bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of micropatterned topographical and biochemical cues to direct neurite growth from spiral ganglion neurons
Authors: Truong Kristy , Leigh Braden , Vecchi Joseph T. , Bartholomew Reid , Xu Linjing , Guymon C. Allan , Hansen Marlan R.
Published: March 2021

Functional outcomes with neural prosthetic devices, such as cochlear implants, are limited in part due to physical separation between the stimulating elements and the neurons they stimulate. One strategy to close this gap aims to precisely guide neurite regeneration to position the neurites in closer proximity to electrode arrays. Here, we explore the ability of micropatterned biochemical and topographic guidance cues, singly and in combination, to direct the growth of spiral ganglion neuron (SGN) neurites, the neurons targeted by cochlear implants. Photopolymerization of methacrylate monomers was used to form unidirectional topographical features of ridges and grooves in addition to multidirectional patterns with 90° angle turns. Microcontact printing was also used to create similar uni- and multi-directional patterns of peptides on polymer surfaces. Biochemical cues included peptides that facilitate (laminin, LN) or repel (EphA4-Fc) neurite growth. On flat surfaces, SGN neurites preferentially grew on LN-coated stripes and avoided EphA4-Fc-coated stripes. LN or EphA4-Fc was selectively adsorbed onto the ridges or grooves to test the neurite response to a combination of topographical and biochemical cues. Coating the ridges with EphA4-Fc and grooves with LN lead to enhanced SGN alignment to topographical patterns. Conversely, EphA4-Fc coating on the grooves or LN coating on the ridges tended to disrupt alignment to topographical patterns. SGN neurites respond to combinations of topographical and biochemical cues and surface patterning that leverages both cues enhance guided neurite growth.
The optimal spatial arrangement of ON and OFF receptive fields
Authors: Jun Na Young , Field Greg , Pearson John
Published: March 2021

Many sensory systems utilize parallel ON and OFF pathways that signal stimulus increments and decrements, respectively. These pathways consist of ensembles or grids of ON and OFF detectors spanning sensory space. Yet encoding by opponent pathways raises a question: How should grids of ON and OFF detectors be arranged to optimally encode natural stimuli? We investigated this question using a model of the retina guided by efficient coding theory. Specifically, we optimized spatial receptive fields and contrast response functions to encode natural images given noise and constrained firing rates. We find that the optimal arrangement of ON and OFF receptive fields exhibits a transition between aligned and anti-aligned grids. The preferred phase depends on detector noise and the statistical structure of the natural stimuli. These results reveal that noise and stimulus statistics produce qualitative shifts in neural coding strategies and provide novel theoretical predictions for the configuration of opponent pathways in the nervous system.

Significance Statement

Across a wide variety of species, cells in the retina specialized for signaling either increases (ON) or decreases (OFF) in light represent one of the most basic building blocks of visual computation. These cells coordinate to form mosaics, with each cell responsible for a small, minimally-overlapping portion of visual space, but the ways in which these mosaics could be spatially coordinated with each other are relatively unknown. Here, we show how efficient coding theory, which hypothesizes that the nervous system minimizes the amount of redundant information it encodes, can predict the relative spatial arrangement of ON and OFF mosaics. The most information-efficient arrangements are determined both by levels of noise in the system and the statistics of natural images.
Regulatory B cells (Bregs) inhibit osteoclastogenesis and prevent bone loss in osteoporotic mice model
Authors: Sapra Leena , Bhardwaj Asha , Mishra Pradyumna K. , Verma Bhupendra K. , Srivastava Rupesh K.
Published: March 2021

Increasing evidences in recent years have suggested that regulatory B cells (Bregs) are crucial modulator in various inflammatory disease conditions. However, the role of Bregs in case of postmenopausal osteoporosis remains unknown. Also, no study till date have ever investigated the significance of Bregs in modulating osteoclastogenesis. In the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs underin vitroconditions and we observed that Bregs suppressed RANKL mediated osteoclastogenesis in bone marrow cells in a dose dependent manner. We further elucidated the mechanism behind the suppression of osteoclasts differentiation by Bregs and found that Bregs inhibit osteoclastogenesis via IL-10 production. To further confirm the bone health modulating potential of Bregs we employed post-menopausal osteoporotic mice model. Remarkably, ourin vivodata clearly suggest a significant reduction (p < 0.01) in both CD19+IL-10+and CD19+CD1dhiCD5+IL-10+B10 Bregs in case of osteoporotic mice model. Moreover, our serum cytokine data further confirms the significant reduction of IL-10 levels in osteoporotic mice. Taken together, the present study for the first time unravels and establish the unexplored role of regulatory B cells in case of osteoporosis and provide new insight into Bregs biology in the context of post-menopausal osteoporosis.
A rapid and efficient learning rule for biological neural circuits
Authors: Sezener Eren , Grabska-Barwińska Agnieszka , Kostadinov Dimitar , Beau Maxime , Krishnagopal Sanjukta , Budden David , Hutter Marcus , Veness Joel , Botvinick Matthew , Clopath Claudia , Häusser Michael , Latham Peter E.
Published: March 2021

