bluuebunny/crossref_metadata_2025 huggingface dataset:
Coronary Artery Disease risk variant dampens the expression of CALCRL by reducing HSF binding to shear stress responsive enhancer in endothelial cells
Authors: Selvarajan Ilakya , Li Jin , Pölönen Petri , Örd Tiit , Õunap Kadri , Ravindran Aarthi , Mäklin Kiira , Toropainen Anu , Stolze Lindsey K. , White Stephen , Romanoski Casey E. , Heinäniemi Merja , Fang Yun , Kaikkonen-Määttä Minna
Published: February 2023

Coronary artery disease (CAD) is one of the major causes of mortality worldwide. Recent genome-wide association studies have started to unravel the genetic architecture of the disease. Such efforts have identified Calcitonin receptor-like (CALCRL), an important mediator of the endothelial fluid shear stress response, associated with CAD risk variants. In this study we functionally characterized the non-coding regulatory elements carrying CAD risks SNPs and studied their role in the regulation ofCALCRLexpression in endothelial cells. We demonstrate that rs880890-harboring regulatory element exhibits high enhancer activity and significant allelic bias with A allele showing 40% more activity than G allele. We also observed that the A allele of rs880890 is favored over the G allele under shear stress. CRISPR deletion of rs880890-enhancer resulted in downregulation ofCALCRLexpression. EMSA further showed that heat shock factors are binding to the enhancer with a preference for A allele over the G allele. In line with this, HSF1 knockdown resulted in a significant decrease inCALCRLexpression.CALCRLknockdown as well as variant perturbation experiments confirmed the role of CALCRL in the regulation of eNOS, apelin, angiopoietin, prostaglandins and endothelin-1 signaling pathways while demonstrating a significant decrease in cell proliferation and tube formation. Overall, our results demonstrate the existence of an endothelial-specific heat shock factor regulated transcriptional enhancer carrying a CAD risk SNP rs880890 that regulatesCALCRLexpression. Better understanding ofCALCRLgene regulation and the role of SNPs in modulation ofCALCRLexpression could provide important steps towards understanding genetic regulation of shear stress signaling responses.
Effect of exportin 1/XPO1 nuclear export pathway inhibition on coronavirus replication
Authors: Rahman Masmudur M. , Estifanos Bereket , Glenn Honor L. , Gutierrez-Jensen Ami D. , Kibler Karen , Li Yize , Jacobs Bertram , McFadden Grant , Hogue Brenda G.
Published: February 2023

Nucleocytoplasmic transport of proteins using XPO1 (exportin 1) plays a vital role in cell proliferation and survival. Many viruses also exploit this pathway to promote infection and replication. Thus, inhibiting the XPO1-mediated nuclear export pathway with selective inhibitors has a diverse effect on virus replication by regulating antiviral, proviral, and anti-inflammatory pathways. The XPO1 inhibitor, Selinexor, is an FDA-approved anticancer drug predicted to have antiviral or proviral functions against viruses. Here, we observed that pretreatment of cultured cell lines from human or mouse origin with nuclear export inhibitor Selinexor significantly enhanced protein expression and replication of Mouse Hepatitis Virus (MHV), a mouse coronavirus. Knockdown of cellular XPO1 protein expression also significantly enhanced the replication of MHV in human cells. However, for SARS-CoV-2, selinexor treatment had diverse effects on virus replication in different cell lines. These results indicate that XPO1-mediated nuclear export pathway inhibition might affect coronavirus replication depending on cell types and virus origin.
A resurrection ecology test for the effects of ionizing radiation and other environmental correlates onDaphniaevolution
Authors: Neely-Streit Twyla , O’Toole Megan C. , Ciolak Emily M. , Islam Musharrat , Heathcote Adam J. , Masterson Andrew L. , Walsh Matthew R. , Stuart Yoel E.
Published: February 2023

Acute exposure to ionizing radiation has well-documented, immediate negative consequences for individuals. However, the evolutionary consequences for populations exposed to ionizing radiation is unclear. For example, a meta-analysis of taxa exposed to Chernobyl fallout found some evidence for elevated mutation rates in animal and plant taxa; however, in people,de novomutation rates in offspring of parents exposed to radiation during and after the Chernobyl accident were no higher than controls. Furthermore, whether irradiation and increased mutation rates drive adaptation to radiation also has mixed support. Ambiguity in both cases likely arises from the difficulty of studying mutation rates and adaptation after rare nuclear events whose ionizing radiation is distributed heterogeneously in time and space. Here, we report an attempt to better address this difficulty with a “resurrection ecology” study ofDaphnia spp. in Utah lakes that experienced nuclear fallout from US Department of Energy weapons testing in the 1950s and 1960s. The idea was to recover dormantDaphniaeggs from sediment cores that spanned the nuclear testing era in the American West. We predicted that survival and fecundity of eggs hatched in the lab would show fitness declines correlated with ionizing radiation fallout and a potential recovery once nuclear testing stopped. We successfully obtained multiple cores from three lakes that dated back to the 1800s. We isolated >4700 dormant eggs from those cores, spanning the nuclear era, but were only able to hatch a single egg in the lab. Thus, we could not conduct life history experiments to test our prediction. The purpose of this manuscript, therefore, is to describe the study and make our radioisotope core dating and sedimentation data available to other paleolimnological researchers. We also report a side study of stable isotope change through time measured from dormant eggs and the sediment.
Odor cueing of declarative memories during sleep enhances coordinated spindles and slow oscillations
Authors: Sánchez-Corzo Andrea , Baum David M , Irani Martín , Hinrichs Svenja , Reisenegger Renate , Whitaker Grace A , Born Jan , Klinzing Jens G , Sitaram Ranganatha
Published: February 2023

