bluuebunny/crossref_metadata_2025 huggingface dataset:
Racial/Ethnic Disparities in Youth Mental Health Traits and Diagnoses within a Community-based Sample
Authors: Dissanayake Andrew , Dupuis Annie , Burton Christie , Soreni Noam , Peters Paul , Gajaria Amy , Arnold Paul D. , Crosbie Jennifer , Schachar Russell
Published: February 2023

Background

Racial/ethnic disparities in the prevalence of mental health diagnoses have been reported but have not accounted for the prevalence of the traits that underlies these disorders. Examining rates of diagnoses in relation to traits may yield a clearer understanding of how racial/ethnic youth differ in their access to assessment and care. We sought to examine differences in self/parent-reported rates of diagnoses for obsessive-compulsive disorder (OCD), attention-deficit/ hyperactivity disorder (ADHD), and anxiety disorders after adjusting for differences in trait levels between youth from three racial/ethnic groups: White, South Asian, and East Asian.

Methods

We collected parent or self-reported ratings of OCD, ADHD and anxiety traits and diagnoses for youth (6-17 years) from a general population sample (Spit for Science). We examined racial/ethnic differences in trait levels and the odds of reporting a diagnosis using mixed-effects linear models and logistic regression models.

Results

East Asian (N = 1301) and South Asian (N = 730) youth reported significantly higher levels of OCD and anxiety traits than White youth (N = 6896). Given the same trait level, East Asian and South Asian youth had significantly lower odds of reporting a diagnosis for OCD (Odds Ratio (OR)East Asian= 0.08 [0.02, 0.41] ; ORSouth Asian= 0.05 [0.00, 0.81]), ADHD (OREast Asian= 0.27 [0.16, 0.45]; ORSouth Asian= 0.09 [0.03, 0.30]), and Anxiety (OREast Asian= 0.21 [0.11, 0.39]; ORSouth Asian= 0.12 [0.05, 0.32]) than White youth.

Conclusions

These results suggest a discrepancy between traits-levels of OCD and anxiety and rates of diagnoses for East Asian and South Asian youth. This discrepancy may be due to increased barriers for ethnically diverse youth to access mental health care. Efforts to understand racial/ethnic barriers to care are needed.

Key Points

Despite having lower prevalence of diagnoses, East and South Asian youth reported significantly higher anxiety and OCD trait levels than White youth

Given the same trait level, East Asian youth were at 92% lower odds of having received an OCD diagnosis, 73% lower odds of having received an ADHD diagnosis, and 79% lower odds of having received an Anxiety diagnosis than White youth

Given the same trait level, South Asian youth were at 95% lower odds of having received an OCD diagnosis, 91% lower odds of having received an ADHD diagnosis, and 88% lower odds of having received an anxiety diagnosis

Future research is needed to understand barriers to mental health care and assessment that may underly the discrepancy between mental health traits and diagnoses for ethnic/racially diverse youth.
Antibiotic utilisation and the impact of antimicrobial resistance action plan on prescribing among older adults in New Zealand between 2005 and 2019
Authors: Chinzowu Tichawona , Chyou Te-yuan , Roy Sandipan , Jamieson Hamish , Nishtala Prasad S
Published: February 2023

Purpose

The objectives of this study were to examine the overall utilisation of systematic antibiotics and the impact of the launch of the antimicrobial resistance action plan in older adults (65 years or more) living in New Zealand between 2005 and 2019, using data from a national database (Pharmaceutical collections), stratified by antibiotic class, patient age, and sex.

Methods

Population-level systemic antibiotic dispensing data for older adults in New Zealand was analysed using repeated cross-sectional analysis between 01/01/2005 and 31/12/2019. Data were extracted on the prescribed systemic antibiotics using a unique identifier for each case. Antibiotic utilisation was measured in DDD/TOPD values. In addition, an interrupted time series (ITS) analysis using the autoregressive integrated moving average (ARIMA) models was performed to determine the impact of the antimicrobial resistance action plan.

Results

Most of the antibiotic classes included in this study showed a significant overall decrease in utilisation ranging from 38.64% for sulphonamides to 80.64% for fluoroquinolones compared to 2005. Systemic antibiotic utilisation decreased by 49.6% from the predicted usage between January 2018 and December 2019 following the launch of the antimicrobial resistance action plan. ARIMA model supported the reduction in utilisation with a step change of -0.2206 and slope change of -0.0029.

