistance, and strategic movements to mitigate unnecessary damages to the host gut microbiota.
AFLOWERING LOCUS Tortholog is associated with photoperiod-insensitive flowering in hemp (Cannabis sativaL.)
Authors: Dowling Caroline A. , Shi Jiaqi , Toth Jacob A. , Quade Michael A. , Smart Lawrence B. , McCabe Paul F. , Melzer Rainer , Schilling Susanne
Published: April 2023

Hemp (Cannabis sativaL.) is an extraordinarily versatile crop, with applications ranging from medicinal compounds to seed oil and fibre products.Cannabis sativais a short-day plant, and its flowering is tightly controlled by photoperiod. However, substantial genetic variation exists for photoperiod sensitivity inC. sativa,and photoperiod-insensitive (“autoflower”) cultivars are available.

Using a bi-parental mapping population and bulked segregant analysis, we identifiedAutoflower2, a 0.5 Mbp locus significantly associated with photoperiod-insensitive flowering in hemp.Autoflower2contains an ortholog of the central flowering time regulatorFLOWERING LOCUS T(FT) fromArabidopsis thalianawhich we termedCsFT1. Extensive sequence divergence between alleles ofCsFT1was identified between photoperiod-sensitive and insensitive cultivars ofC. sativa, including a duplication ofCsFT1and sequence differences especially in introns. Genotyping of several mapping populations and a diversity panel confirmed a strong correlation betweenCsFT1alleles and photoperiod response as well as affirming that at least two independent loci for this agriculturally important trait,Autoflower1andAutoflower2, exist in theC. sativagene pool.

This study reveals the multiple independent origins of photoperiod insensitivity inC. sativa,supporting the likelihood of a complex domestication history in this species. By integrating the genetic relaxation of photoperiod sensitivity into novelC. sativacultivars, expansion to higher latitudes will be permitted, thus allowing the full potential of this versatile crop to be reached.
Isoform-specific translational control is evolutionarily conserved in primates
Authors: Draper Jolene , Philipp Julia , Neeb Zach , Thomas Richard , Katzman Solomon , Salama Sofie , Haussler David , Sanford Jeremy R.
Published: April 2023

Alternative splicing (AS) alters messenger RNA (mRNA) coding capacity, localization, stability, and translation. Here we use comparative transcriptomics to identify cis-acting elements coupling AS to translational control (AS-TC). We sequenced total cytosolic and polyribosome-associated mRNA from human, chimpanzee, and orangutan induced pluripotent stem cells (iPSCs), revealing thousands of transcripts with splicing differences between subcellular fractions. We found both conserved and species-specific polyribosome association patterns for orthologous splicing events. Intriguingly, alternative exons with similar polyribosome profiles between species have stronger sequence conservation than exons with lineage-specific ribosome association. These data suggest that sequence variation underlies differences in the polyribosome association. Accordingly, single nucleotide substitutions in luciferase reporters designed to model exons with divergent polyribosome profiles are sufficient to regulate translational efficiency. We used position specific weight matrixes to interpret exons with species-specific polyribosome association profiles, finding that polymorphic sites frequently alter recognition motifs for trans-acting RNA binding proteins. Together, our results show that AS can regulate translation by remodeling the cis-regulatory landscape of mRNA isoforms.
Sensory Eye Dominance Plasticity in the Human Adult Visual Cortex
Authors: Kam Ka Yee , Chang Dorita H. F.
Published: April 2023

