bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional Activation of Regenerative Hematopoiesis via Vascular Niche Sensing
Authors: Itkin Tomer , Houghton Sean , Schreiner Ryan , Lin Yang , Badwe Chaitanya R. , Voisin Veronique , Murison Alex , Seyedhassantehrani Negar , Kaufmann Kerstin B. , Garcia-Prat Laura , Booth Gregory T. , Geng Fuqiang , Liu Ying , Gomez-Salinero Jesus M. , Shieh Jae-Hung , Redmond David , Xiang Jenny Z. , Josefowicz Steven Z. , Trapnell Cole , Spencer Joel A. , Zangi Lior , Hadland Brandon , Dick John E. , Xie Stephanie Z. , Rafii Shahin
Published: March 2023

Transition between activation and quiescence programs in hematopoietic stem and progenitor cells (HSC/HSPCs) is perceived to be governed intrinsically and by microenvironmental co-adaptation. However, HSC programs dictating both transition and adaptability, remain poorly defined. Single cell multiome analysis divulging differential transcriptional activity between distinct HSPC states, indicated for the exclusive absence of Fli-1 motif from quiescent HSCs. We reveal that Fli-1 activity is essential for HSCs during regenerative hematopoiesis. Fli-1 directs activation programs while manipulating cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche. During regenerative conditions, Fli-1 presets and enables propagation of niche-derived Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional HSC impairments in the absence of Fli-1. Applying FLI-1 modified-mRNA transduction into lethargic adult human mobilized HSPCs, enables their vigorous niche-mediated expansion along with superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immune regenerative medicine.
Maximal coral thermal tolerance is found at intermediate diel temperature variability
Authors: Brown Kristen T. , Martynek Marcelina , Barott Katie L.
Published: March 2023

It has become critically important to identify environmental drivers of enhanced thermal tolerance in coral populations as ocean warming threatens the persistence of coral reef ecosystems globally. Variable temperature regimes that expose corals to sub-lethal heat stress have been recognized as a mechanism to increase coral thermotolerance and lessen coral bleaching; however, there is a need to better understand which thermal regimes are best for promoting coral stress hardening, and if thermal priming results in consistent benefits across species with distinct life-history strategies.

Standardized thermal stress assays were used to determine the relative thermal tolerance of three divergent genera of corals (Acropora, PocilloporaandPorites) originating from six reef sites fluctuating in temperature by up to 7.7°C day-1, with an annual mean diel variability of 1–3°C day-1. Bleaching severity and dark-acclimated photochemical yield (Fv/Fm) were quantified following exposure to five temperature treatments ranging from 23.0 to 36.3°C — up to 9°C above the regional maximum monthly mean.

The greatest thermal tolerance across all species was found at the site with intermediate mean diel temperature variability (2.2°C day-1), suggesting there is an optimal priming exposure that leads to maximal thermotolerance. Interestingly,AcroporaandPocilloporaoriginating from the least thermally variable regimes (i.e., <1.3°C day-1) had lower thermal tolerance than corals from the most variable sites (i.e., > 2.8°C day-1), whereas the opposite was true forPorites, suggesting divergent responses to priming across taxa.

We highlight that fine-scale heterogeneity in temperature dynamics across habitats can increase coral thermal tolerance in diverse coral lineages, although in a non-linear manner. Remarkably, comparisons across global studies revealed that the range in coral thermotolerance uncovered in this study across a single reef system (<5 km) were as large as differences observed across vast latitudinal gradients (>300 km). This important finding indicates that local gene flow could improve thermal tolerance between habitats. However, as climate change continues, exposure to intensifying marine heatwaves is already compromising thermal priming as a mechanism to enhance coral thermal tolerance and bleaching resistance.
PIEZO1-mediated mechanosensing governs NK cell killing efficiency and infiltration in three-dimensional matrices
Authors: Yanamandra Archana K. , Zhang Jingnan , Montalvo Galia , Zhou Xiangda , Biedenweg Doreen , Zhao Renping , Sharma Shulagna , Hoth Markus , Lautenschläger Franziska , Otto Oliver , del Campo Aránzazu , Qu Bin
Published: March 2023

Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK cell killing efficiency in 3D is impaired against softened tumor cells, while it is enhanced against stiffened tumor cells. Notably, the durations required for NK cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness-dependent NK cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK cell functions.
Alopecosa nagpagacts on cardiac ventricular myocytes to kill prey
Authors: Gu Zhixin , Long Chenbo , Lu Yuehua , Huang Biao
Published: March 2023

Spiders are excellent predator to kill their prey by peptide toxins from its venoms.Alopecosa nagpag(A. nagpag) is a new identified wolf spider distributing in Yunnan province and nothing has known about the venom. In this study, venom ofA. nagpagshowed mild toxicity to Kunming mouse with LD50of 3.32 mg/kg. Action potential duration (APD) was prolonged in a frequency-dependent manner and whole currents of neonatal rat ventricular myocytes (NRVMs) were inhibited by venom. Meanwhile, venom ofA. nagpagcould largely increase L calcium currents (ICaL). Whereas sodium current (INa) and rapidly activating delayed rectifier potassium current (IKr) were significantly decreased by 100 μg/mL venoms. No obvious inhibition was found on other ion channels such as rapidly activating and inactivating transient inward (IK1), rapid (IKr) and slow (IKs). As those ion channels play critical role in rhythm of cardiac ventricular myocytes,A. nagpagmay lead prey to death by changing cardiac rhythm.
Analytical Comparability to Evaluate Impact of Manufacturing Changes of ARX788, an Anti-HER2 ADC in Late-Stage Clinical Development
Authors: Yu Wayne , Ramprasad Mysore , Pal Manoj , Chen Chris , Paruchuri Shashi , Skidmore Lillian , Knudsen Nick , Allen Molly , Buechler Ying
Published: March 2023

