bluuebunny/crossref_metadata_2025 huggingface dataset:
A Multi-task Platform for Profiling Cognitive and Motivational Constructs in Humans and Nonhuman Primates
Authors: Watson Marcus R. , Traczewski Nathan , Dunghana Seema , Boroujeni Kianoush Banaie , Neumann Adam , Wen Xuan , Womelsdorf Thilo
Published: November 2023

Background

Understanding the neurobiological substrates of psychiatric disorders requires comprehensive evaluations of cognitive and motivational functions in preclinical research settings. The translational validity of such evaluations will be supported by (1) tasks with high construct validity that are engaging and easy to teach to human and nonhuman participants, (2) software that enables efficient switching between multiple tasks in single sessions, (3) software that supports tasks across a broad range of physical experimental setups, and (4) by platform architectures that are easily extendable and customizable to encourage future optimization and development.

New Method

We describe theMulti-task Universal Suite for Experiments(M-USE), a software platform designed to meet these requirements. It leverages the Unity video game engine and C# programming language to (1) support immersive and engaging tasks for humans and nonhuman primates, (2) allow experimenters or participants to switch between multiple tasks within-session, (3) generate builds that function across computers, tablets, and websites, and (4) is freely available online with documentation and tutorials for users and developers. M-USE includes a task library with seven pre-existing tasks assessing cognitive and motivational constructs of perception, attention, working memory, cognitive flexibility, motivational and affective self-control, relational long-term memory, and visuo-spatial problem solving.

Results

M-USE was used to test NHPs on up to six tasks per session, all available as part of the Task Library, and to extract performance metrics for all major cognitive and motivational constructs spanning the Research Domain Criteria (RDoC) of the National Institutes of Mental Health.

Comparison with Existing Methods

Other experiment design and control systems exist, but do not provide the full range of features available in M-USE, including a pre-existing task library for cross-species assessments; the ability to switch seamlessly between tasks in individual sessions; cross-platform build capabilities; license-free availability; and its leveraging of video-engine capabilities used to gamify tasks.

Conclusions

The new multi-task platform facilitates cross-species translational research for understanding the neurobiological substrates of higher cognitive and motivational functions.
A neuromechanical model accounting for movement history dependency identifies subject-specific neural and non-neural origins of joint hyper-resistance: A simulation study
Authors: Willaert Jente , Desloovere Kaat , Van Campenhout Anja , Ting Lena H. , De Groote Friedl
Published: November 2023

Joint hyper-resistance is a common symptom in neurological disorders. It has both neural and nonneural origins, but it has been challenging to distinguish different origins based on clinical tests alone. Combining instrumented tests with parameter identification based on a neuromechanical model may allow us to dissociate the different origins of joint hyper-resistance in individual patients. However, this requires that the model captures the underlying mechanisms. Here, we propose a neuromechanical model that, in contrast to previously proposed models, accounts for muscle shortrange stiffness and its interaction with muscle tone and reflex activity.

We collected knee angle trajectories during the pendulum test in 15 children with cerebral palsy (CP) and 5 typically developing children. We did the test in two conditions – hold and pre-movement – that have been shown to alter knee movement. We modeled the lower leg as an inverted pendulum actuated by two antagonistic Hill-type muscles extended with SRS. Reflex activity was modeled as delayed, linear feedback from muscle force. We estimated neural and non-neural parameters by optimizing the fit between simulated and measured knee angle trajectories during the hold condition.

The model could fit a wide range of knee angle trajectories in the hold condition. The model with personalized parameters predicted the effect of pre-movement demonstrating that the model captured the underlying mechanism and subject-specific deficits.

Our model thus allows us to determine subject-specific origins of joint hyper-resistance and thereby opens perspectives for improved diagnosis and consequently treatment selection in children with spastic CP.
Chronic pain mediated changes in the appetitive value of affective gentle touch in mice
Authors: Zain Maham , Bennett Laura , Zhang Hantao , Pauli Quinn , Arsenault Juliet , Premachandran Shajenth , Cheung Jenny , Pham Christine , Wowk Lexi , Kaba Sékou-Oumar , Fung Samuel , Lecker Irene , Salter Eric , Wang Feng , Sharif-Naeini Reza , De Koninck Yves , Bonin Robert P.
Published: November 2023

The existence of skin-to-brain circuits for rewarding gentle touch highlight its critical nature across species. However, this gentle affective touch is not always appetitive and can produce aversion or negative affect in disorders such as chronic pain. Sensory neurons expressing the protein MrgprB4 detect gentle stroking in mice and their activation of these neurons known to be positively reinforcing. Here we assess whether activation of channelrhodopsin (ChR2) expressing MrgprB4 afferents signal positively valenced tactile information and whether this is altered in models of chronic pain. We further interrogate how this this sensory information is reflected in the downstream circuits recruited. Optogenetic activation of MrgprB4 lineage afferents was found to be appetitive in control and capsaicin sensitized mice but not nerve injured mice, indicating that the appetitive value is diminished in neuropathic pain. Remarkably, this appetitive value was partially recovered in male nerve injured mice by treatment with the analgesic gabapentin. These behavioral changes were also accompanied by different patterns of neuronal activity throughout the brain, including altered activation of sites that receive direct projections from the spinal cord between sham and nerve injured mice. Together, these findings highlight the plastic nature of these affective tactile circuits under pathological conditions.
HYPOTHESIS GENERATION FOR RARE AND UNDIAGNOSED DISEASES THROUGH CLUSTERING AND CLASSIFYING TIME-VERSIONED BIOLOGICAL ONTOLOGIES
Authors: Bradshaw Michael S. , Gibbs Connor P. , Martin Skylar , Firman Taylor , Gaskell Alisa , Fosdick Bailey K. , Layer Ryan M.
Published: November 2023