Long-term memories are formed by repeated reactivation of newly encoded information during sleep. This process can be enhanced by using memory-associated reminder cues like sounds and odors. While auditory cueing has been researched extensively, few electrophysiological studies have exploited the various benefits of olfactory cueing. We used high-density electroencephalography in an odor-cueing paradigm that was designed to isolate the neural responses specific to the cueing of declarative memories. We show widespread cueing-induced increases in the duration and rate of sleep spindles. Higher spindle rates were most prominent over centro-parietal areas and largely overlapping with a concurrent increase in the amplitude of slow oscillations (SOs). Interestingly, greater SO amplitudes were linked to a higher likelihood of coupling a spindle and coupled spindles expressed during cueing were more numerous in particular around SO up states. We thus identify temporally and spatially coordinated enhancements to sleep spindles and slow oscillations as a candidate mechanism behind the benefits of odor cueing. Our results further demonstrate the feasibility of studying neural activity patterns related to memory processing using olfactory cueing during sleep.

Statement of Significance

Memory cueing during sleep allows insights into memory consolidation. This study is the first to investigate olfactory cueing-induced declarative memory processing using high-density EEG, while robustly controlling for critical confounding factors. The use of odors as cues, instead of more common auditory stimuli, further minimizes possible distortions due to sensory-evoked potentials. We demonstrate intricate changes in brain activity in response to cueing, such as the patterns of sleep spindles, slow oscillations, and their spatiotemporal coupling. We provide evidence that the enhancement of slow oscillation amplitudes, together with associated increases in sleep spindle rates, could be the key mechanism behind cueing-related memory benefits. We moreover show that prior findings obtained using auditory cueing are not the mere result of tone-evoked responses but might be genuine signatures of memory processing.
The Effects of Speech Masking on Neural Tracking of Acoustic and Semantic Features of Natural Speech
Authors: Yasmin Sonia , Irsik Vanessa C. , Johnsrude Ingrid S. , Herrmann Björn
Published: February 2023

Listening environments contain background sounds that mask speech and lead to communication challenges. Sensitivity to slow acoustic fluctuations in speech can help segregate speech from background noise. Semantic context can also facilitate speech perception in noise, for example, by enabling prediction of upcoming words. However, not much is known about how different degrees of background masking affect the neural processing of acoustic and semantic features during naturalistic speech listening. In the current electroencephalography (EEG) study, participants listened to engaging, spoken stories masked at different levels of multi-talker babble to investigate how neural activity in response to acoustic and semantic features changes with acoustic challenges, and how such effects relate to speech intelligibility. The pattern of neural response amplitudes associated with both acoustic and semantic speech features across masking levels was U-shaped, such that amplitudes were largest for moderate masking levels. This U-shape may be due to increased attentional focus when speech comprehension is challenging, but manageable. The latency of the neural responses increased linearly with increasing background masking, and neural latency change associated with acoustic processing most closely mirrored the changes in speech intelligibility. Finally, tracking responses related to semantic dissimilarity remained robust until severe speech masking (−3 dB SNR). The current study reveals that neural responses to acoustic features are highly sensitive to background masking and decreasing speech intelligibility, whereas neural responses to semantic features are relatively robust, suggesting that individuals track the meaning of the story well even in moderate background sound.
The disordered N-terminal tail of SARS CoV-2 Nucleocapsid protein forms a dynamic complex with RNA
Authors: Cubuk Jasmine , Alston Jhullian J. , Incicco J. Jeremías , Holehouse Alex S. , Hall Kathleen B , Stuchell-Brereton Melissa D. , Soranno Andrea
Published: February 2023

The SARS-CoV-2 Nucleocapsid (N) protein is responsible for condensation of the viral genome. Characterizing the mechanisms controlling nucleic acid binding is a key step in understanding how condensation is realized. Here, we focus on the role of the RNA Binding Domain (RBD) and its flanking disordered N-Terminal Domain (NTD) tail, using single-molecule Förster Resonance Energy Transfer and coarse-grained simulations. We quantified contact site size and binding affinity for nucleic acids and concomitant conformational changes occurring in the disordered region. We found that the disordered NTD increases the affinity of the RBD for RNA by about 50-fold. Binding of both nonspecific and specific RNA results in a modulation of the tail configurations, which respond in an RNA length-dependent manner. Not only does the disordered NTD increase affinity for RNA, but mutations that occur in the Omicron variant modulate the interactions, indicating a functional role of the disordered tail. Finally, we found that the NTD-RBD preferentially interacts with single-stranded RNA and that the resulting protein:RNA complexes are flexible and dynamic. We speculate that this mechanism of interaction enables the Nucleocapsid protein to search the viral genome for and bind to high-affinity motifs.
Deep spatial-omics to aid personalization of precision medicine in metastatic recurrent Head & Neck Cancers
Authors: Causer Andrew , Tan Xiao , Lu Xuehan , Moseley Philip , Teoh Min , McGrath Margaret , Kim Taehyun , Simpson Peter , Perry Christopher , Frazer Ian , Panizza Benedict , Ladwa Rahul , Nguyen Quan , Gonzalez-Cruz Jazmina L
Published: February 2023