Conclusions

The ITS analysis has demonstrated that the intervention may have hugely impacted the antibiotic utilisation rate among older adults. Further studies are required to determine whether the reduced consumption rates of antibiotics are associated with reduced rates of antibiotic-associated adverse drug events such as acute kidney injury and haematological abnormalities.
Gymnosiphon fonensis(Burmanniaceae) a new Critically Endangered species from Simandou, Republic of Guinea, W. Africa
Authors: Cheek Martin , Tchiengue Barthelemy , Thiam Aminata , Molmou Denise , Dore Tokpa Seny , Magassouba Sekou
Published: February 2023

A new species ofGymnosiphonBlume (Burmanniaceae),G.fonensisCheek is formally described from the Forêt Classee de Pic de Fon, Simandou Range, Guinee-Forestière, Republic of Guinea (Guinee-Conakry) in West Africa. The new species was formerly confused with and resemblesG. bekensisLetouzey of central Africa in the broad flat outer tepal lobes, perianth tube >10 mm long, and (sub)sessile flower. It differs e.g. in that the length of the corolla tube, (13-)14-18 mm, exceeds the corolla diameter (10-11 mm) (vs length of the corolla tube (12 mm) < the corolla diameter (12-15 mm)), the anthers inserted c. 4 mm deep in the corolla tube (vs inserted at the corolla mouth) and the rhizome lacks scale-leaves (vs scale leaves present).Gymnosiphon fonensisis the first known species of its genus and family in which secondary pollen presentation has been recorded. The species is known from five sites, all with threats, in a single threat-based location, accordingly it is assessed as Critically Endangered (CR B1ab(iii)) using the IUCN 2012 standard, making it the most threatened species ofGymnosiphonin continental Africa. The new species is illustrated by colour photos and line-drawings and is mapped. An identification key is provided to the ten species of the genus now known from Africa-Madagascar.
The effect of ascertainment on penetrance estimates for rare variants: implications for establishing pathogenicity and for genetic counselling
Authors: Paterson Andrew D. , Seok Sang-Cheol , Vieland Veronica J.
Published: February 2023

Next-generation sequencing has led to an explosion of genetic findings for many rare diseases. However, most of the variants identified are very rare and were identified in small pedigrees, which creates challenges in terms of penetrance estimation and translation into genetic counselling in the setting of cascade testing. We use simulations to show that for a rare (dominant) disorder where a variant is identified in a small number of small pedigrees, the penetrance estimate can both have large uncertainty and be drastically inflated, due to underlying ascertainment bias. We have developed PenEst, an app that allows users to investigate the phenomenon across ranges of parameter settings. We also illustrate robust ascertainment corrections via the LOD score, and recommend a LOD-based approach to assessing pathogenicity of rare variants in the presence of reduced penetrance.
A Simple Way to Incorporate Target Structural Information in Molecular Generative Models
Authors: Zhang Wenyi , Zhang Kaiyue , Huang Jing
Published: February 2023

Deep learning generative models are now being applied in various fields including drug discovery. In this work, we propose a novel approach to include target 3D structural information in molecular generative models for structure-based drug design. The method combines a message-passing neural network model that predicts docking scores with a generative neural network model as its reward function to navigate the chemical space searching for molecules that bind favorably with a specific target. A key feature of the method is the construction of target-specific molecular sets for training, designed to overcome potential transferability issues of surrogate docking models through a two-round training process. Consequently, this enables accurate guided exploration of the chemical space without reliance on the collection of prior knowledge about active and inactive compounds for the specific target. Tests on eight target proteins showed a 100-fold increase in hit generation compared to conventional docking calculations, and the ability to generate molecules similar to approved drugs or known active ligands for specific targets without prior knowledge. This method provides a general and highly efficient solution for structure-based molecular generation.
Biodiversity is enhanced by sequential resource utilization and environmental fluctuations via emergent temporal niches
Authors: Bloxham Blox , Lee Hyunseok , Gore Jeff
Published: February 2023

How natural communities maintain their remarkable biodiversity and which species survive in complex communities are central questions in ecology. Resource competition models successfully explain many phenomena but typically predict only as many species as resources can coexist. Here, we demonstrate that sequential resource utilization, or diauxie, with periodic growth cycles can support many more species than resources. We explore how communities modify their own environments by sequentially depleting resources to form sequences of temporal niches, or intermediately depleted environments. Biodiversity is enhanced when community-driven or environmental fluctuations modulate the resource depletion order and produce different temporal niches on each growth cycle. Community-driven fluctuations under constant environmental conditions are rare, but exploring them illuminates the temporal niche structure that emerges from sequential resource utilization. With environmental fluctuations, we find most communities have more stably coexisting species than resources with survivors accurately predicted by the same temporal niche structure and each following a distinct optimal strategy. Our results thus present a new niche-based approach to understanding highly diverse fluctuating communities.
An integrated bioinformatics approach to identify candidate biomarkers and the evaluation of drugs for pheochromocytoma
Authors: Javali S Prashanth , Jeyakanthan J , Chen Chun-Jung , Arumugam Mohanapriya
Published: February 2023

Objectives

Identification of the most potential druggable targets and drugs for treating pheochromocytoma by understanding the molecular mechanisms in the progression of pheochromocytoma and discovering additional biomarkers for early diagnosis.