Sensory eye dominance occurs when the visual cortex weighs one eye’s data more heavily than those of the other. Encouragingly, mechanisms underlying sensory eye dominance in human adults retain a certain degree of plasticity. Notably, perceptual training using dichoptically presented motion signal-noise stimuli has been shown to elicit changes in sensory eye dominance both in visually impaired and normal observers. However, the neural mechanisms underlying these learning-driven improvements are not well understood. Here, we measured changes in fMRI responses before and after a five-day visual training protocol to determine the neuroplastic changes along the visual cascade. Fifty visually normal observers received training on a dichoptic or binocular variant of a signal-in-noise (left-right) motion discrimination task over five consecutive days. We show significant shifts in sensory eye dominance following training, but only for those who received dichoptic training. Pattern analysis of fMRI responses revealed that responses of V1 and hMT+ predicted sensory eye dominance for both groups, but only before training. After dichoptic (but not binocular) visual training, responses of V1 and hMT+ could no longer predict sensory eye dominance. Our data suggest that perceptual training-driven changes in eye dominance are driven by a reweighting of the two eyes’ data in both primary and task-related extrastriate visual areas. These findings may provide insight into developing region-targeted rehabilitative paradigms for the visually impaired, particularly those with severe binocular imbalance.
Uniform cerebral organoid culture on a pillar plate by simple and reproducible spheroid transfer from an ultralow attachment well plate
Authors: Acharya Prabha , Joshi Pranav , Shrestha Sunil , Choi Na Young , Jeong Sehoon , Lee Moo-Yeal
Published: April 2023

Human induced pluripotent stem cell (iPSCs)-derived brain organoids have potential to recapitulate the earliest stages of brain development, serving as an effectivein vitromodel for studying both normal brain development and disorders. However, current brain organoid culture methods face several challenges, including low throughput, high variability in organoid generation, and time-consuming, multiple transfer and encapsulation of cells in hydrogels throughout the culture. These limitations hinder the widespread application of brain organoids including high-throughput assessment of compounds in clinical and industrial lab settings. In this study, we demonstrate a straightforward approach of generating multiple cerebral organoids from iPSCs on a pillar plate platform, eliminating the need for labor-intensive, multiple transfer and encapsulation steps to ensure the reproducible generation of cerebral organoids. We formed embryoid bodies (EBs) in an ultra-low attachment (ULA) 384-well plate and subsequently transferred them to the pillar plate containing Matrigel, using a straightforward sandwiching and inverting method. Each pillar on the pillar plate contains a single spheroid, and the success rate of spheroid transfer was in a range of 95 - 100%. By differentiating the EBs on the pillar plate, we achieved robust generation of cerebral organoids with a coefficient of variation (CV) below 19%. Notably, our spheroid transfer method in combination with the pillar plate allows miniaturized culture of cerebral organoids, alleviates the issue of organoid variability, and has potential to significantly enhance assay throughput by allowingin situorganoid assessment as compared to conventional organoid culture in 6-/24-well plates, petri dishes, and spinner flasks.
Progesterone is an Inducement of Heritable Pulmonary Arterial Hypertension with BMPR2 Mutation
Authors: Hu Wei-Ping , Zhang Si-Jin , Ding Yong-Jie , Fang Jie , Zhou Ling , Xie Si-Min , Ge Xiao , Fu Li-Jun , Li Qing-Yun , Qu Jie-Ming , Li Shan-Qun , Liu Dong
Published: April 2023

Background

Bone morphogenetic protein type II receptor (BMPR2) gene mutation accounts for 80% of patients with heritable pulmonary artery hypertension (HPAH), and female mutation carriers have significantly higher penetrance rate than males. The inducement of HPAH penetrance and the mechanism of sex differential penetrance are still elusive.

Methods

We infected or transfected pulmonary artery smooth muscle cells (PASMCs) with shBMPR2 lentivirus or siBMPR2 to simulate the pathologic condition of BMPR2 heterozygous mutation and treated them with progesterone. The HPAH patient-derived induced pluripotent stem cells (iPSCs) were induced into vascular smooth muscle cells (VSMCs) to further verify the cellular phenotype. Wild-type flox+/-female mice and SM22-cre BMPR2 flox+/-female mice (CKO mice) were administered with 1-month progesterone, and their phenotype of PAH was evaluated by right heart catheterization and histopathological examination.

Results

Progesterone promoted the proliferation of PASMCs with BMPR2-knockdownby activating ERK pathway via progesterone receptor (PGR). Activated ERK not only upregulated the phosphorylation and elevation of cMYC, but also induced the transcription of endothelin (EDN1) by promoting the nuclear entry of c-JUN and combination on the its promoter region. Similar results were confirmed by iPSCs-VSMCs experiment. CKO mice developed PAH spontaneously and had increased expression of EDN1, which was further aggravated by exogenous progesterone.

Conclusions

Progesterone might be an inducement of HPAH penetrance caused by BMPR2 mutation, accounting for sex differential penetrance.