Immune checkpoint inhibitor (ICI) modality has had a limited success (<20%) in treating metastatic recurrent Head & Neck Oropharyngeal Squamous cell carcinomas (OPSCCs). To improve response rates to ICIs, tailored approaches capable to capture the tumor complexity and dynamics of each patient’s disease are needed. Here, we performed advanced analyses of spatial proteogenomic technologies to demonstrate that: (i) compared to standard histopathology, spatial transcriptomics better-identified tumor cells and could specifically classify them into two different metabolic states with therapeutic implications; (ii) our new method (Spatial Proteomics-informed cell deconvolution method orSPiD) improved profiling of local immune cell types relevant to disease progression, (iii) identified clinically relevant alternative treatments and a rational explanation for checkpoint inhibitor therapy failure through comparative analysis of pre- and post-failure tumor data and, (iv) discovered ligand-receptor interactions as potential lead targets for personalized drug treatments. Our work establishes a clear path for incorporating spatial-omics in clinical settings to facilitate treatment personalization.
Real-world body orientation impacts virtual navigation experience and performance
Authors: Moon Hyuk-June , Wu Hsin-Ping , De Falco Emanuela , Blanke Olaf
Published: February 2023

Most human navigation studies in MRI rely on virtual navigation. However, the necessary supine position in MRI makes it fundamentally different from daily ecological navigation. Nonetheless, until now, no study has assessed whether differences in physical body orientation (BO) affect participants' experienced BO during virtual navigation. Here, combining an immersive virtual reality (VR) navigation task with subjective BO measures and implicit behavioral measures, we demonstrate that physical BO (either standing or supine) modulated experienced BO. Also, we show that standing upright BO is preferred during spatial navigation: participants were more likely to experience a standing BO and were better at spatial navigation when standing upright. Importantly, we report that showing a supine virtual agent reduces the conflict between the preferred BO and physical supine BO. Our study provides critical, but missing, information regarding experienced BO during virtual navigation, which should be considered cautiously when designing navigation studies, especially in MRI.
In vivoLocus Coeruleus activity while awake is associated with REM sleep quality in healthy older individuals
Authors: Koshmanova Ekaterina , Berger Alexandre , Beckers Elise , Campbell Islay , Mortazavi Nasrin , Sharifpour Roya , Paparella Ilenia , Balda Fermin , Berthomier Christian , Degueldre Christian , Salmon Eric , Lamalle Laurent , Bastin Christine , Egroo Maxime Van , Phillips Christophe , Maquet Pierre , Collette Fabienne , Muto Vincenzo , Chylinski Daphne , Jacobs Heidi IL , Talwar Puneet , Sherif Siya , Vandewalle Gilles
Published: February 2023

The locus coeruleus (LC) is the primary source of norepinephrine (NE) in the brain, and the LC-NE system is involved in regulating arousal and sleep. It plays key roles in the transition between sleep and wakefulness, and between slow wave sleep (SWS) and rapid eye movement sleep (REMS). However, it is not clear whether the LC activity during the day predicts sleep quality and sleep properties during the night, and how this varies as a function of age. Here, we used 7 Tesla functional Magnetic Resonance Imaging (7T fMRI), sleep electroencephalography (EEG) and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 52 healthy younger (N=33; ~22y; 28 women) and older (N=19; ~61y; 14 women) individuals. We find that, in older, but not in younger participants, higher LC activity, as probed during an auditory mismatch negativity task, is associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS (4-8Hz), which are two sleep parameters significantly correlated in our sample of older individuals. The results remain robust even when accounting for the age-related changes in the integrity of the LC. These findings suggest that the activity of the LC may contribute to the perception of the sleep quality and to an essential oscillatory mode of REMS, and that the LC may be an important target in the treatment of sleep disorders and age-related diseases.
Nesting Bird Communities of Urban Forest Parks Suffer from Recreational Load (on the Example of Kyiv, Ukraine)
Authors: Shupova Tetiana , Gaychenko Vitaliy , Raichuk Liudmila
Published: February 2023