The dominant view in neuroscience is that changes in synaptic weights underlie learning. It is unclear, however, how the brain is able to determine which synapses should change, and by how much. This uncertainty stands in sharp contrast to deep learning, where changes in weights are explicitly engineered to optimize performance. However, the main tool for that, backpropagation, has two problems. One is neuro-science related: it is not biologically plausible. The other is inherent: networks trained with this rule tend to forget old tasks when learning new ones. Here we introduce the Dendritic Gated Network (DGN), a variant of the Gated Linear Network, which offers a biologically plausible alternative to backpropagation. DGNs combine dendritic ‘gating’ (whereby interneurons target dendrites to shape neuronal responses) with local learning rules to yield provably efficient performance. They are significantly more data efficient than conventional artificial networks, and are highly resistant to forgetting. Consequently, they perform well on a variety of tasks, in some cases better than backpropagation. Importantly, DGNs have structural and functional similarities to the cerebellum, a link that we strengthen by usingin vivotwo-photon calcium imaging to show that single interneurons suppress activity in individual dendritic branches of Purkinje cells, a key feature of the model. Thus, DGNs leverage targeted dendritic inhibition and local learning – two features ubiquitous in the brain – to achieve fast and efficient learning.
Paradoxical relationship between speed and accuracy in olfactory figure-background segregation
Authors: Lebovich Lior , Yunerman Michael , Scaiewicz Viviana , Loewenstein Yonatan , Rokni Dan
Published: March 2021

In natural settings, many stimuli impinge on our sensory organs simultaneously. Parsing these sensory stimuli into perceptual objects is a fundamental task faced by all sensory systems. Similar to other sensory modalities, increased odor backgrounds decrease the detectability of target odors by the olfactory system. The mechanisms by which background odors interfere with the detection and identification of target odors are unknown. Here we utilized the framework of the Drift Diffusion Model (DDM) to consider possible interference mechanisms in an odor detection task. We consider effects of background odors on both signal and noise in the decision-making dynamics, and show that these produce different predictions about decision accuracy and speed. To test these predictions, we trained mice to detect target odors that are embedded in random background mixtures in a two-alternative choice task. Trial duration was independent of behavioral reaction times to avoid motivating rapid responses. We found that the behavioral data is most consistent with background odors acting by adding noise to the decision-making dynamics. The added noise decreases the correct rate, but also decreases decision times, thereby creating a paradoxical relationship between speed and accuracy of target detection, where mice make faster and less accurate decisions in the presence of background odors.
Divergence in Population Coding for Space between Dorsal and Ventral CA1
Authors: Chockanathan Udaysankar , Padmanabhan Krishnan
Published: March 2021

Molecular, anatomic, and behavioral studies show that the hippocampus is structurally and functionally heterogeneous, with dorsal hippocampus implicated in mnemonic processes and spatial navigation and ventral hippocampus involved in affective processes. By performing electrophysiological recordings of large neuronal populations in dorsal and ventral CA1 in head-fixed mice navigating a virtual environment, we found that this diversity resulted in different strategies for population coding of space. We found that the populations of neurons in dorsal CA1 had a higher dimensionality and showed more complex patterns of activity, translating to more information being encoded, as compared ensembles in vCA1. Furthermore, a pairwise maximum entropy model was better at predicting the structure of global patterns of activity in ventral CA1 as compared to dorsal CA1. Taken together, we uncovered different coding strategies that likely emerge from anatomical and physiological differences along the longitudinal axis of hippocampus and that may, in turn, underpin the divergent ethological roles of dorsal and ventral CA1.

Highlights

No differences in dCA1 and vCA1 place field size in recordings of neuronal populations in mice navigating a virtual environment

dCA1 has higher single-neuron and population-level spatial information compared to vCA1 due to differences in the sparsity of firing.

Population activity of dCA1 has higher entropy and is higher dimensional than vCA1

Pairwise maximum entropy models are better at predicting population activity in vCA1 compared to dCA1
how_are_we_stranded_here: Quick determination of RNA-Seq strandedness
Authors: Signal Beth , Kahlke Tim
Published: March 2021

Quality control checks are the first step in RNA-Sequencing analysis, which enable the identification of common issues that occur in the sequenced reads. Checks for sequence quality, contamination, and complexity are commonplace, and allow users to implement steps downstream which can account for these issues. Strand-specificity of reads is frequently overlooked and is often unavailable even in published data, yet when unknown or incorrectly specified can have detrimental effects on the reproducibility and accuracy of downstream analyses. We present how_are_we_stranded_here, a Python library that helps to quickly infer strandedness of paired-end RNA-Sequencing data.
Pre-existing health conditions and severe COVID-19 infection: Analysis of commercial health insurance data from 690,000 infected patients
Authors: Wineinger Nathan E. , Li Victoria , Waalen Jill , Topol Eric J.
Published: March 2021