Methods

The differential gene expression in microarray data was analyzed using CRAN packages such as Geoquery, Affy, Limma, Tidyverse, GOchord, etc., and functional and pathway enrichment was performed through the David database, Further PPI network is constructed by retrieving the Protein partners were retrieved from the STRING database. The top 3 ranked gene products from cytohubba were docked with the ligand molecules, which are all in phase III trials. The complex with the highest binding affinity was simulated using molecular dynamics simulations for 100ns, PCA and FEL analysis were performed to determine the stability of the complex at each time interval additionally miRNA and TRFs were predicted for the prominent genes.

Results

As a result of functional enrichment, most of the 97 differentially expressed genes (DEGs) are involved in cancer-causing pathways. Pheochromocytomas were associated with CDC42, VEGFA, PIK3R1, ITGAV, and LAMB-1, among prominent genes among the ten hub genes. Simulated results verified the effectiveness of targeting VEGFA with Lenvatinib.

Conclusions

We found that differentially expressed genes in the interactome and hub genes with high correlations could serve as biomarkers, along with their miRNAs and TRFs. By targeting VEGFA as a drug target, Lenvatinib displays a high affinity for VEGFA, as it interacts with other genes through homodimerization, activation, phosphorylation, and dephosphorylation. It also appears to interact with the VEGFA protein via hydrogen bonds. In conclusion, this study suggests that Lenvatinib might be a promising anticancer agent that could treat pheochromocytoma, and VEGF-A, CDC42, PIK3R1, as well as several predicted miRNAs, such as miR-224 and miR-221, might be biomarkers for the early diagnosis.
Sea Star Wasting Syndrome Reaches the High Antarctic: Two Recent Outbreaks in McMurdo Sound
Authors: Moran Amy , McLachlan Rowan H. , Thurber Andrew R.
Published: February 2023

Sea star wasting syndrome (SSWS) can cause widespread mortality in starfish populations as well as long-lasting changes to benthic community structure and dynamics. SSWS symptoms have been documented in numerous species and locations around the world, but to date there is only one record of SSWS from the Antarctic and this outbreak was associated with volcanically-driven high temperature anomalies. Here we report outbreaks of SSWS-like symptoms that affected ∼30% of individuals ofOdontaster validusat two different sites in McMurdo Sound, Antarctica in 2019 and 2022. Unlike many SSWS events in other parts of the world, these outbreaks were not associated with anomalously warm temperatures. Instead, we suggest they may have been triggered by high nutrient input events on a local scale. Although the exact cause of these outbreaks is not known, these findings are of great concern because of the keystone role ofO. validusand the slow recovery rate of Antarctic benthic ecosystems to environmental stressors.
Audit to Forget: A Unified Method to Revoke Patients’ Private Data in Intelligent Healthcare
Authors: Zhou Juexiao , Li Haoyang , Liao Xingyu , Zhang Bin , He Wenjia , Li Zhongxiao , Zhou Longxi , Gao Xin
Published: February 2023

Revoking personal private data is one of the basic human rights, which has already been sheltered by several privacy-preserving laws in many countries. However, with the development of data science, machine learning and deep learning techniques, this right is usually neglected or violated as more and more patients’ data are being collected and used for model training, especially in intelligent healthcare, thus making intelligent healthcare a sector where technology must meet the law, regulations, and privacy principles to ensure that the innovation is for the common good. In order to secure patients’ right to be forgotten, we proposed a novel solution by using auditing to guide the forgetting process, where auditing means determining whether a dataset has been used to train the model and forgetting requires the information of a query dataset to be forgotten from the target model. We unified these two tasks by introducing a new approach called knowledge purification. To implement our solution, we developed AFS, a unified open-source software, which is able to evaluate and revoke patients’ private data from pre-trained deep learning models. We demonstrated the generality of AFS by applying it to four tasks on different datasets with various data sizes and architectures of deep learning networks. The software is publicly available athttps://github.com/JoshuaChou2018/AFS.
High-quality genome assemblies provide clues on the evolutionary advantage of blue peafowl over green peafowl
Authors: Chakraborty Abhisek , Mondal Samuel , Mahajan Shruti , Sharma Vineet K.
Published: February 2023

An intriguing example of differential adaptability is the case of two Asian peafowl species,Pavo cristatus(blue peafowl) andPavo muticus(green peafowl), where the former has a “Least Concern” conservation status and the latter is an “Endangered” species. To understand the genetic basis of this differential adaptability of the two peafowl species, a comparative analysis of these species is much needed to gain the genomic and evolutionary insights. Thus, we constructed a high-quality genome assembly of blue peafowl with an N50 value of 84.81 Mb (pseudochromosome-level assembly), and a high-confidence coding gene set to perform the genomic and evolutionary analyses of blue and green peafowls with 49 other avian species. The analyses revealed adaptive evolution of genes related to neuronal development, immunity, and skeletal muscle development in these peafowl species. Major genes related to axon guidance showed adaptive evolution in peafowl species. However, blue peafowl showed the presence of 42% more coding genes compared to the green peafowl along with a higher number of unique gene clusters, segmental duplicated genes and expanded gene families, and comparatively higher evolution in neuronal and developmental pathways. Blue peafowl also showed longer branch length compared to green peafowl in the species phylogenetic tree. These genomic insights obtained from the high-quality genome assembly ofP. cristatusconstructed in this study provide new clues on the superior adaptability of the blue peafowl over green peafowl despite having a recent species divergence time.
Structome: Exploring the structural neighbourhood of proteins
Authors: Malik Ashar J. , Verma Chandra S. , Poole Anthony M. , Allison Jane R.
Published: February 2023