The urban environment has a complex effect on the forest diversity. Birds are a suitable object for diagnostic of ecosystem disturbances. The urban recreation load in forest parks was estimated using the author’s methodology according to the total points. To analyze the urban recreation load, we took the characteristics of the forest park and the surrounding landscapes, which are important for the birds’ life, the nesting result, and stable population maintenance: the share of urbanized territory; the share of the territory with unorganized recreation; forest park attendance; the presence of freely rambling pets. The number and distribution of birds were determined by registrations of birds along transects in May–June 2017–2018. 30–54 bird species nest in each forest park with an average density of 1.6 (SD: 0.4)–3.8 (SD: 0.9) pairs/ha.Parus majorL.,Fringilla coelebsL.,Turdus merulaL., sometimesSturnus vulgarisL.,Erithacus rubeculaL.,Turdus pilarisL. are dominant in communities. Urban recreation load leads to a change in the bird nesting strategy, the composition of their communities contributes to the extinction of non-synanthropized species, reduces the abundance of ground-nesters. This leads to a decrease in the number of their populations and some species impoverishment. The synanthropy index of nesting bird communities was 0.38–0.57. A positive correlation between the urban recreation load and the synanthropy index (0.75), Berger–Parker index (0.40), a relative abundance of hollow nesters (0.59), and a negative correlation with the abundance of ground nesters (−0.59) were revealed. To minimize the negative impact of the recreational load on bird communities, to preserve vulnerable species at nesting and maintain the species diversity of avifauna, it is necessary to create areas in forest parks protected from hiking, display in geducational advertising on the importance of preserving animals and their habitats.
Pharmaceutical patent landscaping: A novel approach to understand patents from the drug discovery perspective
Authors: Gadiya Yojana , Gribbon Philip , Hofmann-Apitius Martin , Zaliani Andrea
Published: February 2023

Patents play a crucial role in the drug discovery process by providing legal protection for discoveries and incentivising investments in research and development. By identifying patterns within patent data resources, researchers can gain insight into the market trends and priorities of the pharmaceutical and biotechnology industries, as well as provide additional perspectives on more fundamental aspects such as the emergence of potential new drug targets. In this paper, we used the patent enrichment tool, PEMT, to extract, integrate, and analyse patent literature for rare diseases (RD) and Alzheimer’s disease (AD). This is followed by a systematic review of the underlying patent landscape to decipher trends and applications in patents for these diseases. To do so, we discuss prominent organisations involved in drug discovery research in AD and RD. This allows us to gain an understanding of the importance of AD and RD from specific organisational (pharmaceutical or university) perspectives. Next, we analyse the historical focus of patents in relation to individual therapeutic targets and correlate them with market scenarios allowing the identification of prominent targets for a disease. Lastly, we identified drug repurposing activities within the two diseases with the help of patents. This resulted in identifying existing repurposed drugs and novel potential therapeutic approaches applicable to the indication areas. The study demonstrates the expanded applicability of patent documents from legal to drug discovery, design, and research, thus, providing a valuable resource for future drug discovery efforts. Moreover, this study is an attempt towards understanding the importance of data underlying patent documents and raising the need for preparing the data for machine learning-based applications.
Fitting Force Field parameters to NMR Relaxation Data
Authors: Kümmerer Felix , Orioli Simone , Lindorff-Larsen Kresten
Published: February 2023

We present an approach to optimise force field parameters using time-dependent data from NMR relaxation experiments. To do so, we scan parameters in the dihedral angle potential energy terms describing the rotation of the methyl groups in proteins, and compare NMR relaxation rates calculated from molecular dynamics simulations with the modified force fields to deuterium relaxation measurements of T4 lysozyme. We find that a small modification of Cγmethyl groups improves the agreement with experiments both for the protein used to optimize the force field, and when validating using simulations of CI2 and ubiquitin. We also show that these improvements enable a more effectivea posteriorireweighting of the MD trajectories. The resulting force field thus enables more direct comparison between simulations and side-chain NMR relaxation data, and makes it possible to construct ensembles that better represent the dynamics of proteins in solution.
The ATR inhibitor elimusertib exhibits anti-lymphoma activity and synergizes with the PI3K inhibitor copanlisib
Authors: Sartori Giulio , Tarantelli Chiara , Spriano Filippo , Gaudio Eugenio , Cascione Luciano , Mascia Michele , Barreca Marilia , Arribas Alberto J. , Licenziato Luca , Golino Gaetanina , Ferragamo Adele , Pileri Stefano , Damia Giovanna , Zucca Emanuele , Stathis Anastasios , Politz Oliver , Wengner Antje M. , Bertoni Francesco
Published: February 2023

Purpose

The DNA damage response (DDR) is the cellular process devoted to the preservation of an intact genome. The DDR is often deregulated in lymphoma cells due to high levels of DNA damage, tumor suppressor inactivation, increased replication stress observed after oncogene activation, or high amounts of reactive oxygen species. The ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial factor of DDR in the response to DNA single strand breaks. ATR inhibitors are a class of agents that have shown considerable clinical potential in this context.

Experimental Design

We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a panel of lymphoma cell lines. Furthermore, we evaluated the activity of elimusertib in combination with the clinically approved PI3K inhibitor copanlisib inin vitroandin vivolymphoma models.