ARX788 is an anti-HER2 antibody drug conjugate (ADC) developed using Ambrx proprietary Engineered Precision Biologics technology. The manufacturing process of ARX788 has been optimized during the course of early to late-phase clinical development. A comprehensive evaluation of side-by-side comparability between pre- and post-change process for ARX788 drug substance and drug product from a quality perspective was conducted based on ICH Q5E guidelines consisting of batch release assays, physicochemical and biophysical characterization, biological characterization, and forced degradation studies. All results have demonstrated a high degree of similarity between the pre- and post-change ARX788 drug substance batches and drug product lots, demonstrating that the process manufacturing changes did not impact product quality.
Neuromolecular interactions guiding homeostatic mechanisms underlying healthy ageing: A view from computational microscope
Authors: Saha Suman , Chakraborty Priyanka , Naskar Amit , Roy Dipanjan , Banerjee Arpan
Published: March 2023

Ageing brain is associated with a slow drift in structural network properties over the lifespan accompanied by reorganization in neuromolecular interactions giving rise to changes in global functional markers. What are the guiding principles of the homeostatic mechanisms that maintain the desired performance of functional neural circuits and preserve brain health during healthy ageing? We hypothesize that an ageing brain alters two primary neurotransmitters, glutamate andγ-aminobutyric acid (GABA), responsible for excitation-inhibition regulation, concomitant with anatomical demyelination to preserve critical neural dynamics that are necessary to uphold optimal network performance. Thus, often observed re-organized functional connectivity with age by several investigations is a byproduct of this adaptive process. We demonstrate that the adaptive mechanism is driven by the tuning of glutamate and GABA concentration over a very slow time scale (lifespan) that can be estimated by tracking criticality from co-ordinated neural dynamics at a resting state via a biophysically driven computational framework, introduced as a computational microscope. We validate several empirical observations and model predictions across three independent aging cohorts using this computational microscope. One of the key mechanisms we discover is the reduction in local glutamate levels employed by brain regions to maintain a homeostatic balance with aging. This is further supported by the invariance of measures of global functional integration during the healthy ageing process.
Ability of Bifidobacterium breve 702258 to transfer from mother to infant: the MicrobeMom randomised controlled trial
Authors: Moore Rebecca L. , Feehily Conor , Killeen Sarah Louise , Yelverton Cara A. , Geraghty Aisling A. , Walsh Calum J , O’Neill Ian J. , Nielsan Ida Bush , Lawton Elaine M. , Gallardo Rocio Sanchez , Chandra Nori Sai Ravi , Shanahan Fergus , Murphy Eileen F. , Van Sinderen Douwe , Cotter Paul D. , McAuliffe Fionnuala M.
Published: March 2023

Background

The composition of the infant microbiome can have a variety of short- and long-term implications for health. It is unclear if maternal probiotic supplementation in pregnancy can impact infant gut microbiome.

Objective

The aim of our study was to investigate if maternal supplementation of a formulation of Bifidobacterium breve 702258 from early pregnancy until three months postpartum could transfer to the infant gut.

Study design

This was a double-blinded placebo controlled randomised-controlled trial of B. breve 702258 (minimum 1×109colony forming units) or placebo taken orally from 16-weeks’ gestation until three-months postpartum in healthy pregnant women. The primary outcome was presence of the supplemented strain in infant stool up to 3 months of life, detected by at a least two of three methods, i.e., strain specific PCR, shotgun metagenomic sequencing, or genome sequencing of cultured B. breve. 120 individual infants’ stool samples were required for 80% power to detect a difference in strain transfer between groups. Rates of detection were compared using Fishers exact test.

Results

160 pregnant women with average age 33.6 (3.9) years, mean BMI of 24.3 (22.5, 26.5) kg/m2and 43% with nulliparity (n=58) were recruited from September 2016 to July 2019. Neonatal stool samples were obtained from 135 infants (65 in intervention and 70 in control). The presence of the supplemented strain was detected through at least two methods (PCR and culture) in two infants in the intervention group (n=2/65, 3.1%) and none in the control group (n=0, 0%),p= 0.230.

Conclusion

Direct strain transfer from mothers to infants of B. breve 772058 occurred, albeit infrequently. This study highlights potential for maternal supplementation to introduce microbial strains into the infant microbiome.