Rare diseases affect 1-in-10 people in the United States and despite increased genetic testing, up to half never receive a diagnosis. Even when using advanced genome sequencing platforms to discover variants, if there is no connection between the variants found in the patient’s genome and their phe-notypes in the literature, then the patient will remain undiagnosed. When a direct variant-phenotype connection is not known, putting a patient’s information in the larger context of phenotype relation-ships and protein-protein-interactions may provide an opportunity to find an indirect explanation. Databases such as STRING contain millions of protein-protein-interactions and HPO contains the relations of thousands of phenotypes. By integrating these networks and clustering the entities within we can potentially discover latent gene-to-phenotype connections. The historical records for STRING and HPO provide a unique opportunity to create a network time series for evaluating the cluster sig-nificance. Most excitingly, working with Children’s Hospital Colorado we provide promising hy-potheses about latent gene-to-phenotype connections for 38 patients with undiagnosed diseases. We also provide potential answers for 14 patients listed on MyGene2. Clusters our tool finds significant harbor 2.35 to 8.72 times as many gene-to-phenotypes edges inferred from known drug interactions than clusters find to be insignificant. Our tool, BOCC, is available as a web app and command line tool.
UDP-glucosyltransferase 71C4 regulates seed development by redistributing phenylpropanoid metabolism in cotton
Authors: Cao Yiwen , Han Zegang , He Lu , Huang Chujun , Chen Jinwen , Dai Fan , Xuan Lisha , Yan Sunyi , Si Zhanfeng , Hu Yan , Zhang Tianzhen
Published: November 2023

Seeds are important for plant reproduction, and hence it is important to identify genes regulating seed development. Here, we focused on a member of the glycosyltransferase (GT) family, UDP-glucosyltransferase 71C4 (UGT71C4), which influences the seed width, seed length, and yield traits (lint percentage and seed index) by regulating the lignin and flavonoid pathways of phenylpropane metabolism, affects the oil and protein contents of mature seeds, and controls the seed size by regulating cell proliferation. Overexpression ofUGT71C4leads to seed enlargement by activating expression of peroxiredoxins and the flavonoid metabolism pathway; induces accumulation of ROS, which promotes cell proliferation; and significantly improves yield traits, with the seed index increasing from 10.66 to 11.91 and protein increasing by 5.34%, but oil content decreasing 8.98%. Conversely, knockout ofUGT71C4causes seeds to become smaller; the lignin metabolism pathway to be activated, especially enzymes relating to lignin synthesis leading to increased ectopic deposition of lignin in the ovule and constrained ovule growth and development; and significant improvement of yield traits, with lint percentage increasing from 39.62% to 41.94%, seed index decreasing from 10.66 to 8.60, protein content decreasing 4.28%, and no significant change in oil content. Our research provides new insights into seed size regulation through UDP-glucosyltransferase, providing potential methods for improving plant yield.
The BET inhibitors JQ1, AZD5153, and I-BET151 co-opt ubiquitin proteasome system components for altering expression of the BRD4 interactome in a human B cell line
Authors: Nallur Girish
Published: November 2023

Chemoproteomic analysis of the BET inhibitors, JQ1, AZD5153, and I-BET151, identified an extremely large signature of ubiquitin modified proteins associatingin vitrowith a recombinant BRD4 N-terminal protein fragment. The identified proteins included those with known functions in BRD4 complexes for transcriptional and epigenetic control (acetylated histones, the MED complex, BAF complex, RNA pol II transcription complexes, and chromatin-associated complexes). The BRD4 interactome in response to BET inhibitors is suggested to be orchestrated by compound-specific differential actions of up to 16 E3 ligases, 4 deubiquitinase enzymes, and 51 accessory proteins of the ubiquitin proteasome system (UPS). The UPS response of BET inhibition also involves proteins necessary for Myc enhancer binding and Myc response gene expression. A large cohort of UPS substrates commonly responsive to JQ1 and AZD5153 treatments suggests the existence of distinct mechanisms, one involving compound-activated UPS proteins, and another via their direct actions on BRD4. The findings raise the intriguing possibility that UPS triggers promoting proteostasis changes to the BRD4 interactome may be mechanistically coupled with BRD4 function in a proximity-dependent, chromatin-associated manner. Consequently, BET inhibitors and their downstream effects present highly complex environments which may lead to polypharmacology, the phenotypic outcomes or overall clinical benefits of which are hard to assess. However, many new targets and small molecule combinations suggested in this study may afford a path forward for narrowly and more selectively targeting Myc in the clinic with potentially cleaner profiles compared with BET inhibitors or BRD4 as target.
Phenotypic and genomic analysis of a large-scaleCorynebacterium diphtheriaeoutbreak among migrant populations in Europe
Authors: Hoefer Andreas , Seth-Smith Helena , Palma Federica , Schindler Stefanie , Freschi Luca , Dangel Alexandra , Berger Anja , D’Aeth Joshua , Indra Alexander , Fry Norman K. , Palm Daniel , Sing Andreas , Brisse Sylvain , Egli Adrian ,   the 2022 European diphtheria Consortium
Published: November 2023

Background

Increased numbers of cases ofCorynebacterium diphtheriaeinfections were diagnosed in migrant-related facilities of Europe since summer 2022. Most cases involved cutaneous diphtheria, although some respiratory cases and fatalities were reported. A pan-European consortium was created to assess the clinical, epidemiological and microbiological features of this outbreak.