Results

Elimusertib exhibitedin vitroactivity across a variety of lymphoma subtypes which was associated with expression of genes related to replication stress. Elimusertib also demonstrated wide-spread anti-tumor activity that was stronger compared to ceralasertib, another ATR inhibitor, in several tumor models. This activity was present in both DDR-proficient and DDR-deficient lymphoma models. Furthermore, elimusertib had synergistic antitumor activity in combination with copanlisib.

Conclusions

Potent antitumor activity of elimusertib was demonstrated in several lymphoma models which is associated with high expression of gene transcripts coding for proteins that are involved in DDR and cell cycle regulation. Combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib had synergistic efficacy providing a potential new treatment option for lymphoma patients.

Translational relevance

The DNA damage response (DDR) is often deregulated in lymphoma cells. Here, we characterized the activity of elimusertib, an inhibitor of the ataxia telangiectasia and Rad3-related kinase (ATR) that is involved in the DDR. Elimusertib was demonstrated to exhibit anti-lymphoma activity across several lymphoma cell lines and tumor models. Copanlisib is an inhibitor of PI3K kinase family which has also shown activity in various lymphomas. Combined treatment with elimusertib and copanlisib resulted in a synergistic antitumor effect in lymphoma models. The combination of elimusertib and copanlisib could potentially constitute a new chemotherapy-free treatment option for lymphomas.
Parallel mechanisms detect different photoperiods to independently control seasonal flowering and growth in plants
Authors: Wang Qingqing , Liu Wei , Leung Chun Chung , Tartè Daniel A. , Gendron Joshua M.
Published: February 2023

For nearly 100 years, we have known that both growth and flowering in plants are seasonally regulated by the length of the day (photoperiod). Intense research focus and powerful genetic tools have propelled studies of photoperiodic flowering, but far less is known about photoperiodic growth, in part because tools were lacking. Here, using a new genetic tool that visually reports on photoperiodic growth, we identified a seasonal growth regulation pathway, from photoperiod detection to gene expression. Surprisingly, this pathway functions in long days but is distinct from the canonical long day photoperiod flowering mechanism. This is possible because the two mechanisms detect the photoperiod in different ways: flowering relies on measuring photoperiod by directly detecting duration of light intensity while the identified growth pathway relies on measuring photosynthetic period indirectly by detecting the duration of photosynthetic metabolite production. In turn, the two pathways then control expression of genes required for flowering or growth independently. Finally, our tools allow us to show that these two types of photoperiods, and their measurement systems, are dissociable. Our results constitute a new view of seasonal timekeeping in plants by showing that two parallel mechanisms measure different photoperiods to control plant growth and flowering, allowing these processes to be coordinated independently across seasons.
Predicting changes in neutralizing antibody activity for SARS-CoV-2 XBB.1.5 usingin silicoprotein modeling
Authors: Ford Colby T. , Yasa Shirish , Machado Denis Jacob , White Richard Allen , Janies Daniel
Published: February 2023

The SARS-CoV-2 variant XBB.1.5 is of concern as it has high transmissibility. XBB.1.5 currently accounts for upwards of 30% of new infections in the United States. One year after our group published the predicted structure of the Omicron (B.1.1.529) variant’s receptor binding domain (RBD) and antibody binding affinity, we return to investigate the new mutations seen in XBB.1.5 which is a descendant of Omicron. Using in silicoicomodeling approaches against newer neutralizing antibodies that are shown effective against B.1.1.529, we predict the immune consequences of XBB.1.5’s mutations and show that there is no statistically significant difference in overall antibody evasion when comparing to the B.1.1.529 and other related variants (e.g., BJ.1 and BM.1.1.1). However, noticeable changes in antibody binding affinity were seen due to specific amino acid changes of interest in the newer variants.
GILEA: GAN Inversion-enabled latent eigenvalue analysis for phenome profiling and editing
Authors: Wu Jiqing , Koelzer Viktor H.
Published: February 2023

Modeling heterogeneous disease states by data-driven methods has great potential to advance biomedical research. However, a comprehensive analysis of phenotypic heterogeneity is often challenged by the complex nature of biomedical datasets and emerging imaging methodologies. Here, we propose a novel GAN Inversion-enabled Latent Eigenvalue Analysis (GILEA) framework and apply it to phenome profiling and editing. As key use cases for fluorescence and natural imaging, we demonstrate the power of GILEA using publicly available SARS-CoV-2 datasets stained with the multiplexed fluorescence cell-painting protocol as well as real-world medical images of common skin lesions captured by dermoscopy. The quantitative results of GILEA can be biologically supported by editing latent representations and simulating dynamic phenotype transitions between physiological and pathological states. In conclusion, GILEA represents a new and broadly applicable approach to the quantitative and interpretable analysis of biomedical image data. The GILEA code and video demos are publicly available athttps://github.com/CTPLab/GILEA.
Pervasive environmental chemicals impair oligodendrocyte development
Authors: Cohn Erin F. , Clayton Benjamin L.L. , Madhavan Mayur , Yacoub Sara , Federov Yuriy , Paul-Friedman Katie , Shafer Timothy J. , Tesar Paul J.
Published: February 2023