Trial registration number

ISRCTN53023014
The effects of weather and mobility on respiratory viruses dynamics before and after the COVID-19 pandemic
Authors: Varela-Lasheras Irma , Perfeito Lília , Mesquita Sara , Gonçalves-Sá Joana
Published: March 2023

The flu season is caused by a combination of different pathogens, including influenza viruses (IVS), that cause the flu, and non-influenza respiratory viruses (NIRVs), that cause common colds or influenza-like illness. These viruses have similar circulation patterns, and weather has been considered a main driver of their dynamics, with peaks in the winter and almost no circulation during the summer in temperate regions. However, after the emergence of SARS-CoV2, in 2019, the dynamics of these respiratory viruses were strongly perturbed worldwide: some infections almost disappeared, others were delayed or occurred “off-season”. This disruption raised questions regarding the dominant role of weather while also providing an unique opportunity to investigate the relevance of different driving factors on the epidemiological dynamics of IVs and NIRVs, including viral interactions, non-pharmacological individual measures (such as masking), or mobility. Here, we use epidemiological surveillance data on several respiratory viruses from Canada and the USA from 2016 to 2023, and tested the effects of weather and mobility in their dynamics before and after the COVID-19 pandemic. Using statistical modelling, we found evidence that whereas in the pre-COVID-19 pandemic period, weather had a strong effect and mobility a limited effect on dynamics; in the post-COVID-19 pandemic period the effect of weather was strongly reduced and mobility played a more relevant role. These results, together with previous studies, indicate that at least some of the behavioral changes resulting from the non-pharmacological interventions implemented during COVID-19 pandemic had a strong effect on the dynamics of respiratory viruses. Furthermore, our results support the idea that these seasonal dynamics are driven by a complex system of interactions between the different factors involved, which probably led to an equilibrium that was disturbed, and perhaps permanently altered, by the COVID-19 pandemic.
A combination of annual and nonannual forces drive respiratory disease in the tropics
Authors: Yang Fuhan , Servadio Joseph L , Le Thanh Nguyen Thi , Lam Ha Minh , Choisy Marc , Thai Pham Quang , Nhu Thao Tran Thi , Thao Vy Nguyen Ha , Phuong Huynh Thi , Nguyen Tran Dang , Hoai Tam Dong Thi , Hanks Ephraim M , Vinh Ha , Bjornstad Ottar N , Van Vinh Chau Nguyen , Boni Maciej F
Published: March 2023

Background

It is well known that influenza and other respiratory viruses are wintertime-seasonal in temperate regions. However, respiratory disease seasonality in the tropics remains elusive. In this study, we aimed to characterize the seasonality of influenza-like illness (ILI) and influenza virus in Ho Chi Minh City (HCMC), Vietnam.

Methods

We monitored the daily number of ILI patients in 89 outpatient clinics from January 2010 to December 2019. We collected nasal swabs and tested for influenza from a subset of clinics from May 2012 to December 2019. We used spectral analysis to describe the periodicities in the system. We evaluated the contribution of these periodicities to predicting ILI and influenza patterns through lognormal and gamma hurdle models.

Findings

During ten years of community surveillance, 66,799 ILI reports were collected covering 2.9 million patient visits; 2604 nasal swabs were collected 559 of which were PCR-positive for influenza virus. Both annual and nonannual cycles were detected in the ILI time series, with the annual cycle showing 8.9% lower ILI activity (95% CI: 8.8%-9.0%) from February 24 to May 15. Nonannual cycles had substantial explanatory power for ILI trends (ΔAIC = 183) compared to all annual covariates (ΔAIC = 263). Near-annual signals were observed for PCR-confirmed influenza but were not consistent along in time or across influenza (sub)types.

Interpretation

Our study reveals a unique pattern of respiratory disease dynamics in a tropical setting influenced by both annual and nonannual drivers. Timing of vaccination campaigns and hospital capacity planning may require a complex forecasting approach.

Funding

National Institutes of Health, Wellcome Trust.
Patient engagement in research; benefits, challenges, importance, and implications
Authors: Ivany Caitlyn , Hudson Tess , Schneider Patricia , Farrukh Hadia , Swinton Marilyn , Ghert Michelle
Published: March 2023

Objective

Patient engagement (PE) and patient-oriented research have begun to reshape the thought process behind conducting research with the aim of maximizing the relevance of findings for patients. This study aimed to examine the perceived benefits, challenges, importance, and implications of patient engagement from the perspectives of sarcoma patient advisors and researchers.

Methods

This study utilized a mixed model design. Qualitative data was collected through two focus group discussions with sarcoma patients. Quantitative data was collected via a survey containing Likert scale questions completed by the Centre for Evidence-Based Orthopaedics Musculoskeletal Oncology research team at McMaster University.

Results

Results showed that patients value the opportunity to contribute to research and support future patients. Being a patient advisor also creates a sense of community and fosters support through building connections and communicating with other patients. Members of the research team noted that patient engagement is important for the study of patient relevant topics and provides insight into the improvement of patient care. However, an added challenge is the lack of current guidance surrounding the implementation of patient engagement.

Conclusion

These findings emphasize the potential value of patient engagement while also highlighting the need for further research into best practices for the implementation of patient engagement efforts. Overall, patient engagement is an essential area in need of further exploration to enhance future research and clinical trials.
The association between maternal intra-abdominal pressure, pregnancy induced hypertension
Authors: Jayasundara Sajith , Goonewardene Malik , Dassanayake Lanka
Published: March 2023

Introduction

Pregnancy leads to a state of chronically increased intra-abdominal pressure (IAP) caused by a growing fetus, fluid, and tissue. Increased intra-abdominal pressure is leading to state of Intra-Abdominal Hypertension (IAH) and Abdominal Compartment Syndrome. Clinical features and risk factors of preeclampsia is comparable to abdominal compartment syndrome. Intra-abdominal pressure (IAP) may be associated with the pathogenesis of pregnancy induced hypertension.

