bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections
Authors: Kratochvil Michael J. , Kaber Gernot , Demirdjian Sally , Cai Pamela C. , Burgener Elizabeth B. , Nagy Nadine , Barlow Graham L. , Popescu Medeea , Nicolls Mark R. , Ozawa Michael G. , Regula Donald P. , Pacheco-Navarro Ana E. , Yang Samuel , de Jesus Perez Vinicio A. , Karmouty-Quintana Harry , Peters Andrew M. , Zhao Bihong , Buja Maximilian L. , Johnson Pamela Y. , Vernon Robert B. , Wight Thomas N. ,   Stanford COVID-19 Biobank Study Group, Milla Carlos E. , Rogers Angela J. , Spakowitz Andrew J. , Heilshorn Sarah C. , Bollyky Paul L.
Published: April 2022

Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19 disease, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e. resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We find the percent solids and protein content are greatly elevated in COVID-19 compared to heathy control samples and closely resemble levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) are major components of respiratory secretions in COVID-19 and are likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibit heterogeneous rheological behaviors with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observe increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor–stimulated gene-6 (TSG6) staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicate that increases in HA and DNA in COVID-19 respiratory secretion samples correlate with enhanced inflammatory burden and suggest that DNA and HA may be viable therapeutic targets in COVID-19 infection.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mediated by a stereotyped clonotypic antibody
Authors: Wang Jing Jing , Armour Bridie , Chataway Tim , Troelnikov Alexander , Colella Alex , Yacoub Olivia , Hockley Simon , Tan Chee Wee , Gordon Tom Paul
Published: April 2022

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare thromboembolic complication of adenoviral-vectored SARS-CoV2 vaccines, mediated by antibodies directed against platelet factor 4 (PF4). Given their causal role in VITT, identification of the molecular composition of anti-PF4 antibodies is crucial for developing better diagnostics and treatments. Here, we utilised a novel proteomic workflow to analyse the immunoglobulin variable (IgV) region composition of anti-PF4 antibodies at the level of the secreted proteome. Serum anti-PF4 IgG antibodies from five patients with VITT triggered by ChAdOx1 nCoV-19 vaccination were affinity purified by PF4-coupled magnetic beads and sequenced by mass spectrometry. We revealed a single IgG heavy (H)-chain species paired with a single lambda light (L)-chain species in all five unrelated patients. Remarkably, all L-chains were encoded by the identical IGLV3-21*02 gene subfamily with identical L-chain third complementarity determining region (LCDR3) lengths. Moreover, striking stereotypic features were also identified in heavy-chains anti-PF4 antibodies characterised by identical HCDR3 length and homologous sequences. In summary, we unravelled the molecular signature of highly stereotyped clonotypic anti-PF4 antibodies, indicating shared pathways of antibody production in VITT patients. These discoveries are critical to understand the molecular basis of this serious condition and develop novel therapies aimed at removing pathogenic clones.

KEY POINTS

Anti-PF4 antibodies in VITT comprise highly stereotyped clonotype

A single IGLV3-21*02 encoded light chain is found in unrelated patients
A non-muscle myosin heavy chain 9 genetic variant is associated with graft failure following kidney transplantation
Authors: Poppelaars Felix , Eskandari Siawosh K. , Damman Jeffrey , Seelen Marc A. , Faria Bernardo , da Costa Mariana Gaya
Published: April 2022

Background

Despite current matching efforts to identify optimal donor-recipient pairs in kidney transplantation, alloimmunity remains a major proponent of late transplant failure. While kidney allocation based on human leukocyte antigen (HLA) matching has markedly prolonged short-term graft survival, new data suggests that additional genetic parameters in donor-recipient matching could help improve the long-term outcomes. Here, we studied the impact of a recently discovered non-muscle myosin heavy chain 9 gene (MYH9) polymorphism on kidney allograft failure.

Methods

We conducted a prospective observational cohort study, analyzing the DNA of 1,271 kidney donor-recipient transplant pairs from a single academic hospital for the MYH9 rs11089788 C>A polymorphism. The association of the MYH9 genotype with the risk of graft failure (primary outcome), biopsy-proven acute rejection (BPAR), and delayed graft function (DGF) (secondary outcomes) were determined.

Results

The MYH9 polymorphism in the donor was not associated with 15-year death-censored kidney graft survival, whereas a trend was seen for the association between the MYH9 polymorphism in the recipient and graft failure (recessive model, P=0.056). Having the AA-genotype of the MYH9 polymorphism in recipients was associated with a higher risk of DGF (P=0.031) and BPAR (P=0.021), although the significance was lost after adjustment for potential confounders (P=0.15 and P=0.10, respectively). The combined presence of the MYH9 polymorphism in donor-recipient pairs was significantly associated with long-term kidney allograft survival (P=0.036), in which recipients with an AA-genotype receiving a graft with an AA-genotype had the worst outcome. After adjustment for covariates, this combined genotype remained significantly associated with 15-year death-censored kidney graft survival (HR 1.68, 95%-CI: 1.05 – 2.70, P=0.031).