Exposure to environmental chemicals can impair neurodevelopment1–4. Oligodendrocytes that wrap around axons to boost neurotransmission may be particularly vulnerable to chemical toxicity as they develop throughout fetal development and into adulthood5,6. However, few environmental chemicals have been assessed for potential risks to oligodendrocyte development. Here, we utilized a high-throughput developmental screen and human cortical brain organoids, which revealed environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non-cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDC’s National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our oligodendrocyte toxicity platform. Collectively, our work identifies toxicological vulnerabilities specific to oligodendrocyte development and highlights common household chemicals with high exposure risk to children that warrant deeper scrutiny for their impact on human health.
Meta-analysis and Open-source Database for In Vivo Brain Magnetic Resonance Spectroscopy in Health and Disease
Authors: Gudmundson Aaron T. , Koo Annie , Virovka Anna , Amirault Alyssa L. , Soo Madelene , Cho Jocelyn H. , Oeltzschner Georg , Edden Richard A.E. , Stark Craig
Published: February 2023

Proton (1H) Magnetic Resonance Spectroscopy (MRS) is a non-invasive tool capable of quantifying brain metabolite concentrationsin vivo. Prioritization of standardization and accessibility in the field has led to the development of universal pulse sequences, methodological consensus recommendations, and the development of open-source analysis software packages. One on-going challenge is methodological validation with ground-truth data. As ground-truths are rarely available forin vivomeasurements, data simulations have become an important tool. The diverse literature of metabolite measurements has made it challenging to define ranges to be used within simulations. Especially for the development of deep learning and machine learning algorithms, simulations must be able to produce accurate spectra capturing all the nuances ofin vivodata. Therefore, we sought to determine the physiological ranges and relaxation rates of brain metabolites which can be used both in data simulations and as reference estimates. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we’ve identified relevant MRS research articles and created an open-source database containing methods, results, and other article information as a resource. Using this database, expectation values and ranges for metabolite concentrations and T2relaxation times are established based upon a meta-analyses of healthy and diseased brains.
Alpaca Single B Cell Interrogation and Heavy-Chain-Only Antibody Discovery on an Optofluidic Platform
Authors: Shapiro Mariya B , Boucher Jacqueline , Brousseau Anna , Dehkharghani Amin , Gabriel Justin , Kamat Vishal , Patil Ketan , Gao Feng , Walker Jennifer , Kelly Ryan , Souders Colby A
Published: February 2023

In vivodiscovery approaches for single domain antibodies such as VHH have been limited by the lack of methodologies available for camelid B cell interrogation. Here, we report a novel application of the Berkeley Lights Beacon® optofluidic platform to the discovery of heavy-chain-only antibodies by screening single B cells from alpacas immunized with two different targets. Custom methods for alpaca B cell enrichment, culture, on-Beacon IgG2/3 detection, and sequencing were developed and used to discover target-specific VHH candidates from an alpaca immunized with either human prostate specific membrane antigen (PSMA) or a second blinded target, in a proof-of-concept study. PSMA-specific VHH hits discovered on the Beacon were recombinantly expressed as VHH-Fc, purified, and characterized using label-free techniques. All but one VHH-Fc bound PSMA with a single-digit nanomolar affinity, and four candidates were successfully humanizedin silicousing a rapid bulk humanization approach. In addition, next-generation repertoire sequencing was performed at longitudinal timepoints after immunization, uncovering additional variants within the clonal lineages of the validated hits discovered on the Beacon platform. The establishment of this single B cell VHH discovery workflow extends the powerful Beacon technology to enable rapid discovery of VHH directly from natural camelid immune repertoires.
Continuous Prediction of Leg Kinematics during Walking using Inertial Sensors, Smart Glasses, and Embedded Computing
Authors: Tsepa Oleksii , Burakov Roman , Laschowski Brokoslaw , Mihailidis Alex
Published: February 2023

Unlike traditional hierarchical controllers for robotic leg prostheses and exoskeletons, continuous systems could allow persons with mobility impairments to walk more naturally in real-world environments without requiring high-level switching between locomotion modes. To support these next-generation controllers, we developed a new system calledKIFNet(Kinematics and Image Fusing Network) that uses lightweight and efficient deep learning models to continuously predict the leg kinematics during walking. We tested different sensor fusion methods to combine kinematics data from inertial sensors and computer vision data from smart glasses and found that adaptive instance normalization achieved the lowest RMSE predictions for knee and ankle joint kinematics. We also deployed our model on an embedded device. Without inference optimization, our model was 20 times faster than the previous state-of-the-art and achieved 20% higher prediction accuracies, and during some locomotor activities like stair descent, decreased RMSE up to 300%. With inference optimization, our best model achieved 125 FPS on an NVIDIA Jetson Nano. These results demonstrate the potential to build fast and accurate deep learning models for continuous prediction of leg kinematics during walking based on sensor fusion and embedded computing, therein providing a foundation for real-time continuous controllers for robotic leg prostheses and exoskeletons.
Encoding of predictive associations in human prefrontal and medial temporal neurons during Pavlovian conditioning
Authors: Aquino Tomas G. , Courellis Hristos , Mamelak Adam N. , Rutishauser Ueli , O’Doherty John P.
Published: February 2023