Protein structures carry signal of common ancestry and can therefore aid in reconstructing their evolutionary histories. To expedite the structure-informed inference process, a web server, Structome, has been developed, that allows users to rapidly identify protein structures similar to a query protein and to assemble datasets useful for structure-based phylogenetics. Structome was created by clustering∼94% of the structures in RCSB PDB using 90% sequence identity and representing each cluster by a centroid structure. Structure similarity between centroid proteins was calculated, and annotations from PDB, SCOP and CATH were integrated. To illustrate utility, an H3 histone was used as a query, and results show that the protein structures returned by Structome span both sequence and structural diversity of the histone fold. Additionally, the pre-computed nexus-formated distance matrix, provided by Structome, enables analysis of evolutionary relationships between proteins not identifiable using searches based on sequence similarity alone. Our results demonstrate that, beginning with a single structure, Structome can be used to rapidly generate a dataset of structural neighbours and allows deep evolutionary history of proteins to be studied. Structome is available at:https://structome.bii.a-star.edu.sg
Citizenship status and career self-efficacy: An intersectional study of biomedical trainees in the United States
Authors: Chatterjee Deepshikha , Nogueira Ana T. , Wefes Inge , Chalkley Roger , Varvayanis Susi Sturzenegger , Fuhrmann Cynthia N. , Varadarajan Janani , Jacob Gabrielle A. , Gaines Christiann H. , Hubbard Nisan M. , Chaudhary Sunita , Layton Rebekah L.
Published: February 2023

This study examines the intersectional role of citizenship and gender with career self-efficacy amongst 10,803 doctoral and postdoctoral trainees in US universities. These biomedical trainees completed surveys administered by 17 US institutions that participated in the National Institutes of Health Broadening Experiences in Scientific Training (NIH BEST) Programs. Findings indicate that career self-efficacy of non-citizen trainees is significantly lower than that of US citizen trainees. While lower career efficacy was observed in women compared with men, it was even lower for non-citizen female trainees. Results suggest that specific career interests may be related to career self-efficacy. Relative to US citizen trainees, both male and female non-citizen trainees showed higher interest in pursuing a career as an academic research investigator. In comparison with non-citizen female trainees and citizen trainees of all genders, non-citizen male trainees expressed the highest interest in research-intensive (and especially principal investigator) careers. The authors discuss potential causes for these results and offer recommendations for increasing trainee career self-efficacy which can be incorporated into graduate and postdoctoral training.
System analysis of differentially expressed miRNAs in hexaploid wheat display tissue-specific regulatory role during Fe deficiency response
Authors: Sharma Shivani , Singh Dalwinder , Joon Riya , Shukla Vishnu , Singh Ajit Pal , Singh Palvinder , Mantri Shrikant , Pandey Ajay K
Published: February 2023

Background

Iron (Fe) is an essential mineral element, and its deficiency in soil largely affects crop productivity. In plants, the molecular mechanisms underlying the genetic regulation of Fe deficiency responses have yet to be well understood. Specifically, microRNA (miRNA) mediated regulation of Fe deficiency response and its regulatory network is largely elusive. In the current work, we utilized a whole genome transcriptomic approach to identify the Fe deficiency-responsive miRNAs to understand the molecular mechanisms of Fe deficiency response in wheat seedlings. The study also identifies nine novel miRNAs putatively involved in Fe deficiency response. Further, the identified miRNAs showed tissue preferences relating them to differential mechanisms against Fe deficiency.

Results

In the present study, we performed small RNA-targeted whole genome transcriptome analysis to identify the involvement of sRNAs in Fe deficiency response. The analysis identified 105 differentially expressed miRNAs corresponding to Fe deficiency response, among them, 9 miRNAs were found to be novel in this study. Interestingly, tissue-specific regulation of Fe deficiency response also participates through miRNA-mediated regulation. We identified 17 shoot specific miRNAs and 18 root-specific miRNAs with altered expression. We validated the tissue specificity of thesemiRNAsby stem-loop quantitative RT-PCR. Further, an attempt was made to predict their targets to speculate their participation in Fe deficiency response. This miRNA target prediction analysis suggested a few major targets of the identified miRNAs, such as multicopper oxidases, E3 ubiquitin ligases, GRAS family, and WRKY transcription factors previously known to play key roles in Fe homeostasis. Our analysis of selected miRNAs also confirmed a temporal regulation of the response.