Methods

All 363 toxigenicC. diphtheriaeinfection cases from ten European countries were included. Data from case interviews regarding countries of origin and transit routes of migrants were collected. Bacterial isolates underwent whole genome sequencing and antibiotic susceptibility testing. Phylogenetic relationships of outbreak isolates and their antimicrobial resistance genes were studied.

Results

Four major genomic clusters were identified, revealing the multiclonal nature of the outbreak. Genes ermX, coding for erythromycin resistance, and genes pbp2m and blaOXA-2 for beta-lactam resistance, were detected in a subset of isolates. Isolates harboring ermX were resistant to erythromycin, and isolates carrying pbp2m were resistant to penicillin, but susceptible to amoxicillin, whereas those carrying blaOXA-2 remained susceptible to beta-lactams. Genomic variation within the four genomic clusters led to estimate their most recent common ancestors between 2017 and 2020.

Conclusions

The multi-country distribution of each cluster demonstrated repeated cross-border spread. The increased number ofC. diphtheriaecases among migrants is a cause for concern, particularly considering antimicrobial resistance phenotypes that threaten the efficacy of first-line treatments. This work provides important knowledge on modernC. diphtheriaeinfections, useful for addressing the reemergence of diphtheria in vulnerable populations and to guide clinical management and measures to control further dissemination.
Mutation in CDC42 gene set as a response biomarker for immune checkpoint inhibitor therapy
Authors: Wang Kun , Zhang Yingying , Su Zhaoming , Wang Bei , Zhou Yuanyang , Tong Xiaochu , Xie Chengying , Luo Xiaomin , Zhang Sulin , Zheng Mingyue
Published: November 2023

Background

Immunotherapy has proven notably effective in treating tumors across diverse patient populations. However, some patients do not respond to immune checkpoint inhibitors (ICIs). Thus, there is a need for reliable biomarkers that can predict clinical responses to ICI treatment accurately.

Methods

Our focus is on CDC42, a protein that stimulates multiple signaling pathways, promoting tumor growth. We hypothesize that its defective function may indicate a patient’s response to ICI therapy. We consider CDC42, along with its downstream binding and effector proteins, as a gene set. This is because their mutation could result in defective CDC42 function. We investigated the mutations in the CDC42 gene set as a potential biomarker for clinical benefits from ICI treatment. We also examined whether the combined use of a CDC42 inhibitor and ICI could enhance the efficacy of ICI.

Results

The presence of mutations in the CDC42 gene set correlated with improved overall survival (OS: p = 2.9E-4) and progression-free survival (PFS: p = 2.92E-6). Furthermore, our analysis of immune response landscapes among different CDC42 gene set statuses supports its potential as a biomarker for ICI therapy. Animal experiments also revealed that combining the CDC42 inhibitor (ML141) with anti-PD-1 blockade can synergistically reduce tumor growth.

Conclusions

Our study suggests that the CDC42 gene set could serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insight into the potential of combining ICI and CDC42 inhibitor use.
Network Enrichment Significance Testing in Brain-Phenotype Association Studies
Authors: Weinstein Sarah M. , Vandekar Simon N. , Alexander-Bloch Aaron F. , Raznahan Armin , Li Mingyao , Gur Raquel E. , Gur Ruben C. , Roalf David R. , Park Min Tae M. , Chakravarty Mallar , Baller Erica B. , Linn Kristin A. , Satterthwaite Theodore D. , Shinohara Russell T.
Published: November 2023

Functional networks often guide our interpretation of spatial maps of brain-phenotype associations. However, methods for assessing enrichment of associations within networks of interest have varied in terms of both scientific rigor and underlying assumptions. While some approaches have relied on subjective interpretations, others have made unrealistic assumptions about the spatial structure of imaging data, leading to inflated false positive rates. We seek to address this gap in existing methodology by borrowing insight from a method widely used in genomics research for testing enrichment of associations between a set of genes and a phenotype of interest. We propose Network Enrichment Significance Testing (NEST), a flexible framework for testing the specificity of brain-phenotype associations to functional networks or other sub-regions of the brain. We apply NEST to study phenotype associations with structural and functional brain imaging data from a large-scale neurodevelopmental cohort study.
OOCYTE AND EMBRYO CULTURE UNDER OIL PROFOUNDLY ALTERS EFFECTIVE CONCENTRATIONS OF SMALL MOLECULE INHIBITORS
Authors: Labrosse Gaudeline Rémillard , Cohen Sydney , Boucher Éliane , Gagnon Kéryanne , Vasilev Filip , Mihajlović Aleksandar I , FitzHarris Greg
Published: November 2023