Objectives

The study aimed to determine the antepartum and postpartum IAP levels in women undergoing caesarean delivery (CD) and association between hypertension in pregnancy, and antepartum and postpartum IAP levels in women undergoing caesarean delivery (CD).

Method

Seventy pregnant women (55 normotensive, 15 hypertension in pregnancy) undergoing antepartum, non-emergency CD, had their intravesical pressure measured before and after the CD, the intravesical pressure measurements obtained with the patient in the supine position were considered to correspond to the IAP. Multivariable linear regression models were used to study associations between intraabdominal pressure and baseline characteristics in normotensive pregnancies and hypertensive pregnancies.

Results

In normotensive pregnancies at mean gestation age of 38 weeks +2days (95%CI 37+6 to 38 +4), mean antepartum IAP was 12.7 mmHg(95%CI 11.6 to 13.8) and the mean postpartum IAP was 7.3 mmHg (95% CI 11.6 to 13.8).

Multivariable linear regression models showed hypertension in pregnancy group antepartum IAP positively associated with coefficient value of 1.617 (p= 0.268) comparing with normotensive pregnancy group.

Postpartum IAP in hypertension in pregnancy group positively associated with coefficient value of 2.519 (p= 0.018) comparing with normotensive pregnancy group.

IAP difference is negatively associated with hypertension in pregnancy (coefficient -1.013, p= 0.179)

Conclusion

In normotensive pregnancies at term, the IAP was in the IAH range of the non-pregnant population. Higher Antepartum IAP and Postpartum IAP are associated with hypertension in pregnancy. Reduction of IAP from antepartum period to postpartum period was less with hypertension in pregnancy.
Analysis of the Health Economics Portfolio Funded by the National Institutes of Health in Response to Published Guidance
Authors: Burgdorf Caitlin E. , Riley William T. , Akbar Farheen , Zuehlke Abbey D. , Bibb Katrina , Eshleman Heather D. , Shah Ami , Belis Deshiree , Spittel Michael , Fearon Paula
Published: March 2023

Health economics is one of the interdisciplinary sciences that the National Institutes of Health (NIH) supports in order to pursue its overall mission to improve health. In 2015, NIH guidance was published to clarify the type of health economics research that NIH would continue to fund. This analysis aimed to determine if there were changes in the number of health economics applications received and funded by NIH after the release of the guidance. Health economics applications submitted to NIH both before and after the guidance was released were identified using a machine learning approach with input from subject matter experts. Application and funding trends were examined by fiscal year, method of application (solicited vs. unsolicited), and activity code. This study found that application and funding rates of health economics research was decreasing prior to guidance. Following publication of this guidance, the application and funding rate of health economics applications increased.
WITHDRAWN: Not To Skip Yet: Impact of Intravenous Thrombolysis on Final Infarction Volume and Clinical Outcomes in Early Arrivals Acute Large Vessel Occlusion: A Retrospective Cohort Study
Authors: Mohamed Ghada A , Essibayi Muhammed Amir , Sharf Valerie , Ali Hamid , Myeralis Pavlos , Lee William , Fugatt Robert , Jacks Kevin , Aboul-Nour Hassan , Spampinato M Vittoria , Wabnitz Ashley M , Holmstedt Christine
Published: March 2023

Withdrawal Statement

The authors have withdrawn their manuscript because it was posted without the author’s permission and encompasses non-finalized data analysis and conclusions. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
Transcriptional profiling of populations in the clamRuditapes decussatussuggests genetically determined differentiation in gene-expression along parallel temperature gradients and between races of the Atlantic Ocean and West Mediterranean sea
Authors: Saavedra Carlos , Milan Massimo , Leite Ricardo , Cordero David , Patarnello Tomaso , Cancela Leonor , Bargelloni Luca
Published: March 2023

Ongoing ocean warming due to climate change poses new challenges for marine life and its exploitation. We have used transcriptomics to find genetically-based responses to increased temperature in natural populations of the marine clamRuditapes decussatusliving along parallel thermal gradients in southern Europe. Clams of the Atlantic and West Mediterranean races were collected in a northern (cool) and a southern (warm) localities. The animals were kept in running seawater in the warm, Atlantic southern locality for a 15-week period, during which water temperature raised to typical southern European summer values. After this period, the expression profile was obtained for a total of 34 clams and 11,025 probes by means of an oligonucleotide microarray. We found distinct transcriptional patterns for each population based on a total of 553 differentially expressed genes (DEG), indicating innate differences which probably have a genetic basis. Race and latitude contributed significantly to gene expression differences, with very different sets of DEG. A gene ontology analysis showed that races differed mainly at genes involved in ribosomal function and protein biosynthesis, while genes related to glutathione metabolism and ATP synthesis in the mitochondria were the most outstanding as to north/south transcriptional differences.
Cultured Mesenchymal Cells from Nasal Turbinate as a Cellular Model of the Neurodevelopmental Component of Schizophrenia Etiology
Authors: Tung Victoria Sook Keng , Mathews Fasil , Boruk Marina , Suppa Gabrielle , Foronjy Robert , Pato Michele , Pato Carlos , Knowles James A. , Evgrafov Oleg V.
Published: March 2023

Study of the neurodevelopmental molecular mechanisms of schizophrenia requires the development of adequate biological models such as patient-derived cells and their derivatives. We previously used cell lines with neural progenitor properties (CNON) derived from superior or middle turbinates of patients with schizophrenia and control groups to study gene expression specific to schizophrenia.