Conclusion

The first information generated here will classify the repository of wheatmiRNAs(with few novel miRNAs) for their role in Fe deficiency response. Our work provides insights into miRNA-mediated regulatory pathways during Fe deficiency.
Merizo: a rapid and accurate domain segmentation method using invariant point attention
Authors: Lau Andy M. , Kandathil Shaun M. , Jones David T.
Published: February 2023

Abstract

The AlphaFold Protein Structure Database (AFDB), containing predictions for over 200 million proteins, has been met with enthusiasm over its potential in enriching structural biological research and beyond. Currently, access to the information within the AFDB is precluded by an urgent need of tools that allow the efficient traversal, discovery and documentation of its contents. Identifying the regions that correspond to domains in the AFDB is a non-trivial endeavour and doing so will aid our understanding of protein structure and function, while facilitating drug discovery and comparative genomics. Here, we describe a deep learning method for accurate domain segmentation called Merizo, which learns to cluster residues into domains in a bottom-up manner. Merizo is trained on CATH domains and fine-tuned on a subset of AFDB models via self-distillation, enabling it to be applicable to both experimental and AFDB models. As proof of concept, we apply Merizo to models of the human proteome, and identify 40,818 putative domains that can be matched to CATH representative domains. Merizo is available athttps://github.com/psipred/Merizo.
Detecting and validating influential organisms for rice growth: An ecological network approach
Authors: Ushio Masayuki , Saito Hiroki , Tojo Motoaki , Nagano Atsushi J.
Published: February 2023

How to achieve sustainable food production while reducing environmental impacts is a major concern in agricultural science, and advanced breeding techniques are promising for achieving such goals. However, rice is usually grown under field conditions and influenced by surrounding ecological community members. How ecological communities influence the rice performance in the field has been underexplored despite the potential of ecological communities to establish an environment-friendly agricultural system. In the present study, we demonstrate an ecological-network-based approach to detect potentially influential, previously overlooked organisms for rice (Oryza sativa). First, we established small experimental rice plots, and measured rice growth and monitored ecological community dynamics intensively and extensively using quantitative environmental DNA metabarcoding in 2017 in Japan. We detected more than 1000 species (including microbes and macrobes such as insects) in the rice plots, and nonlinear time series analysis detected 52 potentially influential organisms with lower-level taxonomic information. The results of the time series analysis were validated under field conditions in 2019 by field manipulation experiments. In 2019, we focused on two species,Globisporangium nunnandChironomus kiiensis, whose abundance was manipulated in artificial rice plots. The responses of rice, namely, the growth rate and gene expression patterns, were measured before and after the manipulation. We confirmed that, especially in theG. nunn-added treatment, rice growth rate and gene expression pattern were changed. In the present study, we demonstrated that intensive monitoring of an agricultural system and the application of nonlinear time series analysis were helpful to identify influential organisms under field conditions. Although the effects of the manipulations were relatively small, the research framework presented here has future potential to harness the ecological complexity and utilize it in agriculture. Our proof-of-concept study would be an important basis for the further development of field-basis system management.
The distinctive mechanical and structural signatures of residual force enhancement in myofibers
Authors: Hessel Anthony L. , Kuehn Michel , Palmer Bradley M. , Nissen Devin , Mishra Dhruv , Joumaa Venus , Freundt Johanna , Ma Weikang , Nishikawa Kiisa C. , Irving Thomas , Linke Wolfgang A.
Published: February 2023

In muscle, titin proteins connect myofilaments together and are thought to be critical for contraction, especially during residual force enhancement (RFE) when force is elevated after an active stretch. We investigated titin’s function during contraction using small-angle X-ray diffraction to track structural changes before and after 50% titin cleavage and in the RFE-deficient,mdmtitin mutant. We report that the RFE state is structurally distinct from pure isometric contractions, with increased thick filament strain and decreased lattice spacing, most likely caused by elevated titin-based forces. Furthermore, no RFE structural state was detected inmdmmuscle. We posit that decreased lattice spacing, increased thick filament stiffness, and increased non-crossbridge forces are the major contributors to RFE. We conclude that titin directly contributes to RFE.

One-Sentence Summary

Titin contributes to active force production and residual force enhancement in skeletal muscles.
FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity
Authors: Wieder Nicolas , Fried Juliana Coraor , Kim Choah , Sidhom Eriene-Heidi , Brown Matthew R. , Marshall Jamie L. , Arevalo Carlos , Dvela-Levitt Moran , Kost-Alimova Maria , Sieber Jonas , Gabriel Katlyn R. , Pacheco Julian , Clish Clary , Abbasi Hamdah Shafqat , Singh Shantanu , Rutter Justine , Therrien Martine , Yoon Haejin , Lai Zon Weng , Baublis Aaron , Subramanian Renuka , Devkota Ranjan , Small Jonnell , Sreekanth Vedagopuram , Han Myeonghoon , Lim Donghyun , Carpenter Anne E. , Flannick Jason , Finucane Hilary , Haigis Marcia C. , Claussnitzer Melina , Sheu Eric , Stevens Beth , Wagner Bridget K. , Choudhary Amit , Shaw Jillian L. , Pablo Juan Lorenzo , Greka Anna
Published: February 2023

Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.