Culture of oocytes and embryos in media under oil is a cornerstone of fertility treatment, and extensively employed in experimental investigation of early mammalian development. It has been noted anecdotally by some that certain small molecule inhibitors might lose activity in oil-covered culture systems, presumably by drug partitioning into the oil. Here we took a pseudo-pharmacological approach to appraise this formally. Using different culture dish designs with defined media:oil volume ratios, we show that the EC50of the widely employed microtubule poison nocodazole shifts as a function of the media:oil ratio, such that nocodazole concentrations that prevent cell division in oil-free culture fail to in oil-covered media drops. Relatively subtle changes in culture dish design lead to measurable changes in EC50. This effect is not specific to one type of culture oil, and can be readily observed both in oocyte and embryo culture experiments. We subsequently applied a similar approach to a small panel of widely employed cell cycle-related inhibitors, finding that most lose activity in standard oil-covered oocyte/embryo culture systems. Our data suggest that loss of small molecule activity in oil-covered oocyte and embryo culture is a widespread phenomenon with potentially far-reaching implications for data reproducibility, and we recommend avoiding oil-covered culture for experiments employing inhibitors/drugs wherever possible.
A behavioral roadmap for the development of agency in the rodent
Authors: Mitelut C , Diez Castro M , Peterson RE , Gonçalves M , Li J , Gamer MM , Nilsson SRO , Pereira TD , Sanes DH
Published: November 2023

Behavioral interactions within the nuclear family play a pivotal role in the emergence of agency: the capacity to regulate physiological, psychological and social needs. While behaviors may develop over days or weeks in line with nervous system maturation, individual behaviors can occur on sub-second time scales making it challenging to track development in lab studies with brief observation periods, or in field studies with limited temporal precision and animal identification. Here we study development in families of gerbils, a highly social rodent, collecting tens of millions of behavior time points and implementing machine learning methods to track individual subjects. We provided maturing gerbils with a large, undisturbed environment between postnatal day 15 and the age at which they would typically disperse from the family unit (day 30). We identified complex and distinct developmental trajectories for food and water acquisition, solitary exploration, and social behaviors, some of which displayed sex differences and diurnal patterns. Our work supports the emergence of well-delineated autonomous and social behavior phenotypes that correlate with specific periods and loci of neural maturation.
Genetic discovery and risk prediction for type 1 diabetes in individuals without high-risk HLA-DR3/DR4 haplotypes
Authors: McGrail Carolyn , Chiou Joshua , Elgamal Ruth , Luckett Amber M , Oram Richard A , Benaglio Paola , Gaulton Kyle J
Published: November 2023

Over 10% of type 1 diabetes (T1D) cases do not have high-risk HLA-DR3 or DR4 haplotypes with distinct clinical features such as later onset and reduced insulin dependence. To identify genetic drivers of T1D in the absence of DR3/DR4, we performed association and fine-mapping analyses in 12,316 non-DR3/DR4 samples. Risk variants at the MHC and other loci genome-wide had heterogeneity in effects on T1D dependent on DR3/DR4, and non-DR3/DR4 T1D had evidence for a greater polygenic burden. T1D-assocated variants in non-DR3/DR4 were more enriched for loci, regulatory elements, and pathways for antigen presentation, innate immunity, and beta cells, and depleted in T cells, compared to DR3/DR4. Non-DR3/DR4 T1D cases were poorly classified based on an existing genetic risk score GRS2, and we created a new GRS which highly discriminated non-DR3/DR4 T1D from both non-diabetes and T2D. In total we identified heterogeneity in T1D genetic risk and disease mechanisms dependent on high-risk HLA haplotype and which enabled accurate classification of T1D across HLA background.
Closed-loop Cortical Network Stimulation as treatment for refractory epilepsy originating from the primary motor cortex
Authors: van Blooijs D. , Blok S. , Aarnoutse E.J. , van Klink N.E.C. , Huiskamp G.J.M. , Bourez-Swart M.D. , Gebbink T.A. , van Eijsden P. , van der Salm S.M.A. , Ramsey N.F. , Leijten F.S.S.
Published: November 2023

Background

In epilepsy patients, cortical electrical stimulation is therapeutically applied in the seizure onset zone (SOZ) to reduce seizures. However, in patients with epilepsy arising from the primary motor cortex (M1), stimulation can result in undesired muscle contractions or loss of motor control. We postulate that seizure frequency reduction can also be obtained by cortical network stimulation in a site outside M1 with a connection to the SOZ in M1.

Methods

Patients with electroclinical seizures suspected to arise from M1 were selected. SOZ was delineated during chronic intracranial EEG monitoring. Using Single Pulse Electrical Stimulation, the underlying effective corticocortical network was determined and a site for stimulation was selected that was connected to the SOZ. One subdural strip was implanted on top of the SOZ, and one on the stimulus location. A subcutaneous neurostimulator (Activa®PC+S, Medtronic), capable of recording and closed-loop stimulation, was connected to both strips. Seizure data was collected for three to five months and used to optimize a seizure detection algorithm. After this, closed-loop cortical network stimulation was applied during seven to nine months.

Results

In five subjects (two females, mean age 34 years, range: 21-51 years), a neurostimulation system was implanted. One subject was seizure free for 17 months post- implantation without applying any electrical stimulation. Two subjects were responders with a mean seizure frequency reduction of 73%. In two subjects, seizure frequency was reduced by on average 35%.