Conclusions

Our results reveal that recipients with an AA-genotype MYH9 polymorphism receiving a donor kidney with an AA-genotype, have a significantly elevated risk of graft failure after kidney transplantation.

Key points

In recipients, the MYH9 SNP was associated with delayed graft function and biopsy-proven acute rejection after kidney transplantation, although the significance was lost in multivariable analysis.

Presence of the MYH9 variant in both the donor and recipient significantly associated with long-term kidney allograft survival in multivariable analysis.

Our present findings suggests that matching donor-recipient transplant pairs based on the MYH9 polymorphism may attenuate the risk of graft loss.
Estimating the impact of the wMel release program on dengue and chikungunya incidence in Rio de Janeiro, Brazil
Authors: Ribeiro dos Santos Gabriel , Durovni Betina , Saraceni Valeria , Souza Riback Thais Irene , Pinto Sofia B. , Anders Katherine L. , Moreira Luciano A. , Salje Henrik
Published: April 2022

Background

Introgression of the insect bacterium Wolbachia into Aedes aegypti mosquito populations been shown in randomised and non-randomised trials to reduce the incidence of dengue in treated communities, however evidence for the real-world effectiveness of large-scale Wolbachia mosquito deployments for arboviral disease control in endemic settings is still limited and no effectiveness studies have been conducted for chikungunya virus. A large Wolbachia (wMel strain) program was implemented in 2017 in Rio de Janeiro, Brazil. Here we assess the impact of the release program on dengue and chikungunya incidence.

Methods and findings

The program released 67 million wMel infected mosquitoes across 28,489 release locations over a 86.8km2 area in Rio de Janeiro between August 2017 and the end of 2019. Following releases, mosquitoes were trapped and the presence of wMel determined. To assess the impact of the release program on dengue and chikungunya incidence, we used spatiotemporally explicit models applied to geocoded dengue (N=194,330) and chikungunya cases (N=58,364) from 2010 (2016 for chikungunya) to 2019 from across the city. On average, 32% of mosquitoes collected from the release zones between 1 and 29 months after releases were positive for wMel. Reduced wMel introgression occurred in locations and seasonal periods when dengue and chikungunya cases were historically high. Despite incomplete introgression, we found that the releases were associated with a 38% (95%CI: 32-44%) reduction in dengue incidence and a 10% (95%CI: 4-16%) reduction in chikungunya incidence.

Conclusions

Stable establishment of wMel in this diverse, urban setting appears more complicated than has been observed elsewhere. However, even intermediate levels of wMel appear to reduce the incidence of two different arboviruses.
Effect of xenon and argon inhalation on erythropoiesis and steroidogenesis: a systematic review
Authors: Bezuglov Eduard , Morgans Ryland , Khalikov Ruslan , Bertholz Vladislav , Emanov Anton , Talibov Oleg , Astakhov Evgeniy , Lazarev Artemii , Shoshorina Maria
Published: April 2022

Background

Xenon and argon inhalation were included in the WADA Prohibited List in 2014 due to the reported positive effects on erythropoiesis and steroidogenesis occurs as a result of the use of these substances. Currently, xenon is on the WADA Prohibited List notable affecting erythropoiesis as a Hypoxia-inducible factor (HIF) activating agent. At the same time, argon inhalation was allowed again in 2019. Thus, the systematic review of studies supporting these notions is of interest.

Methods

A thorough search for articles on the effects of xenon and argon inhalation on erythropoiesis and steroidogenesis, as well as their negative effects on human health and methods of their detection in body fluids was conducted. Pubmed, Google Scholar databases and the Cochrane Library were researched, as well as the special research section of the WADA website. The search was conducted in accordance with PRISMA guidelines. All articles in English published between 2000 and 2021 were analyzed, as well as reference studies meeting the search criteria.

Results

At present, there are only two publications in healthy human subjects evaluating the effects of xenon inhalation on erythropoiesis were found with no conclusive evidence of a positive effect on erythropoiesis. Both articles were published after 2014 when the gases were included on the WADA Prohibited List. Both articles had a high risk of bias. There were no studies on the effect of argon inhalation on erythropoiesis. No studies were found on the effect of xenon or argon inhalation on steroidogenesis in healthy subjects. No studies related to the effects of xenon or argon inhalation on erythropoiesis and steroidogenesis were found on the WADA website.