In this study, we compared single cell-RNA seq data from two CNON cell lines, one derived from an individual with schizophrenia (SCZ) and the other from a control group, with two biopsy samples from the middle turbinate (MT), also from an individual with SCZ and a control. In addition, we compared our data with previously published data from olfactory neuroepithelium (1). Our data demonstrated that CNON originated from a single cell type which is present both in middle turbinate and olfactory neuroepithelium. CNON express multiple markers of mesenchymal cells. In order to define relatedness of CNON to the developing human brain, we also compared CNON datasets with scRNA-seq data of embryonic brain (2) and found that the expression profile of CNON very closely matched one of the cell types in the embryonic brain. Finally, we evaluated differences between SCZ and control samples to assess usability and potential benefits of using single cell RNA-seq of CNON to study etiology of schizophrenia.
Radiosynthesis automation, non-human primate biodistribution and dosimetry of K+channel tracer [11C]3MeO4AP
Authors: Zhou Yu-Peng , Wilks Moses Q. , Dhaynaut Maeva , Guehl Nicolas J. , Moon Sung-Hyun , Fakhri Georges El , Normandin Marc D. , Brugarolas Pedro
Published: March 2023

Purpose

4-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination. In preclinical studies, [11C]3MeO4AP has shown promise due to its high brain permeability, high metabolic stability, high plasma availability, and highin vivobinding affinity. To prepare for the translation to human studies, we developed a cGMP-compliant automated radiosynthesis protocol and evaluated the whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP in non-human primates (NHPs).

Methods

Automated radiosynthesis was carried out using a GE TRACERlab FX-C Pro synthesis module. One male and one female adult rhesus macaques were used in the study. A high-resolution CT from cranial vertex to knee was acquired. PET data were collected using a dynamic acquisition protocol with 4 bed positions and 13 passes over a total scan time of ∼150 minutes. Based on the CT and PET images, volumes of interest (VOIs) were manually drawn for selected organs. Non-decay corrected time-activity curves (TACs) were extracted for each VOI. Radiation dosimetry and effective dose were calculated from the integrated TACs using OLINDA software.

Results

Fully automated radiosynthesis of [11C]3MeO4AP was achieved with 7.3 ± 1.2 % (n = 4) of non-decay corrected radiochemical yield within 38 min of synthesis and purification time. [11C]3MeO4AP distributed quickly throughout the body and into the brain. The organs with highest dose were the kidneys. The average effective dose of [11C]3MeO4AP was 4.27 ± 0.57 μSv/MBq. No significant changes in vital signs were observed during the scan.

Conclusion

The cGMP compliant automated radiosynthesis of [11C]3MeO4AP was developed. The whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP was successfully evaluated in NHPs. [11C]3MeO4AP shows lower average effective dose than [18F]3F4AP and similar average effective dose as other carbon-11 tracers.
A reference assembly for the legume cover crop, hairy vetch (Vicia villosa)
Authors: Fuller Tyson , Koch Lisa M. , Kucek Lisa Kissing , Ali Shahjahan , Mangelson Hayley , Hernandez Timothy , Smith Timothy P.L. , Bickhart Derek M. , Riday Heathcliffe , Sullivan Michael L.
Published: March 2023

Vicia villosais an incompletely domesticated annual legume of the Fabaceae family native to Europe and Western Asia.V. villosais widely used as a cover crop and as a forage due to its ability to withstand harsh winters. A reference-quality genome assembly (Vvill1.0) was prepared from low error rate long sequence reads to improve genetic-based trait selection of this species. The Vvill1.0 assembly includes seven scaffolds corresponding to the seven estimated linkage groups and comprising approximately 68% of the total genome size of 2.03 gigabase pairs (Gbp). This assembly is expected to be a useful resource for genetic improvement of this emerging cover crop species as well as to provide useful insights into plant genome evolution.
Deep Learning Initialized Compressed Sensing (Deli-CS) in Volumetric Spatio-Temporal Subspace Reconstruction
Authors: Iyer Siddharth S. , Schauman S. Sophie , Sandino Christopher M. , Yurt Mahmut , Cao Xiaozhi , Liao Congyu , Ruengchaijatuporn Natthanan , Chatnuntawech Itthi , Tong Elizabeth , Setsompop Kawin
Published: March 2023

Introduction

Spatio-temporal MRI methods enable whole-brain multi-parametric mapping at ultra-fast acquisition times through efficient k-space encoding, but can have very long reconstruction times, which limit their integration into clinical practice. Deep learning (DL) is a promising approach to accelerate reconstruction, but can be computationally intensive to train and deploy due to the large dimensionality of spatio-temporal MRI. DL methods also need large training data sets and can produce results that don’t match the acquired data if data consistency is not enforced. The aim of this project is to reduce reconstruction time using DL whilst simultaneously limiting the risk of deep learning induced hallucinations, all with modest hardware requirements.