Discussion

In this clinical trial with five subjects suffering from refractory epilepsy arising in M1, seizure frequency was reduced with electrical stimulation in all subjects. This is a proof of concept showing that closed-loop cortical network stimulation can reduce seizure frequency as equal to direct SOZ stimulation in non-primary motor epilepsy.
Age is Associated with Dampened Circadian Patterns of Rest and Activity: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Erickson Melissa L. , Blackwell Terri L. , Mau Theresa , Cawthon Peggy M. , Glynn Nancy W. , Qiao Yujia (Susanna) , Cummings Steven R. , Coen Paul M. , Lane Nancy E. , Kritchevsky Stephen B. , Newman Anne B. , Farsijani Samaneh , Esser Karyn A.
Published: November 2023

Background

Aging is associated with declines in circadian functions. The effects of aging on circadian patterns of behavior are insufficiently described. We characterized age-specific features of rest-activity rhythms (RAR) in community dwelling older adults, both overall, and in relation, to sociodemographic characteristics.

Methods

We analyzed baseline assessments of older adults with wrist-worn free-living wrist-worn actigraphy data (N=820, Age=76.4 yrs, 58.2% women) participating in the Study of Muscle, Mobility and Aging (SOMMA). We applied an extension to the traditional cosine curve to map RAR to activity data, calculating the parameters: rhythmic strength (amplitude); robustness (pseudo-F statistic); and timing of peak activity (acrophase). We also used function principal component analysis to determine 4 components describing underlying patterns of activity accounting for RAR variance. Linear models were used to examine associations between RAR and sociodemographic variables.

Results

Age was associated with several metrics of dampened RAR; women had stronger and more robust RAR metrics vs. men (allP< 0.05). Total activity (56%) and time of activity (20%) accounted for most the RAR variance. Compared to the latest decile of acrophase, those in the earliest decile had higher average amplitude (P<0.001). Compared to the latest decile of acroaphase, those is the earliest and midrange categories had more total activity (P=0.02). RAR was associated with some sociodemographic variables.

Conclusions

Older age was associated with dampened circadian behavior; and behaviors were sexually dimorphic. We identified a behavioral phenotype characterized by early time-of-day of peak activity, high rhythmic amplitude, and more total activity.
Application of the Fluctuation Test to the data of Morbidity and Mortality by COVID-19 in China 2020-2023
Authors: López-Ramírez Anyi Yannire , Fernández-Ramírez María Alejandra , Grassi Hilda Cristina , de Jesús Andrades Efrén , Andrades-Grassi Jesús Enrique
Published: November 2023

In this work the Luria and Delbruck Fluctuation Test was applied to the data of Morbidity and Mortality by COVID-19 in China from January 2020 to August 2023. Three types of data were used:es.statista.com,datosmacro.expansion.comand larepublica.co without modification, but trying to avoid and justify the anomalies and inconsistencies observed. The methods originally used to establish the interactions of two populations were evaluated: the viral population with that of its host and the drift of both organisms. Only the fluctuations of the weekly Variance of daily increase of Cases (Morbidity) and of the weekly Variance of daily increase of Deaths (Mortality) were studied. The results showed that the Fluctuation Test is applicable to the selected data from China and other data from India, Japan and South Korea, used as controls. The study was separated into two periods: a first initial period from January 2020 to September 2021 and a second final period from October 2021 to August 2023. Results were obtained for Morbidity and Mortality that relate the fluctuations of the first with the fluctuations of the second. However, it was possible to detect some anomalies and uncertainties that were possibly derived from inconsistencies in the original data. A repeated fluctuation was observed in the boreal winter in January, February and March of each one of the year studied. A clear decrease in fluctuation was detected in that period in 2021 that could be attributed to the strict confinement during the quarantine in China between 2020 and 2021. Massive, extensive and intensive vaccinations failed to completely eliminate the most important fluctuations. In this work we tried to correlate the appearance of some virus variants with the fluctuations. The most relevant results of said correlation are presented. With the results of this work, the animal origin cannot be confirmed nor can the human or laboratory origin of the SARS CoV-2 virus that caused the initial emerging infection, be ruled out. However, it was concluded that this method could be used to search for clues about its origin. One of these keys is the comparison of the result of the first important fluctuation in the boreal winter of 2020 in each of the countries studied as controls: India, Japan and South Korea. The comparison of this result with the first fluctuation of China for that same period could give clues about the origin of the virus.
The Parkinson’s drug entacapone disrupts gut microbiome homeostasis via iron sequestration
Authors: Pereira Fátima C. , Ge Xiaowei , Kristensen Jannie Munk , Kirkegaard Rasmus H. , Maritsch Klara , Zhu Yifan , Decorte Marie , Hausmann Bela , Berry David , Wasmund Kenneth , Schintlmeister Arno , Boettcher Thomas , Cheng Ji-Xin , Wagner Michael
Published: November 2023