Highlights

FALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effects

FALCON is applicable to many and diverse cell types

A subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidity

New approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for disease

C-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling
Quantitative model of aging-related muscle degeneration: a Drosophila study
Authors: Chechenova Maria , Stratton Hannah , Kiani Kaveh , Gerberich Erik , Alekseyenko Alesia , Tamba Natasya , An SooBin , Castillo Lizzet , Czajkowski Emily , Talley Christina , Bryantsev Anton
Published: February 2023

Changes in the composition and functionality of somatic muscles is a universal hallmark of aging that is displayed by a wide range of species. In humans, complications arising from muscle decline due to sarcopenia aggravate morbidity and mortality rates. The genetics of aging-related deterioration of muscle tissue is not well understood, which prompted us to characterize aging-related muscle degeneration inDrosophila melanogaster(fruit fly), a leading model organism in experimental genetics. Adult flies demonstrate spontaneous degeneration of muscle fibers in all types of somatic muscles, which correlates with functional, chronological, and populational aging. Morphological data imply that individual muscle fibers die by necrosis. Using quantitative analysis, we demonstrate that muscle degeneration in aging flies has a genetic component. Chronic neuronal overstimulation of muscles promotes fiber degeneration rates, suggesting a role for the nervous system in muscle aging. From the other hand, muscles decoupled from neuronal stimulation retain a basal level of spontaneous degeneration, suggesting the presence of intrinsic factors. Based on our characterization,Drosophilacan be adopted for systematic screening and validation of genetic factors linked to aging-related muscle loss.
Butyrate, valerate, and niacin ameliorate anaphylaxis by suppressing IgE-dependent mast cell activation: Roles of GPR109A, PGE2, and epigenetic regulation
Authors: Nagata Kazuki , Ando Daisuke , Ashikari Tsubasa , Ito Kandai , Miura Ryosuke , Fujigaki Izumi , Ando Miki , Ito Naoto , Kawazoe Hibiki , Iizuka Yuki , Inoue Mariko , Yashiro Takuya , Hachisu Masakazu , Kasakura Kazumi , Nishiyama Chiharu
Published: February 2023

Short chain fatty acids (SCFAs) were recently shown to modulate the development and functions of immune-related cells. However, the molecular mechanisms by which SCFAs regulate mast cells (MCs) are not fully understood. We found that the oral administration of valerate or butyrate ameliorated passive systemic anaphylaxis in mice. Butyrate and valerate suppressed the IgE-mediated degranulation of bone marrow-derived MCs, which were eliminated by pertussis toxin and by the knockdown ofGpr109a. A treatment with trichostatin A suppressed IgE-mediated MC activation and reduced the surface expression level of FcεRI on MCs. Acetylsalicylic acid and indomethacin attenuated the suppressive effects of SCFAs on degranulation. The degranulation degree was significantly decreased by the treatment with PGE2whose release from MCs was markedly enhanced by SCFAs. The SCFA-mediated amelioration of anaphylaxis was exacerbated by COX inhibitors and an EP3 antagonist. The administration of niacin, a ligand of GPR109A, alleviated the symptoms of passive cutaneous anaphylaxis, which was inhibited by COX inhibitors and the EP3 antagonist.

Key Messages

Short chain fatty acids (SCFAs), particularly butyrate and valerate, suppress the IgE-mediated activation of mast cells (MCs)in vivoandin vitro.

SCFAs enhance the release of PGE2from MCs, which inhibits the IgE-mediated activation of MCs.

Niacin, a ligand of GPR109A, ameliorates IgE-dependent anaphylaxis.

The administration of COX inhibitors or an antagonist of PGE2receptor 3 (EP3) inhibited the suppressive effects of butyrate and niacin on IgE-dependent anaphylaxis.
Feasibility randomised controlled trial of online group Acceptance and Commitment Therapy for Functional Cognitive Disorder (ACT4FCD)
Authors: Poole Norman , Cope Sarah , Vanzan Serena , Duffus Aimee , Mantovani Nadia , Smith Jared , Barrett Barbara , Tokley Melanie , Scicluna Martin , Beardmore Sarah , Turner Kati , Edwards Mark , Howard Rob
Published: February 2023

Introduction

Functional cognitive disorder is seen increasingly in clinics commissioned to assess cognitive disorders. Patients complain of frequent cognitive, especially memory, failures. The diagnosis can be made clinically, and unnecessary investigations avoided. While there is some evidence that psychological treatments can be helpful, they are not routinely available. Therefore, we have developed a brief psychological intervention using the principles of Acceptance and Commitment Therapy (ACT) that can be delivered in groups and online. We are conducting a feasibility study to assess whether the intervention can be delivered within a randomised controlled trial. We aim to study the feasibility of recruitment, willingness to be randomised to intervention or control condition, adherence to the intervention, completion of outcome measures, and acceptability of treatment.