Conclusion

There is still inconclusive evidence to support the administration of xenon and argon inhalations on erythropoiesis and steroidogenesis and their positive effects on health. Further research is needed to establish the effects of these gases. Additionally, improved communication between the anti-doping authorities and all key stakeholders is required to support the inclusion of various substances on the Prohibited List.
Safety and Efficacy of Dupilumab for the Treatment of Hospitalized Patients with Moderate to Severe COVID 19: A Phase IIa Trial
Authors: Sasson Jennifer , Donlan Alexandra N. , Ma Jennie Z. , Haughey Heather M. , Coleman Rachael , Nayak Uma , Mathers Amy J. , Laverdure Sylvain , Dewar Robin , Jackson Patrick E. H. , Heysell Scott K. , Sturek Jeffrey M. , Petri William A.
Published: April 2022

Background

A profound need remains to develop further therapeutics for treatment of those hospitalized with COVID-19. Based on data implicating the type 2 cytokine interleukin (IL)-13 as a significant factor leading to critical COVID-19, this trial was designed to assess dupilumab, a monoclonal antibody that blocks IL-13 and IL-4 signaling, for treatment of inpatients with COVID-19.

Methods

We conducted a phase IIa randomized double-blind placebo-controlled trial to assess the safety and efficacy of dupilumab plus standard of care versus placebo plus standard of care in mitigating respiratory failure and death in those hospitalized with COVID-19. Subjects were followed prospectively for 60 days. The primary endpoint was the proportion of patients alive and free of invasive mechanical ventilation at 28 days.

Findings

Forty eligible subjects were enrolled from June to November of 2021. There was no difference in adverse events nor in ventilator free survival at day 28 between study arms. However, for the secondary endpoint of mortality at day 60, subjects randomized to dupilumab had a higher survival rate compared to the placebo group (89.5% vs 76.2%, adjusted HR 0.05, 95% CI: 0.0-0.72, p=0.03). There were fewer subjects admitted to the ICU in the dupilumab group compared to placebo (33.3% vs 66.7%; adjusted HR 0.44, 95% CI: 0.09-2.09, p=0.30). Lastly, we saw downstream evidence of IL-4 and IL-13 signaling blockade in the dupilumab group through analysis of immune biomarkers over time.

Interpretation

Dupilumab was well tolerated and improved 60-day survival in patients hospitalized with moderate to severe COVID-19.

Trial Registration

This trial is registered with ClinicalTrials.gov, NCT04920916.

Funding

Virginia Biosciences Health Research Corporation, PBM C19, Henske Family Foundation, National Institutes of Health, National Cancer Institute
Age at cancer diagnosis by breed, weight, sex, and cancer type in a cohort of over 3,000 dogs: determining the optimal age to initiate cancer screening in canine patients
Authors: Rafalko Jill M. , Kruglyak Kristina M. , McCleary-Wheeler Angela L. , Goyal Vidit , Phelps-Dunn Ashley , Wong Lilian K. , Warren Chelsea D. , Brandstetter Gina , Rosentel Michelle C. , McLennan Lisa M. , Grosu Daniel S. , Chibuk Jason , Tsui Dana W.Y. , Chorny Ilya , Flory Andi
Published: April 2022

The goal of cancer screening is to detect disease at an early stage when treatment may be more effective. Until recently, cancer screening in dogs has relied upon annual physical examinations and routine laboratory tests, which are largely inadequate for detecting preclinical disease. With the introduction of non-invasive “liquid biopsy” cancer detection methods, the discussion is shifting from “Howto screen dogs for cancer” to “Whento screen dogs for cancer”. To address this question, data from 3,452 cancer-diagnosed subjects were analyzed to determine the age at which dogs of certain breeds and weights are typically diagnosed with cancer. In the study population, the median age at cancer diagnosis was 8.8 years, with males diagnosed at younger ages than females, and spayed/neutered dogs diagnosed at significantly later ages than intact dogs. Overall, weight was inversely correlated with age at cancer diagnosis, and purebred dogs were diagnosed at significantly younger ages than mixed-breed dogs. For breeds with 10 or more subjects, a breed-based median age at diagnosis was calculated. A weight-based linear regression model was developed to predict the median age at diagnosis for breeds represented by fewer than 10 subjects and for mixed-breed dogs. The study findings support a general recommendation to start cancer screening for all dogs at the age of 7, and as early as 4 years of age for breeds with a lower median age at cancer diagnosis, in order to increase the chances of early detection and treatment.
Spatial, transcriptomic and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition
Authors: Arokiaraj Cynthia M. , Leone Michael J. , Kleyman Michael , Chamessian Alexander , Phan BaDoi N. , Lopes Bettega C. , Cherupally Vijay Kiran , Noh Myung-Chul , Corrigan Kelly A. , Yeramosu Deepika , Franusich Michael E. , Podder Riya , Lele Sumitra , Shiers Stephanie , Kang Byungsoo , Kennedy Meaghan M , Chen Viola , Chen Ziheng , Dum Richard P. , Lewis David A. , Qadri Yawar , Price Theodore J. , Pfenning Andreas R. , Seal Rebecca P.
Published: April 2022