Pavlovian conditioning is thought to involve the formation of learned associations between stimuli and values, and between stimuli and specific features of outcomes. Here we leveraged human single neuron recordings in ventromedial prefrontal, dorsomedial frontal, hippocampus and amygdala neurons while patients performed a sequential Pavlovian conditioning task containing both stimulus-value and stimulus-stimulus associations. Neurons in the ventromedial prefrontal cortex encoded predictive value along with the amygdala, but also encoded predictions about the identity of stimuli that would subsequently be presented, suggesting a role for neurons in this region in encoding predictive information beyond value. Unsigned error signals were found in dorsomedial prefrontal areas and hippocampus, potentially supporting learning of non-value related outcome features. Our findings implicate distinct human prefrontal and medial temporal neuronal populations in mediating predictive associations which could partially support model-based mechanisms during Pavlovian conditioning.

Significance statement

Pavlovian conditioning is a fundamental form of learning, allowing organisms to associate stimuli and outcomes. Recent Pavlovian work suggests that phenomena such as devaluation sensitivity and sensory preconditioning can be explained by a model-based learning framework. How human neurons perform model-based learning during Pavlovian conditioning is still an open question. We recorded single neurons from epilepsy patients during a two-step Pavlovian conditioning task and found that ventromedial prefrontal neurons encoded expected rewards along with amygdala neurons, but also predicted the identity of upcoming stimuli as required for model-based cognition. Additionally, medial frontal neurons were found to encode error signals that could be used for stimulus-outcome learning. This is the first study mapping model-based computations during Pavlovian conditioning in human neurons.
CaV3.1 Channels Facilitate Calcium Wave Generation and Myogenic Tone Development in Mouse Mesenteric Arteries
Authors: El-Lakany Mohammed A. , Haghbin Nadia , Arora Naman , Hashad Ahmed M. , Mironova Galina Yu. , Sancho Maria , Welsh Donald G.
Published: February 2023

Background

The myogenic response is the mechanism whereby intraluminal pressure elicits arterial constriction pursuant to the maintenance of tissue perfusion. Smooth muscle [Ca2+] is a key determinant of constriction, a process intimately tied to L-type (CaV1.2) Ca2+channels. While important, other Ca2+channels, in particular T-type, are expressed and could contribute to pressure regulation within defined voltage ranges. This study examined the role of one T-type Ca2+channel using mesenteric arteries from C57BL/6 wild type and CaV3.1-/-mice.

Methods

Patch-clamp electrophysiology, pressure myography, non-invasive blood pressure measurements and rapid Ca2+imaging were employed to define the CaV3.1-/-phenotype relative to C57BL/6. Proximity ligation assay tested the closeness of CaV3.1 channels to inositol triphosphate receptors (IP3R). Nifedipine (0.3 μM) and 2-APB (50 μM) were used to block L-type Ca2+channels and IP3Rs, respectively.

Results

Initial experiments confirmed the absence of CaV3.1 expression and whole-cell current in global deletion mice, a change that coincided with a reduction in systemic blood pressure. Mesenteric arteries from CaV3.1-/-mice produced less myogenic tone than C57BL/6, particularly at lower pressures (20-60 mmHg) where membrane potential is more hyperpolarized. This reduction in myogenic tone correlated with diminished Ca2+wave generation in the CaV3.1-/-mice. These asynchronous events are dependent upon Ca2+release from the sarcoplasmic reticulum which is insensitive to L-type Ca2+channel blockade. A close physical association (<40 nm) between IP3R1 and CaV3.1 was confirmed by proximity ligation assay; blockade of IP3R in nifedipine-treated C57BL/6 arteries rendered a CaV3.1-/-contractile phenotype.

Conclusion

Findings indicate that Ca2+influx through CaV3.1 channels contributes to myogenic tone development at hyperpolarized voltages by triggering a Ca2+-induced Ca2+release mechanism tied to the sarcoplasmic reticulum. This study helps establish CaV3.1 as a potential therapeutic target in the control of blood pressure.
Complementary effects of above- and belowground biodiversity on ecosystem functions across global grasslands
Authors: Martins Catarina S. C. , Delgado-Baquerizo Manuel , Jayaramaiah Ramesha H. , Wang Jun-Tao , Sáez-Sandino Tadeo , Liu Hongwei , Maestre Fernando T. , Reich Peter B. , Singh Brajesh K.
Published: February 2023