Methods

Deep Learning Initialized Compressed Sensing (Deli-CS) is proposed to reduce the reconstruction time of iterative reconstructions by “kick-starting” the iterative reconstruction with a DL generated starting point. The proposed framework is applied to volumetric multi-axis spiral projection MRF that achieves whole-brain T1 and T2 mapping at 1-mm isotropic resolution for a 2-minute acquisition. First, the traditional reconstruction is optimized from over two hours to less than 40 minutes while using more than 90% less RAM and only 4.7 GB GPU memory, by using a memory-efficient GPU implementation. The Deli-CS framework is then implemented and evaluated against the above reconstruction.

Results

Deli-CS achieves comparable reconstruction quality with 50% fewer iterations bringing the full reconstruction time to 20 minutes.

Conclusion

Deli-CS reduces the reconstruction time of subspace reconstruction of volumetric spatio-temporal acquisitions by providing a warm start to the iterative reconstruction algorithm.
Changes in local interaction rules during ontogeny underlie the evolution of collective behavior
Authors: Paz Alexandra , Holt Karla J. , Clarke Anik , Aviles Ari , Abraham Briana , Keene Alex C. , Duboué Erik R. , Fily Yaouen , Kowalko Johanna E.
Published: March 2023

Collective motion emerges from individual interactions which produce groupwide patterns in behavior. While adaptive changes to collective motion are observed across animal species, how local interactions change when these collective behaviors evolve is poorly understood. Here, we use the Mexican tetra,A. mexicanus,which exists as a schooling surface form and a non-schooling cave form, to study differences in how fish alter their swimming in response to neighbors across ontogeny and between evolutionarily diverged populations. We find that surface fish undergo a transition to schooling during development that occurs through increases in inter-individual alignment and attraction mediated by changes in the way fish modulate speed and turning relative to neighbors. Cavefish, which have evolved loss of schooling, exhibit neither of these schooling-promoting interactions at any stage of development. These results reveal how evolution alters local interaction rules to produce striking differences in collective behavior.
A 20th-centuryCannabispollen increase in a Pyrenean varved record and its potential causes
Authors: Rull Valentí , Vegas-Vilarrúbia Teresa
Published: March 2023

The continuous, varved and absolutely dated sedimentary record of Lake Montcortès (Iberian Pyrenees) has provided evidence for a distinct and characteristic 20thcentury (1980s) increase inCannabispollen (20C) that persists today. This event was coeval with the geographical shift of the hemp production center in the Iberian Peninsula from east to northeast (where Lake Montcortès lies), which was accompanied by a significant production increase. This increasing trend was fostered by the renewed interest of the paper industry in hemp and was promoted by the onset of European Union subsidies to hemp cultivation. Illegal cannabis crops could have also contributed to theCannabispollen increase, but sound evidence is still lacking. These preliminary conclusions should be reinforced by increasing the resolution of the current palynological record and modeling the dispersal ofCannabispollen around the Montcortès region. More similar high-resolution records are needed to verify the geographical extent of the 20C event. Additionally, Lake Montcortès varved sediments are proposed as a suitable candidate to characterize the onset of the “Anthropocene” epoch (mid-20thcentury), as currently defined by the Anthropocene Working Group.
Structural insights into ligand recognition and selectivity of the human hydroxycarboxylic acid receptor HCAR2
Authors: Pan Xin , Ye Fang , Ning Peiruo , Zhang Zhiyi , Zhang Binghao , Chen Geng , Gao Wei , Qiu Chen , Wu Zhangsong , Gong Kaizheng , Li Jiancheng , Xia Jiang , Du Yang
Published: March 2023

Hydroxycarboxylic acid receptor 2 (HCAR2) belongs to the family of class A G-protein-coupled receptors with key roles in regulating lipolysis and free fatty acid formation in humans. It is deeply involved in many pathophysiological processes and serves as an attractive target for the treatment of neoplastic, autoimmune, neurodegenerative, inflammatory, and metabolic diseases. Here, we report four cryo-EM structures of human HCAR2-Gi1 complexes with or without agonists, including the drugs niacin and acipimox, and the highly subtype-specific agonist MK-6892. Combined with molecular docking and functional analysis, we have revealed the recognition mechanism of HCAR2 for different agonists and summarized the general pharmacophore features of HCAR2 agonists, which are based on three key residues R1113.36, S17945.52, and Y2847.43. Notably, the MK-6892-HCAR2 structure shows an extended binding pocket relative to other agonist-bound HCAR2 complexes. In addition, the key residues that determine the ligand selectivity between the HCAR2 and HCAR3 are also illuminated. Our findings provide structural insights into the ligand recognition, selectivity, activation, and G protein coupling mechanism of HCAR2, which sheds light on the design of new HCAR2-targeting drugs for greater efficacy, higher selectivity, and fewer or no side effects.
Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F/MAPTP301Smouse model of Alzheimer’s disease
Authors: Jiang Lulu , Roberts Rebecca , Wong Melissa , Zhang Lushuang , Webber Chelsea Joy , Kilci Alper , Jenkins Matthew , Sun Guangxin , Rashad Sherif , Sun Jingjing , Dedon Peter C , Daley Sarah Anne , Xia Weiming , Ortiz Alejandro Rondón , Dorrian Luke , Saito Takashi , Saido Takaomi C. , Wolozin Benjamin
Published: March 2023