Key mechanisms underlying chronic pain occur within the neural circuitry of the dorsal horn. Recent genome-wide association studies (GWAS) have identified genetic variants associated with the predisposition to chronic pain. However, most of these variants lie in regulatory non-coding regions that have so far not been linked to spinal cord function. Here, we take a multi-species approach to determine whether chronic pain variants impact regulatory elements of dorsal horn neurons. We first built a more comprehensive single cell atlas; filling gaps by generating a high-quality Rhesus macaque atlas and integrating it with human and mouse. With cellular-resolution spatial transcriptomics, we mapped the laminar distributions of the resulting species-conserved neuron subtypes, uncovering an unexpected organization. Lastly, we generated a mouse single-nucleus open chromatin atlas to partition the heritability of chronic pain traits. From this, we identified strong, selective associations between specific, conserved neuron subtypes and major forms of chronic pain.
Reproducible stool metagenomic biomarkers linked to the melanoma immunotherapy positive outcome
Authors: Olekhnovich Evgenii I. , Ivanov Artem B. , Babkina Anna A. , Sokolov Arseniy A. , Ulyantsev Vladimir I. , Fedorov Dmitry E. , Ilina Elena N.
Published: April 2022

The human gut microbiome plays an important role both in human’s health and disease. Recent studies have shown the undeniable influence of gut microbiota composition on cancer immunotherapy efficacy. However, these researches show a lack of consensus in defining reproducible metagenomic markers for a positive immunotherapy outcome. Accordingly, extended published data re-analysis may help reveal clearer associations between the composition of the gut microbiota and treatment response. In this study, we analyzed 358 stool metagenomes from 5 studies published earlier: 210 metagenomes from melanoma patients with positive immunotherapy outcome, 148 metagenomes from melanoma patients with negative immunotherapy outcome. The biomarkers were selected by the group comparison of patients’ stool samples with different treatment responses (47 responders vs 55 non-responders, 102 metagenomes). Selected biomarkers were verified using the available data describing the influence of the fecal microbiota transplantation on melanoma immunotherapy outcomes (9 donors, 6 responders, 19 non-responders, 256 metagenomes). According to our analysis, the resulting cross-study reproducible taxonomic biomarkers correspond to 12 Firmicutes, 4 Bacteroidetes, and 3 Actinobacteria. 140 gene groups were identified as reproducible functional biomarkers, including those potentially involved in production of immune-stimulating molecules and metabolites. In addition, we ranked taxonomic biomarkers by the number of functional biomarkers found in their metagenomic context. In other words, we predicted a list of the potential “most beneficial” bacteria for a positive response to melanoma immunotherapy. The obtained results can be used to make recommendations for the gut microbiota correction in cancer immunotherapy, and the resulting list of biomarkers can be considered for potential diagnostic ways for predicting melanoma immunotherapy outcome. Another important point is the functional biomarkers of positive immunotherapy outcome are distributed in different bacterial species that can explain the lack of consensus of defining melanoma immunotherapy beneficial species between different studies.
Newfoundland and Labrador: A mosaic founder population of an Irish and British diaspora from 300 years ago
Authors: Gilbert Edmund , Zurel Heather , MacMillan Margaret E. , Demiriz Sedat , Mirhendi Sadra , Merrigan Michael , O’Reilly Seamus , Molloy Anne M. , Brody Lawrence C. , Bodmer Walter , Leach Richard A. , Scott Roderick E. M. , Mugford Gerald , Randhawa Ranjit , Stephens J. Claiborne , Symington Alison L. , Cavalleri Gianpiero L. , Phillips Michael S.
Published: April 2022

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to geographic and cultural isolation, where historical records describe a migration of European settlers primarily from Ireland and England to NL in the 18th and 19th centuries. Whilst its historical isolation, and increase prevalence of certain monogenic disorders, have been appreciated, the fine-scale genetic structure and ancestry of the population has not been well described. Understanding the genetic background on which functional, disease causing, genetic variation resides on would aid informed genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results elucidate novel insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery.