Methods and analysis

We aim to recruit 48 participants randomised 50:50 to either the ACT intervention and Treatment as Usual (TAU), or TAU alone. ACT will be provided to participants in the treatment arm following completion of baseline outcome measures. Completion of these outcome measures will be repeated at 8, 16, and 26 weeks. The measures will assess several domains including psychological flexibility, subjective cognitive symptoms, mood and anxiety, health related quality of life and functioning, healthcare utilisation, and satisfaction with care and participant-rated improvement. Fifteen participants will be selected for in-depth qualitative interviews about their experiences of living with FCD and of the ACT intervention.

Ethics and dissemination

The study received a favourable opinion from the South East Scotland Research Ethics Committee 02 on 30th September 2022 (REC reference: 22/SS/0059). HRA approval was received on 1stNovember 2022 (IRAS 313730). The study has been registered with the ISRCTN (ISRCTN12939037). The results will be published in full in an open access journal.

ISRCTN Registration

https://doi.org/10.1186/ISRCTN12939037

Grant Number

National Institute for Health and Care Research (NIHR) grant number: NIHR202743

Strengths and limitations of this study

Novel intervention with potential to be delivered at scale

Adherence to principles of an evidence-based intervention (ACT)

Utilising qualitative and quantitative methodologies which is key to contextualising patient experiences in a clinically meaningful measurement framework

Recruiting from the full range of services that assess cognition in adults in the UK

Participants not blinded to their intervention
OptIC Notch reveals mechanism that regulates receptor interactions with CSL
Authors: Townson Jonathan M. , Gomez-Lamarca Maria J. , Santa Cruz Mateos Carmen , Bray Sarah J.
Published: February 2023

Active Notch signalling is elicited through receptor-ligand interactions that result in release of the Notch intracellular domain (NICD), which translocates into the nucleus. NICD activates transcription at target genes forming a complex with the DNA-binding transcription factor CSL (CBF1/Su(H)/Lag-1) and co-activator Mastermind. Despite this, CSL lacks its own nuclear localisation sequence, and it remains unclear where the tripartite complex is formed. To probe mechanisms involved, we designed an optogenetic approach to control NICD release (OptIC-Notch) and monitored consequences on complex formation and target gene activation. Strikingly we observed that, when uncleaved, OptIC-Notch sequestered CSL in the cytoplasm. Hypothesising that exposure of a juxta membrane ΦWΦP motif is key to sequestration, we masked this motif with a second light sensitive domain in OptIC-Notch{ω}, which was sufficient to prevent CSL sequestration. Furthermore, NICD produced by light-induced cleavage of OptIC-Notch or OptIC-Notch{ω} chaperoned CSL into the nucleus and induced target gene expression, showing efficient light controlled activation. Our results demonstrate that exposure of the ΦWΦP motif leads to CSL recruitment and suggest this can occur in the cytoplasm prior to nuclear entry.

Summary statement

Light controlled exposure of the Notch ΦWΦP motif leads to CSL sequestration and suggest this interaction could occur prior to nuclear entry during normal signalling.
Cerebellar Morphological Differences in Bipolar Disorder Type I
Authors: Harmata Gail I. S. , Barsotti Ercole John , Casten Lucas G. , Fiedorowicz Jess G. , Williams Aislinn , Shaffer Joseph J. , Richards Jenny Gringer , Sathyaputri Leela , Schmitz Samantha L. , Christensen Gary E. , Long Jeffrey D. , Gaine Marie E. , Xu Jia , Michaelson Jake J. , Wemmie John A. , Magnotta Vincent A.
Published: February 2023

Background

The neural underpinnings of bipolar disorder (BD) remain poorly understood. The cerebellum is ideally positioned to modulate emotional regulation circuitry yet has been understudied in BD. Previous studies have suggested differences in cerebellar activity and metabolism in BD, however findings on cerebellar structural differences remain contradictory.

Methods

We collected 3T anatomical MRI scans from participants with (N = 131) and without (N = 81) BD type I. Differences in cerebellar volumes were assessed along with factors that influence the results.

Results

The cerebellar cortex was smaller bilaterally in participants with BD. Polygenic propensity score (bipolar N = 103, control N = 64) did not predict any cerebellar volumes, suggesting that non-genetic factors may have greater influence on the cerebellar volume difference we observed in BD. Cerebellar white matter volumes increased with more adverse childhood events, but we did not observe any associations with parental psychiatric illness. We also evaluated time from onset and symptom burden and found no associations with cerebellar volumes, suggesting neurodevelopment may differ prior to onset. Finally, we found taking sedatives was associated with larger cerebellar white matter and non-significantly larger cortical volume.

Limitations

This study was cross-sectional, limiting interpretation of possible mechanisms. Most of our participants were White, which could limit the generalizability. Additionally, we did not account for potential polypharmacy interactions.