Increasing evidence shows that many human-targeted drugs alter the gut microbiome, leading to implications for host health. However, much less is known about the mechanisms by which drugs target the microbiome and how drugs affect microbial function. Here we combined quantitative microbiome profiling, long-read metagenomics, stable isotope probing and single cell chemical imaging to investigate the impact of two widely prescribed nervous system targeted drugs on the gut microbiome.Ex vivosupplementation of physiologically relevant concentrations of entacapone or loxapine succinate to faecal samples significantly impacted the abundance of up to one third of the microbial species present. Importantly, we demonstrate that the impact of these drugs on microbial metabolism is much more pronounced than their impact on abundances, with low concentrations of drugs reducing the activity, but not the abundance of key microbiome members likeBacteroides, RuminococcusorClostridiumspecies. We further demonstrate that entacapone impacts the microbiome due to its ability to complex and deplete available iron, and that microbial growth can be rescued by replenishing levels of microbiota-accessible iron. Remarkably, entacapone-induced iron starvation selected for iron-scavenging organisms carrying antimicrobial resistance and virulence genes. Collectively, our study unveils the impact of two under-investigated drugs on whole microbiomes and identifies metal sequestration as a mechanism of drug-induced microbiome disturbance.
OprF functions as a latch to direct Outer Membrane Vesicle release inPseudomonas aeruginosa
Authors: Mathur Shrestha , Erickson Susan K. , Goldberg Leah R. , Hills Sonia , Radin Abigail G.B. , Schertzer Jeffrey W.
Published: November 2023

Bacterial Outer Membrane Vesicles (OMVs) contribute to virulence, competition, immune avoidance and communication. This has led to great interest in how they are formed. To date, investigation has focused almost exclusively on what controls the initiation of OMV biogenesis. Regardless of the mechanism of initiation, all species face a similar challenge before an OMV can be released: How does the OM detach from the underlying peptidoglycan (PG) in regions that will ultimately bulge and then vesiculate? The OmpA family of OM proteins (OprF inP. aeruginosa) is widely conserved and unusually abundant in OMVs across species considering their major role in PG attachment. OmpA homologs also have the interesting ability to adopt both PG-bound (two-domain) and PG-released (one-domain) conformations. Using targeted deletion of the PG-binding domain we showed that loss of cell wall association, and not general membrane destabilization, is responsible for hypervesiculation in OprF-modified strains. We therefore propose that OprF functions as a ‘latch’, capable of releasing PG in regions destined to become OMVs. To test this hypothesis, we developed a protocol to assess OprF conformation in live cells and purified OMVs. While >90% of OprF proteins exist in the two-domain conformation in the OM of cells, we show that the majority of OprF in OMVs is present in the one-domain conformation. With this work, we take some of the first steps in characterizing late-stage OMV biogenesis and identify a family of proteins whose critical role can be explained by their unique ability to fold into two distinct conformations.

Significance

Vesicular transport is now recognized to operate in all domains of life. However, the study of OMV biogenesis has been challenging because genetic screens failed to identify proteins analogous to those involved in eukaryotic vesicular transport. With this work we identify the first protein whose direct action can both define the location and govern the mechanism of OMV release. Our latch model is consistent with previous observations linking OmpA family proteins to OMV biogenesis, but further describes a physical mechanism that has broad implications for vesicle production and function across species. The work presented here advances our understanding of a fundamental virulence-associated process in bacteria, while underscoring stark differences in how transport vesicles are formed in prokaryotesversuseukaryotes.
A population code for spatial representation in the larval zebrafish telencephalon
Authors: Yang Chuyu , Mammen Lorenz , Kim Byoungsoo , Li Meng , Robson Drew N , Li Jennifer M
Published: November 2023

The vertebrate telencephalon is the site of complex cognitive processes, such as spatial cognition. The larval zebrafish telencephalon is a compact circuit of only ∼10,000 neurons that contains potentially homologous structures to the mammalian basal ganglia and limbic system (e.g., the hippocampus). However, despite long-standing evidence that spatial navigation and learning in zebrafish requires an intact telencephalon, cells believed to underlie spatial cognition in the mammalian hippocampus (e.g., place cells) have yet to be established in any fish species. Using a tracking microscope to image brain-wide activity at cellular resolution in freely swimming larval zebrafish, we compute the spatial information of neurons throughout the zebrafish brain. Strikingly, in every animal we recorded, cells with the highest spatial specificity are enriched in the zebrafish telencephalon. These cells form a population code of space, from which we can decode the animal’s spatial location across time. By continuous recording of population-level activity, we find that the activity manifold of place cells gradually untangles over time. Through systematic manipulation of allothetic and idiothetic cues, we demonstrate that place cells in the zebrafish telencephalon integrate multiple sources of information. By analysis of neighborhood distance between cells across environments, we find that the spatial representation in the zebrafish telencephalon partially generalizes across environments, suggesting that preconfigured network states may have been a feature of spatial computation that emerged early in vertebrate evolution.
Carboxydovores from the Pseudomonadota colonise volcanic soils during succession
Authors: Dawson Robin A. , Aguila Patricia , King Gary M. , Hernández Marcela
Published: November 2023