The study for the pathophysiology study of Alzheimer’s disease (AD) has been hampered by lack animal models that recapitulate the major AD pathologies, including extracellular β-amyloid (Aβ) deposition, intracellular aggregation of microtubule associated protein tau (MAPT), inflammation and neurodegeneration. We now report on a double transgenic APPNL-G-FMAPTP301Smouse that at 6 months of age exhibits robust Aβ plaque accumulation, intense MAPT pathology, strong inflammation and extensive neurodegeneration. The presence of Aβ pathology potentiated the other major pathologies, including MAPT pathology, inflammation and neurodegeneration. However, MAPT pathology neither changed levels of amyloid precursor protein nor potentiated Aβ accumulation. The APPNL-G-F/MAPTP301Smouse model also showed strong accumulation of N6-methyladenosine (m6A), which was recently shown to be elevated in the AD brain. M6A primarily accumulated in neuronal soma, but also co-localized with a subset of astrocytes and microglia. The accumulation of m6A corresponded with increases in METTL3 and decreases in ALKBH5, which are enzymes that add or remove m6A from mRNA, respectively. Thus, the APPNL-G-F/MAPTP301Smouse recapitulates many features of AD pathology beginning at 6 months of aging.
Active-feedback 3D single-molecule tracking using a fast-responding galvo scanning mirror
Authors: Tan Xiaochen , Hou Shangguo , Zhang Chen , Niver Anastasia , Johnson Alexis , Welsher Kevin D.
Published: March 2023

Real-time three-dimensional single-particle tracking (RT-3D-SPT) allows continuous detection of individual freely diffusing objects with high spatiotemporal precision by applying closed-loop active feedback in an optical microscope. However, the current tracking speed in RT-3D-SPT is primarily limited by the response time of control actuators, impeding long-term observation of fast diffusive objects such as single molecules. Here, we present an RT-3D-SPT system with improved tracking performance by replacing the XY piezoelectric stage with a galvo scanning mirror with an approximately five-time faster response rate (~5 kHz). Based on the previously developed 3D single-molecule active real-time tracking (3D-SMART), this new implementation with a fast-responding galvo mirror eliminates the mechanical movement of the sample and allows more rapid response to particle motion. The improved tracking performance of the galvo mirror-based implementation is verified through simulation and proof-of-principle experiments. Fluorescent nanoparticles and ~ 1 kB double-stranded DNA molecules were tracked via both the original piezoelectric stage and new galvo mirror implementations. With the new galvo-based implementation, notable increases in tracking duration, localization precision, and the degree to which the objects are locked to the center of the detection volume were observed. These results suggest faster control response elements can expand RT-3D-SPT to a broader range of chemical and biological systems.
Real time analysis of SARS-CoV-2 induced cytolysis reveals distinct variant-specific replication profiles
Authors: Scheuermann Sarah E , Goff Kelly , Rowe Lori A , Beddingfield Brandon J , Maness Nicholas J
Published: March 2023

The continuous evolution of new SARS-CoV-2 variants with enhanced immune evasion capacity suggests the entire population is and will continue to be potentially vulnerable to infection despite pre-existing immunity. The ability of each new variant to evade host humoral immunity is the focus of intense research across the globe. Each variant may also harbor unique replication capabilities relevant for disease and transmission. Here we demonstrate the utility of a new approach to assessing viral replication kinetics using Real Time Cell Analysis (RTCA). Virus induced cell death is measured in real time by the detection of electrical impedance through cell monolayers. Using this system, we quantified replication kinetics of five clinically important viral variants; USA WA1/2020 (an A1 ancestral lineage isolate), Delta, and Omicron subvariants BA.1, BA.4, and BA.5. We identified multiple kinetic measures that proved useful in variant replication comparisons including time (in hours) to the maximum rate of cell death at each log10 viral dilution and the slope at the maximum rate of cell death. We found that WA1/2020 and Delta were the most rapid but in distinct ways. While WA1/2020 induced cell death most rapidly after inoculation, Delta was slightly slower to reach cell death, it appeared to kill cells faster once cytotoxic effects began. Interestingly, BA.1, showed substantially reduced replication kinetics relative to all other variants. Together, these data show that real time analysis of cell death is a robust method to assess replicative capacity of any given SARS-CoV-2 variant rapidly and quantitatively, which may be useful in assessment of newly emerging variants.
Terpenes fromCannabis sativaInduce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2AReceptors
Authors: Schwarz Abigail M. , Keresztes Attila , Bui Thai , Hecksel Ryan J. , Peña Adrian , Lent Brianna , Gao Zhan-Guo , Gamez-Rivera Martín , Seekins Caleb A. , Chou Kerry , Appel Taylor L. , Jacobson Kenneth A. , Al-Obeidi Fahad A. , Streicher John M.
Published: March 2023