Significance Statement

Newfoundland and Labrador (NL) has been identified as a founder population, though evidence of its magnitude and subsequent isolation is unclear. Here, analysis of 1,807 NL individuals demonstrates population structure associated with geographical isolation in coastal communities and religious denomination (Catholic or Protestant Christian). Further, NL European ancestry primarily descends from settlers from south-east Ireland and south-west England. This history is associated with increased sharing of longer haplotypes in NL, and NL-specific drift in some communities more than others, providing strong evidence of a founder event occurring about 10-15 generations ago. This study elucidates the detailed population structure of NL and shows enrichment for otherwise low frequency functional variants due to genetic drift useful for potential future biomarker discovery studies.
Microstructural alterations in tract development in college football: a longitudinal diffusion MRI study
Authors: Goubran Maged , Mills Brian D. , Georgiadis Marios , Karimpoor Mahta , Mouchawar Nicole , Sami Sohrab , Dennis Emily L. , Akers Carolyn , Mitchell Lex A. , Boldt Brian , Douglas David , DiGiacomo Phil , Rosenberg Jarrett , Grant Gerald , Wintermark Max , Camarillo David , Zeineh Michael
Published: April 2022

Background and Objectives

Repeated concussive and sub-concussive impacts in high-contact sports can affect the brain’s microstructure, which can be studied using diffusion MRI. Most prior imaging studies, however, employ a cross-sectional design, do not include low-contact players as controls, or use traditional diffusion tensor imaging without investigating novel tractspecific microstructural metrics.

Methods

We examined brain microstructure in 63 high-contact (American football) and 34 low-contact (volleyball) collegiate athletes with up to 4 years of follow-up (315 total scans) using advanced diffusion MRI, a comprehensive set of multi-compartment models, and automated fiber quantification tools. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of sub-concussive and concussive impacts, as well as associations between diffusion changes with clinical, behavioral, and sports-related measures.

Results

Significant longitudinal increases in fractional anisotropy and axonal water fraction were detected in volleyball players, but not in football players, along with decreases in radial and mean diffusivity as well as orientation dispersion index (all findings absolute T-statistic > 3.5, p < .0001). This pattern was present in the callosum forceps minor, left superior longitudinal fasciculus, left thalamic radiation, and right cingulum hippocampus. Longitudinal group differences were more prominent and observed in a larger number of tracts in concussed (previously or in-study) football players (p < .0001), while smaller effects were noted in un-concussed players. An analysis of immediate-post concussion scans in football players demonstrated a transient localized increase in axial diffusivity, mean and radial kurtosis in the left uncinate and right cingulum hippocampus (p < .0001). Finally, football players with high position-based sub-concussive risk demonstrated increased orientation dispersion index over time (p < .0001).

Discussion

The observed longitudinal changes in our volleyball cohort likely reflect normal development in this age range, while the relative attenuation of these effects seen in football, and especially concussed athletes, could possibly reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, non-decreasing axonal dispersion. This prospective longitudinal study demonstrates significantly divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and/or repeated sub-concussive impact-related alteration of normal white matter development in football athletes.
Visuo-tactile integration in texture perception: A replication and extension study
Authors: Kangur Karina , Giesel Martin , Harris Julie M. , Hesse Constanze
Published: April 2022

Employing a sensory conflict paradigm, previous research has found that vision and touch contribute, on average, equally to the visuo-tactile perception of surface texture. Our study aimed to, firstly, replicate the original findings using a comparable setup and stimulus set; secondly, examine whether equal modality contributions can also be observed on an individual basis (using a within-subject design); and thirdly, explore how visuo-tactile integration is affected by illumination angle (top vs. oblique). Participants explored a discrepant standard consisting of different abrasive papers by vision, touch, and using both modalities simultaneously, and subsequently had to find the closest visual, tactile, and visuo-tactile match from a set of matching stimuli. We replicated equal contribution from vision and touch across the whole sample in both illumination conditions. We also found considerable inter-individual variations in the modality contributions when the stimuli were illuminated from the top. Interestingly, this variation decreased under oblique illumination, with most participants showing an about-equal contribution from both modalities to the combined texture percept. These findings are consistent with the assumption that the perceived discrepancy between vision and touch was reduced under oblique illumination suggesting overall that visual and tactile information are only weighted equally within a certain range of experienced discrepancy. Outside this individual range, one of the modalities is weighted higher with no clear preference for either modality.
hemispheR: an R package for fisheye canopy image analysis
Authors: Chianucci Francesco , Macek Martin
Published: April 2022

Hemispherical photography is a relevant tool to estimate canopy attributes such as leaf area index (LAI). Advancements in digital photography and image processing tools have supported long-lasting use of digital hemispherical photography (DHP). While some open-source tools have been made available for DHP, very few solutions have been made available in R programming packages, and none of these allows a full processing workflow to retrieve LAI and other canopy attributes from fisheye images.

To fill this gap, we developed an R package (hemispheR) to support the whole processing of DHP images in an automated, fast, and reproducible way. The package functions, which are designed for step-by-step single-image analysis, can be performed sequentially in a pipeline, while allowing inspecting the quality of each image processing step. The package allows to analyze both circular and fullframe fisheye images, collected either with upward facing (forest canopies) or downward facing (short canopies and crops) camera orientation. In addition, the package allows to implement two consolidated LAI methods (LAI-2000/2200 and 57° method).