Carbon monoxide (CO) degrading microorganisms are present in volcanic deposits throughout succession, with vegetation and soil influencing the communities present. The carboxydovores are a subset of CO degraders that use CO only as an energy source, raising the question of how the physiological and metabolic features of the carboxydovores can make these bacteria more competitive in harsh volcanic ecosystems. An enrichment strategy was modified, which enabled the isolation of two carboxydovore representatives from genera that were abundant in the native soils,Cupriavidussp. CV2T(92.3% ANI vs.Cupriavidus basilensisDSM 11853) and a putative strain ofParaburkholderia terrae(Pb. terraeCOX) (96.42% ANI vs.Pb. terraeKU-64T). These isolates oxidise CO across a very broad range of concentrations, and genome sequence analysis indicated that they use form-I carbon monoxide dehydrogenase (CODH) to do so.Cupriavidussp. CV2TandPb. terraeCOX each oxidised CO specifically at stationary phase, but the conditions for induction of CODH expression were distinct.Cupriavidussp. CV2Texpressed CODH only in the presence of CO, whilePb. terraeCOX expressed CODH regardless of the presence of CO. Based on metabolic and phylogenetic analyses,Cupriavidussp. CV2Tis recommended as a novel species within the genusCupriavidus. Therefore, we propose the nameCupriavidus ulmosensissp. nov. for the type strain CV2T(= NCIMB 15506T, = CECT 30956T). This study provides valuable insights into the physiology and metabolism of carboxydovores, which colonise volcanic ecosystems during succession.

Importance

Volcanic ecosystems harbour many bacteria that contribute to the environmentally important process of carbon monoxide (CO) oxidation. We demonstrate a modified method for isolating bacteria, which consume CO at very low concentrations as a supplementary energy source (carboxydovory), leading to the isolation of two novel strains (Cupriavidussp. CV2TandParaburkholderia terraeCOX) from volcanic strata that formed in 1917 and 2015, respectively. The conditions under which CO consumption occurs were investigated; each strain consumed CO during stationary phase, butPb. terraeCOX consumed CO regardless of the prior growth conditions whileCupriavidussp. CV2 was more controlled.Cupriavidussp. CV2 is a type strain of a new species,Cupriavidus ulmosensisstr. CV2, which demonstrates relatively high tolerance for CO. These strains provide the basis for further study of the physiology, metabolism, and genetics of CO oxidation by carboxydovores, and will help us to understand how bacteria colonise harsh volcanic ecosystems.
Cerebellar α1D-adrenergic receptors mediate stress-induced dystonia in totteringtg/tgmice
Authors: Bohne Pauline , Josten Mareike , Rambuschek Lina , Zhu Xinran , Rybarski Max O. , Mark Melanie D.
Published: November 2023

Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs, but not α2-ARs, on cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE) from the locus coeruleus (LC), differentially expressed and required for initiation of dystonia. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tgmice but had no impact on ataxia amelioration.In vivorecordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of calcium from intracellular stores, thus preventing stress-induced dystonia. Furthermore, chemogenetic inhibition of the LC-NE pathway alleviated the frequency and symptoms of stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tgmice and, thereby providing a potential new therapeutic target to treat stress-induced dystonia in EA2.
Ancestry diversity in the genetic determinants of the human plasma proteome and associated new drug targets
Authors: Said Saredo , Pozarickij Alfred , Lin Kuang , Morris Sam , Kartsonaki Christiana , Wright Neil , Fry Hannah , Chen Yiping , Du Huaidong , Bennett Derrick , Avery Daniel , Schmidt Dan Valle , Li Liming , Lv Jun , Yu Canqing , Sun Dianjianyi , Pei Pei , Chen Junshi , Hill Michael , Peto Richard , Collins Rory , Clarke Robert , Millwood Iona Y , Chen Zhengming , Walters Robin G
Published: November 2023

The proteome is fundamental to human biology and disease but little is known about ancestral diversity of its genetic determinants. In GWAS of plasma levels of 1,451 proteins in 3,974 Chinese adults, we identified pQTLs for 1,082 proteins, including 743 with at least onecis-pQTL. Fine-mapping defined credible sets for 3,336 independent pQTLs, of which 31% did not overlap with corresponding analyses in European adults. We assessed 777 sentinelcis-pQTLs in phenome-wide MR analyses using GWAS Catalog and identified Bonferroni-significant associations for 22 protein-disease pairs. Among 10 protein-disease pairs identified from East Asian-specific GWAS, four had evidence of colocalisation. Evaluation of current drug development confirmed indications for one protein target, identified potential repurposing for seven, and discovered nine potential novel targets, including GP2 for Type-2-diabetes. The findings demonstrate the importance of extending genome-wide plasma proteomic analyses to non-European ancestry populations to identify potential novel drug targets for major diseases.
Mapping the Interplay of Atrial Fibrillation, Brain Structure and Cognitive Dysfunction
Authors: Petersen Marvin , Chevalier Céleste , Naegele Felix L. , Ingwersen Thies , Omidvarnia Amir , Hoffstaedter Felix , Patil Kaustubh , Eickhoff Simon B. , Schnabel Renate B. , Kirchhof Paulus , Schlemm Eckhard , Cheng Bastian , Thomalla Götz , Jensen Märit
Published: November 2023

Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. The investigation of the cognitive sequelae and alterations of brain structure linked to AF is crucial to help address ensuing health care needs. In this study, we conducted a comprehensive neuropsychological and neuroimaging analysis of 1335 stroke-free individuals with AF (30% women, average age 69.1 years) and compared them with 2683 demographically and cardiovascular risk-matched controls (31% women, average age 69.1 years). Primary study outcomes were neuropsychological test scores and advanced magnetic resonance imaging (MRI) measures of gray matter morphology, gray and white matter microstructure, and white matter hyperintensity (WMH) load. Our analysis identified deficits in attention/executive function, information processing speed and reasoning in individuals with AF. These cognitive impairments were accompanied by a complex imaging profile suggestive of small vessel pathology: (1) reduced cortical thickness and gray matter volume in areas including primary motor, somatosensory and visual cortices as well as the orbitofrontal, lateral prefrontal, posterior insular, and temporal cortices; (2) increased extracellular free-water content in the anterior cingulate, insula, medial prefrontal cortex, medial temporal lobe, and precuneus; (3) widespread microstructural anomalies in the cerebral white matter, marked by lower fractional anisotropy (FA), higher mean diffusivity (MD) and extracellular free-water, and a higher burden of markers of small vessel disease (WMH load and peak width of skeletonized mean diffusivity). Crucially, brain structural differences statistically mediated the link between AF and cognitive performance. By integrating a multimodal analysis approach with extensive clinical and MRI data, our study highlights small vessel pathology as a possible unifying link between AF, cognitive decline and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies.
Prodromal symptoms of rheumatoid arthritis in a primary care database: variation by ethnicity and socioeconomic status
Authors: d’Elia Alexander , Baranskaya Aliaksandra , Haroon Shamil , Hammond Ben , Adderley Nicola J , Nirantharakumar Krishnarajah , Chandan Joht Singh , Falahee Marie , Raza Karim
Published: November 2023

Objectives

To assess whether prodromal symptoms of rheumatoid arthritis (RA), as recorded in the Clinical Practice Research Datalink Aurum (CPRD) database of English primary care records, differ by ethnicity and socioeconomic status.

Methods

A cross-sectional study to determine the coding of common symptoms (≥0.1 % in the sample) in the 24 months preceding RA diagnosis in CPRD Aurum, recorded between January 1st2004 to May 1st2022. Eligible cases were adults with a code for RA diagnosis. For each symptom, a logistic regression was performed with the symptom as dependent variable, and ethnicity and socioeconomic status as independent variables. Results were adjusted for sex, age, BMI, and smoking status. White ethnicity and the highest socioeconomic quintile were comparators.

Results

In total, 70115 cases were eligible for inclusion, of which 66.4 % female. Twenty-one symptoms were coded in more than 0.1 % of cases so were included in the analysis. Patients of South Asian ethnicity had higher frequency of codes for several symptoms, with the largest difference by odds ratio being muscle cramps (OR 1.71, 1.44-2.57) and shoulder pain (1.44, 1.25-1.66). Patients of Black ethnicity had higher prevalence of several codes including unintended weight loss (2.02, 1.25-3.28) and ankle pain (1.51, 1.02-2.23). Low socioeconomic status was associated with morning stiffness (1.74, 1.08-2.80) and falls (1.37, 2.03-1.82)

Conclusion

There are significant differences in coded symptoms between demographic groups, which must be considered in clinical practice in diverse populations and to avoid algorithmic bias in prediction tools derived from routinely collected healthcare data.

Key messages

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There are differences in symptom reporting in new onset rheumatoid arthritis across ethnic groups.

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These differences should be considered in clinical practice in diverse populations.

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The findings are relevant in avoiding bias in prediction tools derived from healthcare data.
The association between chrononutrition behaviors and muscle health among older adults: The Study of Muscle, Mobility and Aging (SOMMA)
Authors: Mao Ziling , Cawthon Peggy M , Kritchevsky Stephen B , Toledo Frederico G S , Esser Karyn A , Erickson Melissa L , Newman Anne B , Farsijani Samaneh
Published: November 2023

Background

Emerging studies highlight chrononutrition’s impact on body composition through circadian clock entrainment, but its effect on older adults’ muscle health remains largely overlooked.

Objective

To determine the associations between chrononutrition behaviors and muscle health in older adults.

Methods

Dietary data from 828 older adults (76±5y) recorded food/beverage amounts and their clock time over the past 24 hours. Studied chrononutrition behaviors included:1)The clock time of the first and lastfood/beverage intake;2)Eating window(the time elapsed between the first and last intake); and3)Eating frequency(Number of self-identified eating events logged with changed meal occasion and clock time). Muscle mass (D3-creatine), leg muscle volume (MRI), grip strength (hand-held dynamometer), and leg power (Keiser) were used as outcomes. We used linear regression to assess the relationships between chrononutrition and muscle health, adjusting for age, sex, race, marital status, education, study site, self-reported health, energy, protein, fiber intake, weight, height, and moderate-to-vigorous physical activity.

Results

Average eating window was 11±2 h/d; first and last intake times were at 8:22 and 19:22, respectively. After multivariable adjustment, a longer eating window and a later last intake time were associated with greater muscle mass (β±SE: 0.18±0.09; 0.27±0.11, respectively,P<0.05). The longer eating window was also marginally associated with higher leg power (P=0.058). An earlier intake time was associated with higher grip strength (−0.38±0.15;P=0.012).

Conclusions

Chrononutrition behaviors, including longer eating window, later last intake time, and earlier first intake time were associated with better muscle mass and function in older adults.

GRAPHICAL ABSTRACT

Key findings

Chrononutrition behaviors, including longer eating window, later last intake time, and earlier first intake time were associated with better muscle mass and function in older adults.