Terpenes are small hydrocarbon compounds that impart aroma and taste to many plants, includingCannabis sativa. A number of studies have shown that terpenes can produce pain relief in various pain states in both humans and animals. However, these studies were methodologically limited and few established mechanisms of action. In our previous work, we showed that the terpenes geraniol, linalool, β-pinene, α- humulene, and β-caryophyllene produced cannabimimetic behavioral effects via multiple receptor targets. We thus expanded this work to explore the efficacy and mechanism of theseCannabisterpenes in relieving chronic pain. We first tested for antinociceptive efficacy by injecting terpenes (200 mg/kg, IP) into male and female CD- 1 mice with chemotherapy-induced peripheral neuropathy (CIPN) or lipopolysaccharide-induced inflammatory pain, finding that the terpenes produced roughly equal efficacy to 10 mg/kg morphine or 3.2 mg/kg WIN55,212. We further found that none of the terpenes produced reward as measured by conditioned place preference, while low doses of terpene (100 mg/kg) combined with morphine (3.2 mg/kg) produced enhanced antinociception vs. either alone. We then used the adenosine A2Areceptor (A2AR) selective antagonist istradefylline (3.2 mg/kg, IP) and spinal cord-specific CRISPR knockdown of the A2AR to identify this receptor as the mechanism for terpene antinociception in CIPN.In vitrocAMP and binding studies andin silicomodeling studies further suggested that the terpenes act as A2AR agonists. Together these studies identifyCannabisterpenes as potential therapeutics for chronic neuropathic pain, and identify a receptor mechanism in the spinal cord for this activity.
Adaptable, Turn-On Monobody (ATOM) Fluorescent Biosensors for Multiplexed Detection in Cells
Authors: Sekhon Harsimranjit , Ha Jeung-Hoi , Presti Maria F. , Procopio Spencer B. , Mirsky Paige O. , John Anna M. , Loh Stewart N.
Published: March 2023

A grand challenge in biosensor design is to develop a single molecule, fluorescent protein-based platform that can be easily adapted to recognize targets of choice. Conceptually, this can be achieved by fusing a small, antibody-like binding domain to a fluorescent protein in such a way that target binding activates fluorescence. Although this design is simple to envision, its execution is not obvious. Here, we created a family of adaptable, turn-on monobody (ATOM) biosensors consisting of a monobody, circularly permuted at one of two positions, inserted into a fluorescent protein at one of three surface loops. Multiplexed imaging of live human cells co-expressing cyan, yellow, and red ATOM sensors detected the biosensor targets (WDR5, SH2, and hRAS proteins) that were localized to the nucleus, cytoplasm, and plasma membrane, respectively, with high specificity. ER- and mitochondria-localized ATOM sensors also detected ligands that were targeted to those organelles. Fluorescence activation involved ligand-dependent chromophore maturation with fluorescence turn-on ratios of >20-fold in cells and up to 100-foldin vitro. The sensing mechanism was validated with three arbitrarily chosen monobodies inserted into jellyfish as well as anemone lineages of fluorescent proteins, suggesting that ATOM sensors with different binding specificities and additional colors can be generated relatively quickly.
Deep repertoire mining uncovers ultra-broad coronavirus neutralizing antibodies targeting multiple spike epitopes
Authors: Hurtado Jonathan , Rogers Thomas F. , Jaffe David B. , Adams Bruce A. , Bangaru Sandhya , Garcia Elijah , Capozzola Tazio , Messmer Terrence , Sharma Pragati , Song Ge , Beutler Nathan , He Wanting , Dueker Katharina , Musharrafieh Rami , Stubbington Michael J.T. , Burton Dennis R. , Andrabi Raiees , Ward Andrew B. , McDonnell Wyatt J. , Briney Bryan
Published: March 2023

Development of vaccines and therapeutics that are broadly effective against known and emergent coronaviruses is an urgent priority. Current strategies for developing pan-coronavirus countermeasures have largely focused on the receptor binding domain (RBD) and S2 regions of the coronavirus Spike protein; it has been unclear whether the N-terminal domain (NTD) is a viable target for universal vaccines and broadly neutralizing antibodies (Abs). Additionally, many RBD-targeting Abs have proven susceptible to viral escape. We screened the circulating B cell repertoires of COVID-19 survivors and vaccinees using multiplexed panels of uniquely barcoded antigens in a high-throughput single cell workflow to isolate over 9,000 SARS-CoV-2-specific monoclonal Abs (mAbs), providing an expansive view of the SARS-CoV-2-specific Ab repertoire. We observed many instances of clonal coalescence between individuals, suggesting that Ab responses frequently converge independently on similar genetic solutions. Among the recovered antibodies was TXG-0078, a public neutralizing mAb that binds the NTD supersite region of the coronavirus Spike protein and recognizes a diverse collection of alpha- and beta-coronaviruses. TXG-0078 achieves its exceptional binding breadth while utilizing the same VH1-24 variable gene signature and heavy chain-dominant binding pattern seen in other NTD supersite-specific neutralizing Abs with much narrower specificity. We also report the discovery of CC24.2, a pan-sarbecovirus neutralizing mAb that targets a novel RBD epitope and shows similar neutralization potency against all tested SARS-CoV-2 variants, including BQ.1.1 and XBB.1.5. A cocktail of TXG-0078 and CC24.2 provides protection againstin vivochallenge with SARS-CoV-2, suggesting potential future use in variant-resistant therapeutic Ab cocktails and as templates for pan-coronavirus vaccine design.