A case study is presented to demonstrate the reliability of canopy attributes derived from hemispheR in temperate deciduous forests with variable canopy density and structure. Canopy attributes were validated against either results obtained from a reference proprietary software, either by benchmarking measurements obtained from terrestrial laser scanning. Results indicated hemispheR provide reliable openness and leaf area index values in forest canopies as compared with reference values.

By providing a simple, transparent, and flexible image processing procedure, hemispheR supported the use of DHP for routine measurements and monitoring of forest canopy attributes. Hosting the package in a Git repository will further support development of the package, through either collaborative coding or forking projects.
A deep hierarchy of predictions enables assignment of semantic roles in online speech comprehension
Authors: Su Yaqing , MacGregor Lucy J. , Olasagasti Itsaso , Giraud Anne-Lise
Published: April 2022

Understanding speech requires mapping fleeting and often ambiguous soundwaves to meaning. While humans are known to exploit their capacity to contextualize to facilitate this process, how internal knowledge is deployed on-line remains an open question. Here, we present a model that extracts multiple levels of information from continuous speech online. The model applies linguistic and nonlinguistic knowledge to speech processing, by periodically generating top-down predictions and incorporating bottom-up incoming evidence in a nested temporal hierarchy. We show that a nonlinguistic context level provides semantic predictions informed by sensory inputs, which are crucial for disambiguating among multiple meanings of the same word. The explicit knowledge hierarchy of the model enables a more holistic account of the neurophysiological responses to speech compared to using lexical predictions generated by a neural-network language model (GPT-2). We also show that hierarchical predictions reduce peripheral processing via minimizing uncertainty and prediction error. With this proof-of-concept model we demonstrate that the deployment of hierarchical predictions is a possible strategy for the brain to dynamically utilize structured knowledge and make sense of the speech input.
Western spotted skunks provide important food web linkages in forest of the Pacific Northwest
Authors: Tosa Marie I. , Lesmeister Damon B. , Allen Jennifer M. , Levi Taal
Published: April 2022

There are increasing concerns about the decreasing population trends of small mammalian carnivores around the world. With limited knowledge about their ecology and natural history, small mammal conservation and management remains difficult. To address one of these deficiencies for western spotted skunks (Spilogale gracilis), we investigated their diet in the Oregon Cascades of the Pacific Northwest during 2017 – 2019. We collected 130 spotted skunk scats opportunistically and with detection dog teams and identified prey items using DNA metabarcoding and mechanical sorting. Western spotted skunk diet consisted of invertebrates such as wasps, millipedes, and gastropods, vertebrates such as small mammals, amphibians, and birds, and plants such as Gaultheria, Rubus, and Vaccinium. Diet also consisted of items such as black-tailed deer that were likely scavenged. Comparison in diet by season revealed that spotted skunks consumed more insects during the dry season (June - August) and marginally more mammals during the wet season (September – May). We observed similar diet in areas with no record of human disturbance and areas with a history of logging. Western spotted skunks provide important food web linkages between aquatic, terrestrial, and arboreal systems by facilitating energy and nutrient transfer, and serve important functional roles of seed dispersal and scavenging. Through prey-switching, western spotted skunks may dampen the effects of irruptions of prey, such as wasps during dry springs and summers, which could then provide ecosystem resilience to environmental change.
Data integration across conditions improves turnover number estimates and metabolic predictions
Authors: Wendering Philipp , Arend Marius , Razaghi-Moghadamkashani Zahra , Nikoloski Zoran
Published: April 2022

Turnover numbers characterize a key property of enzymes, and their usage in constraint-based metabolic modeling is expected to increase prediction accuracy of diverse cellular phenotypes. In vivo turnover numbers can be obtained by ranking of estimates obtained by integrating reaction rate and enzyme abundance measurements from individual experiments; yet, their contribution to improving predictions of condition-specific cellular phenotypes remains elusive. Here we show that available in vitro and in vivo turnover numbers lead to poor prediction of condition-specific growth rates with protein-constrained models of Escherichia coli and Saccharomyces cerevisiae, particularly in the ultimate test scenario when protein abundances are integrated in the model. We demonstrate that in vivo estimation of turnover number by simultaneous consideration of heterogeneous physiological data leads to improved prediction of condition-specific growth rates. Moreover, the obtained estimates are more precise than the available in vivo turnover numbers. Therefore, our approach provides the means to decrease the bias of in vivo turnover numbers and paves the way towards cataloguing in vivo kcatomes of other organisms.
Functional Cell Types in the Mouse Superior Colliculus
Authors: Li Ya-tang , Meister Markus
Published: April 2022