Grasslands are integral to maintaining biodiversity and key ecosystem services under climate change. Plant and soil biodiversity, and their interactions, support the provision of multiple ecosystem functions (multifunctionality). However, whether plant and soil biodiversity explain unique, or shared, contributions to supporting multifunctionality across global grasslands remains virtually unknown. Here, we combine results from a global survey of 101 grasslands with a novel microcosm study, controlling for both plant and soil microbial diversity to identify their individual and interactive contribution to support multifunctionality under aridity and experimental drought. We found that, plant and soil microbial diversity independently predict a unique portion of variation in above- and belowground functioning, suggesting both types of biodiversity complement each other. Interactions between plant and soil microbial diversity regulated primary productivity, nutrient storage, and plant productivity. Our findings were also context dependent, since soil fungal diversity was strongly associated to multifunctionality in less arid regions, while plant diversity was strongly linked to multifunctionality in more arid regions. Our results highlight the need to conserve both above- and belowground diversity to sustain grassland multifunctionality in a drier world and indicate climate change may shift the relative contribution of plant and soil biodiversity to multifunctionality across global grasslands.
Impact of COVID-19 Outbreak on Healthcare Workers in a Tertiary Healthcare Center in India - A cross sectional study
Authors: Mirza Shahzad , VR Arvinden , Rophina Mercy , Bhawalkar Jitendra , Chothani Bhavin , Khan Uzair , Singh Shivankur , Sharma Tanya , Dwivedi Aryan , Pandey Ellora , Garg Shivam , Sadrudin Mukhida Sahjid , Sange Zeeshan Shabbir Ahmed , Bhaumik Shalini , Varughese Jessin , Devkar Vishwamohini Yallappa , Singh Jyoti , mol V K Anju , K Veena , Mandviwala Husen Shabbir Husen , Scaria Vinod , Gupta Aayush
Published: February 2023

Numerous speculations have continually emerged, trying to explore the association between COVID-19 infection and a varied range of demographic and clinical factors. Frontline healthcare workers have been at the forefront of this illness exposure. However, there is a paucity of large cohort-based association studies, performed among Indian health care professionals, exploring their potential risk and predisposing factors. This study aims to systematically utilize the demographic and clinical data of over 3000 healthcare workers from a tertiary hospital in India to gain significant insights on the associations between disease prevalence, severity, and post-infection symptoms.

Article Summary

Potential associations between various demographic and clinical factors with disease severity and post COVID syndromes among a large cohort of healthcare workers in India suggest that Smokers were discovered to be more vulnerable to COVID-19 infection because of their immunocompromised lung health and Blood group B, like previous studies, was found to possess an increased risk of predisposition to long COVIDs
ADAM10 mediates macroglial cell fate decisions in the developing brain
Authors: Wang Yihui , Liang Yue , Ai Daosheng , Li Jun-Liszt , Feng Ziyan , Guo Zhibao , Chen Xing-jun , Zhang Tingting , Zou Xiaoxiao , Gao Jun-Li , Gao Xiaofei , Hu Xiao-Ling , Wu Long-Jun , Sun Wenzhi , Zhu Suiqiang , Duan Shumin , Wang Wei , Ge Woo-ping
Published: February 2023

ADAMs (a disintegrinandmetalloproteinase) are transmembrane proteins with cell adhesion and protease activities that contain disintegrin and metalloproteinase domains. ADAM10, a member of the ADAM family, is widely expressed in the brain. There are >40 substrates reported for ADAM10, including Notch, Delta-like ligand-1 (Dll1), and N-cadherin. To date, however, its function in the brain has been largely unknown. We used genetic manipulation to deleteAdam10specifically from glial progenitors in developing brains and observed that conditional knockout mice showed locomotor abnormalities. They all died within 4 months with apparent defects in the cerebellum. By comprehensively analyzing data from bulk RNA sequencing, single-cell RNA sequencing, and staining of the cerebellum, we found that ADAM10 promoted astrocyte generation under physiological conditions. Upon the removal ofAdam10in glial progenitors, the production of oligodendrocytes vastly increased, whereas the generation of astrocytes was substantially inhibited. Our results showed that ADAM10 plays a critical role in macroglial cell fate decisions during brain development.
Cold Comfort: metabolic rate and tolerance to low temperatures predict latitudinal distribution in ants
Authors: Willot Quentin , Ørsted Michael , Malte Hans , Overgaard Johannes
Published: February 2023

Metabolic compensation has been proposed as a mean for ectotherms to cope with colder climates. For example, under the metabolic cold adaptation/metabolic homeostasis hypotheses (MCA/MHH), it has been formulated that cold-adapted ectotherms should display higher/more thermally sensitive metabolic rates (MRs) at lower temperatures. However, whether such compensation can truly be associated with distribution, and whether it interplays with cold-tolerance to support species’ climatic niches, remains largely unclear despite broad ecological implications thereof. Here, we teased apart the relationship between MRs, cold-tolerance, and distribution, to confront the MCA/MHH among 13 ant species. We report clear metabolic compensation effects, consistent with the MCA and MHH, where MR parameters strongly correlated with latitude and climatic factors across species’ distributions. The combination of both cold-tolerance and MR further upheld the best predictions of species’ climatic niches. To our knowledge, this is the first study showing that the association of metabolic data with cold-tolerance supports increased predictive value for biogeographical models in social insects. These results also highlight that adaptation to higher latitudes in ants involved adjustments of both cold-tolerance and MRs, potentially at the expense of metabolic performance at warmer temperatures, to allow this extremely successful group of insects to thrive under colder climates.