Conclusions

These findings suggest that external influences, such as medications, may influence cerebellum structure in BD and may mask underlying differences. Accounting for medication may be critical for consistent findings in future studies.
Field cancerization impacts tumor development, T-cell exhaustion and clinical outcomes in bladder cancer
Authors: Strandgaard Trine , Nordentoft Iver , Birkenkamp-Demtröder Karin , Salminen Liina , Prip Frederik , Rasmussen Julie , Andreasen Tine Ginnerup , Lindskrog Sia Viborg , Christensen Emil , Lamy Philippe , Knudsen Michael , Steiniche Torben , Jensen Jørgen Bjerggaard , Dyrskjøt Lars
Published: February 2023

Bladder field cancerization may be associated with disease outcome in patients with bladder cancer. To investigate this, we analyzed biopsies from bladder urothelium and urine samples by genomics and proteomics analyses. Samples were procured from multiple timepoints from 134 patients with early stage bladder cancer and detailed long term follow-up. We measured the field cancerization in normal-appearing bladder biopsies and found that high levels were associated with high tumor mutational burden, high neoantigen load, and high tumor-associated CD8 T-cell exhaustion. Non-synonymous mutations in known bladder cancer driver genes such asKDM6AandTP53were identified as early disease drivers in normal urothelium. High field cancerization was associated with worse outcome but not with response to BCG. The level of urinary tumor DNA (utDNA) reflected the bladder tumor burden and originated from both tumors and field cancerization. High utDNA levels after BCG were associated with worse clinical outcomes for the patients. Our results indicate that the level of field cancerization may affect clinical outcome, tumor development and immune responses. utDNA measurements have significant prognostic value and reflect the disease status of the bladder.
Rie1 and Sgn1 form an RNA-binding complex that enforces the meiotic entry cell fate decision
Authors: Gaspary Alec , Laureau Raphaelle , Dyatel Annie , Dursuk Gizem , Berchowitz Luke E.
Published: February 2023

Budding yeast cells have the capacity to adopt few but distinct physiological states depending on environmental conditions. Vegetative cells proliferate rapidly by budding while spores can survive prolonged periods of nutrient deprivation and/or desiccation. Whether or not a yeast cell will enter meiosis and sporulate represents a critical decision which could be lethal if made in error. Most cell fate decisions, including those of yeast, are understood as being triggered by the activation of master transcription factors. However, mechanisms that enforce cell fates post-transcriptionally have been more difficult to attain. Here, we perform a forward genetic screen to determine RNA-binding proteins that affect meiotic entry at the post-transcriptional level. Our screen revealed several candidates with meiotic entry phenotypes, the most significant beingRIE1which encodes an RRM-containing protein. We demonstrate that Rie1 binds RNA, is associated with the translational machinery, and acts post-transcriptionally to enhance protein levels of the master transcription factor Ime1 in sporulation conditions. We also identified a physical binding partner of Rie1, Sgn1, which is another RRM-containing protein that plays a role in timely Ime1 expression. We demonstrate that these proteins act independently of cell size regulation pathways to promote meiotic entry. We propose a model explaining how constitutively expressed RNA-binding proteins, such as Rie1 and Sgn1, can act in cell-fate decisions both as switch-like enforcers and as repressors of spurious cell fate activation.
Ribosomal intergenic spacers are filled with transposon remnants
Authors: Bendich Arnold J. , Rogers Scott O.
Published: February 2023

Eukaryotic ribosomal DNA (rDNA) comprises tandem units of highly-conserved coding genes separated by rapidly-evolving spacer DNA. The spacers of all 12 species examined were filled with short direct repeats (DRs) and multiple long tandem repeats (TRs), completing the rDNA maps that previously contained unannotated and inadequately studied sequences. The external transcribed spacers also were filled with DRs and some contained TRs. We infer that the spacers arose from transposon insertion, followed by their imprecise excision, leaving short DRs characteristic of transposon visitation. The spacers provided a favored location for transposon insertion because they occupy loci containing hundreds to thousands of gene repeats. The spacers’ primary cellular function may be to link one rRNA transcription unit to the next, whereas transposons flourish here because they have colonized the most frequently-used part of the genome.

Author Summary

The DNA loci containing the ribosomal RNA genes (the rDNA) in eukaryotes are puzzling. The sections encoding the rRNA are so highly conserved that they can be used to assess evolutionary relationships among diverse eukaryotes, yet the rDNA sequences between the rRNA genes (the intergenic spacer sequences; IGS) are among the most rapidly evolving in the genome, including varying within and between species and between individuals of a species, and within cells of an individual. Here we report the presence of large numbers of direct repeats (DRs) throughout the IGSs of a diverse set of organisms. Parasitic DNA and RNA elements often leave short DRs when they are excised resulting in “molecular scars” in the DNA. These “scars” are absent from the coding sections of the rDNA repeats, indicating that the IGSs have long been targets for integration of these parasitic elements that have been eliminated from the coding sections by selection. While these integration events are mostly detrimental to the organism, occasionally they have caused beneficial changes in eukaryotes, thus allowing both the parasites and the hosts to survive and co-evolve.