The superior colliculus (SC) represents a major visual processing station in the mammalian brain that receives input from many types of retinal ganglion cells (RGCs). How many parallel channels exist in the SC, and what information does each encode? Here we recorded from mouse superficial SC neurons under a battery of visual stimuli including those used for classification of RGCs. An unsupervised clustering algorithm identified 24 functional types based on their visual responses. They fall into two groups: one that responds similarly to RGCs, and another with more diverse and specialized stimulus selectivity. The second group is dominant at greater depths, consistent with a vertical progression of signal processing in the SC. Cells of the same functional type tend to cluster near each other in anatomical space. Compared to the retina, the visual representation in the SC has lower dimensionality, consistent with a sifting process along the visual pathway.
Genomic legacies of ancient adaptation illuminate the GC-content evolution in bacterial genomes
Authors: Teng Wenkai , Liao Bin , Chen Mengyun , Shu Wensheng
Published: April 2022

In conventional views, the bacterial adaptation is characterized by strong purifying selection as well as rapid evolution in changing environments. However, the genomic GC content varies greatly but has some degree of phylogenetic stability. Using 11,083 representative genomes, we report a phylogenetically constrained bimodal distribution of the genomic GC. Results suggest that such divergence of the genomic GC can be well explained by the DNA replication and repair (DRR) system, in which multiple pathways are observed correlated to the genomic GC. The biased conservations of various stress-related genes especially the DRR-related ones imply distinct adaptive evolution of the ancestral lineages of high or low GC clades which may be induced by major environmental changes in early evolution. Furthermore, our findings support that the mutational biases resulted from these legacies of adaptation have changed the course of adaptive evolution in bacteria thus causing great variation in the genomic GC. This study demonstrates the importance of indirect effects from natural selection which may be easily misinterpreted as neutral processes.
Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation
Authors: Su Hua , Yang Fei , Fu Rao , Trinh Brittney , Sun Nina , Liu Junlai , Kumar Avi , Baglieri Jacopo , Siruno Jeremy , Dozier Stephen , Nair Ajay , Filliol Aveline , Rosenthal Sara Brin , Santini Jennifer , Metallo Christian M. , Molina Anthony , Schwabe Robert F. , Lowy Andrew M. , Brenner David , Sun Beicheng , Karin Michael
Published: April 2022

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis1. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support2–5 or restrain PDAC progression and may impede blood supply and nutrient availability6–8. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-κB-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-κB or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-κB-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.
The Insulin receptor regulates the persistence of mechanical nociceptive sensitization in flies and mice
Authors: Wang Yan , Lopez-Bellido Roger , Huo Xiaojiao , Kavelaars Annemieke , Galko Michael J.
Published: April 2022

Early phase diabetes is often accompanied by pain sensitization. In the fruit flyDrosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. WhetherDrosophilaInR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the gene encoding the Insulin receptor (Insr) show normal nociceptive baselines, however, it is not known whether deletion ofInsrin nociceptive sensory neurons leads to persistent nociceptive hypersensitivity in an inflammatory pain paradigm. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies,InRmutants and larvae with sensory neuron-specific expression of RNAi transgenes targetingInRexhibited persistent mechanical hypersensitivity, as previously observed for the thermal sensory modality. Mice with a specific deletion of theInsrgene in NaV1.8+ nociceptive sensory neurons showed normal nociceptive thermal and mechanical baselines similar to controls. In an inflammatory paradigm, however, these mutant mice showed persistent mechanical (but not thermal) hypersensitivity, particularly in female mice. Mice with the NaV1.8+ sensory neuron specific deletion ofInsrdid not show metabolic abnormalities that would be typical of a systemic defect in insulin signaling. Our results show that some aspects of the regulation of nociceptive hypersensitivity by the Insulin receptor are shared between flies and mice and that this regulation is likely independent of metabolic effects.
epiAneufinder: identifying copy number variations from single-cell ATAC-seq data
Authors: Ramakrishnan Akshaya , Symeonidi Aikaterini , Hanel Patrick , Schubert Michael , Colomé-Tatché Maria
Published: April 2022

Single-cell open chromatin profiling via the single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) assay has become a mainstream measurement of open chromatin in single-cells. Here we present a novel algorithm, epiAneufinder, that exploits the read count information from scATAC-seq data to extract genome-wide copy number variations (CNVs) for individual cells, allowing to explore the CNV heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show how epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNV profiles. These profiles are concordant with the ones inferred from single-cell whole genome sequencing data for the same samples. epiAneufinder allows the addition of single-cell CNV information to scATAC-seq data, without the need of additional experiments, unlocking a layer of genomic variation which is otherwise unexplored.
Remodeling of gene regulatory networks underlying thermogenic stimuli-induced adipose beiging
Authors: Lee Seoyeon , Benvie Abigail M. , Park Hui Gyu , Spektor Roman , Harlan Blaine , Brenna J Thomas , Berry Daniel C. , Soloway Paul D.
Published: April 2022

Beige adipocytes are induced by cold temperatures or β3-adrenergic receptor (Adrb3) agonists. They create heat through glucose and fatty acid (FA) oxidation, conferring metabolic benefits. The distinct and shared mechanisms by which these treatments induce beiging are unknown. Here, we performed single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq) on adipose tissue from mice exposed to cold or an Adrb3 agonist to identify cellular and chromatin accessibility dynamics during beiging. Both stimuli induce chromatin remodeling that influence vascularization and inflammation in adipose. Beige adipocytes from cold-exposed mice have increased accessibility at genes regulating glycolytic processes, whereas Adrb3 activation increases cAMP responses. While both thermogenic stimuli increase accessibility at genes regulating thermogenesis, lipogenesis, and beige adipocyte development, the kinetics and magnitudes of the changes are distinct for the two stimuli. Accessibility changes at lipogenic genes are linked to functional changes in lipid composition of adipose. Both stimuli tend to decrease the proportion of palmitic acids, a saturated FA in adipose. However, Adrb3 activation increases the proportion of monounsaturated FAs, whereas cold increases the proportion of polyunsaturated FAs. These findings reveal common and distinct mechanisms of cold and Adrb3 induced beige adipocyte biogenesis, and identify the unique functional consequences of manipulating these pathways in vivo.
Lumbar time-varying muscle synergies in trunk flexion and bending movements at different velocities
Authors: Rouchi Mahdi Bagheri , Davoudi Mehrdad , Meftahi Narges , Rashedi Ehsan , Parnianpour Mohamad , Khalaf Kinda
Published: April 2022

Purpose

Although the extent of which the central nervous system uses muscle synergies as a movement control strategy remains an open area of research, it is widely agreed that synergies facilitate the robustness of the neuromuscular system, allowing for effective postural control and flexible movement. This work aimed to investigate the muscle activation patterns of the trunk and time-varying muscle synergies using a novel 18-muscle 3-DOF, 3-D musculoskeletal model of the lumbar spine developed by the authors.

Methods

24 different biaxial trunk movements were simulated via the optimization of kinetic and kinematic measures towards obtaining the corresponding muscle activation patterns at 3 different velocities. These patterns were subsequently used to extract the principal (phasic and tonic) spatio-temporal synergies associated with the observed muscle activation patterns in the range of simulated movements.

Results

Four dominant synergies were able to explain a considerable percent (about 75%) of the variance of the simulated muscle activities. The extracted synergies were spatially tuned in the direction of the main simulated movements (flexion/extension and right/left lateral bending). The temporal patterns demonstrated gradual monotonic shifts in tonic synergies and biphasic modulatory components in phasic synergies with spatially tuned time-delays. The increase in velocity resulted in an elevated amplitude coefficient and accelerated activation of phasic synergies.

Conclusion

Our results suggest the plausibility of a time-varying synergies strategy in the dynamic control of trunk movement. Further work is needed to explore leveraging these concepts in various applications, such as rehabilitation and musculoskeletal biomechanics, towards providing more insight into the mechanisms underlying trunk stability and flexibility.
Motifizer: a tool for parsing high-throughput sequencing datasets and quantitative comparative analyses of transcription factor-binding sites
Authors: Khan Soumen , Bhattacharjee Abhik , Badhe Pranav , Dongaonkar Chinmay , Gaglani Yash
Published: April 2022

Background

Comparative analysis of Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), combined with transcriptomics data (RNA-seq), can provide critical insights into gene regulatory networks controlled by transcription factors in a given biological context. While multiple programs exist, which need to be individually installed and executed to generate such information, a user-friendly tool with low system requirements which combines the various computational processes into one package, using a docker container, is lacking.

Results

In this study, we present a user-interactive, infrastructure-independent computational pipeline, called Motifizer, which uses open source tools for processing ChIP-Seq and RNA-seq datasets. Motifizer performs extensive analysis of raw input data, performing peak calling, de-novo motif analysis and differential gene expression analysis on ChIP and RNA-seq datasets. Additionally, Motifizer can be used for analysis and quantitative comparison of transcription factor binding sites in user defined genomic regions. Motifizer also allows easy addition and/or changes of parameters, thereby adding to the versatility of the tool.

Conclusion

The Motifizer tool is an easy to use tool which uses a docker container system to install and execute ChIP-seq and RNA-seq data parsing. The Analysis module of Motifizer can be employed to identify putative targets involved in gene regulatory networks. Motifizer can be accessed by a large user base and does not require programming skill by the user. Motifizer can be locally installed from the repository (https://github.com/abhikbhattacharjee/Motifizer)