The development and distribution of new vaccines promises an end to the COVID-19 pandemic. With the elderly and front line workers first in line, the vaccination strategy for the general population remains unclear. In this study we identified 690,000 patients infected with COVID-19 with commercial health insurance coverage across the country between April 1, 2020 and September 30, 2020. From prior health care claims, we determined each person’s pre-existing diseases among 26 common chronic diseases. Across age-sex strata we determined the relationships between these conditions and severe COVID-19 infections: ICU admission and extended in-patient stay. We classify disease according to risk, develop multivariable models to predict infection outcomes, and created an online risk assessment tool to estimate risk of ICU admission based on pre-existing health conditions. Our results could be used to help guide risk, vaccination health policy, and personal decision-making as these become available to the general population.
Seroprevalence of SARS-CoV-2 Infection in Cincinnati Ohio USA from August to December 2020
Authors: Davis Greg , York Allen J. , Bacon Willis Clark , Suh-Chin Lin , McNeal Monica Malone , Yarawsky Alexander E. , Maciag Joseph J. , Miller Jeanette L. C. , Locker Kathryn C. S. , Bailey Michelle , Stone Rebecca , Hall Michael , Gonzalez Judith , Sproles Alyssa , Woodle E. Steve , Safier Kristen , Justus Kristine A. , Spearman Paul , Ware Russell E. , Cancelas Jose A. , Jordan Michael B. , Herr Andrew B. , Hildeman David A. , Molkentin Jeffery D.
Published: March 2021

The world is currently in a pandemic of COVID-19 (Coronavirus disease-2019) caused by a novel positive-sense, single-stranded RNA β-coronavirus referred to as SARS-CoV-2. Fortunately, most infected individuals recover and are then resistant to re-infection for a period, indicating that a vaccination approach can be successful. Elucidation of rates of past SARS-CoV-2 infection within select regions across the United States of America (USA) will help direct vaccination efforts and together will inform our approach towards achieving herd immunity. Here we investigated rates of SARS-CoV-2 infection in the greater Cincinnati, Ohio, USA metropolitan area from August to December 2020, just prior to initiation of the national vaccination program. Examination of 9,550 adult blood donor volunteers for serum IgG antibody positivity against the SARS-CoV-2 Spike protein showed an overall prevalence of 8.40%, measured as 7.56% in the first 58 days of this time frame, versus a significant increase to 9.24% in the last 58 days, and a final rate of 12.86% in December 2020. Approximately 56% of Spike seropositive individuals also had immunoreactivity against the receptor binding domain (RBD) within the Spike protein, which is associated with viral neutralization. Males and females in the Cincinnati area showed nearly identical rates of past infection, and rates among Hispanics, African Americans and Caucasians were not significantly different. Interestingly, donors under 30 years of age had the highest rates of past infection, while those over 60 had the lowest. Geographic analysis showed that the West side of Cincinnati had a rate of 9.63% versus 8.13% on the East side (demarcated by Interstate-75), while the adjoining area of Kentucky was 7.04% (as demarcated by the Ohio River). These results among healthy blood donors will be critical in calculating the time needed to achieve regional herd immunity in conjunction with the national vaccination campaign.
BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for BMI
Authors: Lundgren Sara , Kuitunen Sara , Pietiläinen Kirsi H. , Hurme Mikko , Kähönen Mika , Männistö Satu , Perola Markus , Lehtimäki Terho , Raitakari Olli , Kaprio Jaakko , Ollikainen Miina
Published: March 2021

Background

Obesity is a heritable complex phenotype which can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various “epigenetic clocks.” Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely relates with mortality.

Objectives

We aimed to assess the cross-sectional association of BMI with age acceleration in twins to limit confounding by genetics and shared environment.

Methods and Results

Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twins, and DNAm was measured using the Illumina 450k array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10−12) per 1-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI > 3 kg/m2) had an epigenetic age 5.2 months older than their lighter co-twin (p-value = 0.0074). We also found a positive association between log(HOMA-IR) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 0.0025) from adjusted models.

Conclusion

We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.
Day Camp in the Time of COVID-19: What Went Right?
Authors: Nachman Sharon , Brauner Gabrielle , Beleck Aviva , Handel Andrew S.
Published: March 2021

Objective

To evaluate whether a successful camp experience can be achieved with implementation of COVID-19 education, screening and hygiene protocols, and designated cohorts during the summer of 2020.

Study Design

A survey study of summer day camp directors in the metro-New York area was conducted in September, 2020. The survey inquired about camper demographics, COVID-10 related policies, and the number of COVID-19 cases and exposures at each camp.

Results

Responses were received from 77% (23/30) of camp directors at the completion of the 2020 summer. There were 8,480 camper children and 3,698 staff across the 23 camps surveyed. A variety of precautions were taken to limit COVID-19 incidence among campers and staff, most often including COVID-19 screening at entry, cohorting campers, maximizing outdoor activities, mandating mask use when indoors, and frequent hand sanitizing. Six staff and one camper tested positive for COVID-19. There was no secondary spread within the staff or campers in any of the camps.

Conclusion

Camps successfully stayed open in the summer of 2020. The low level of COVID-19 in the community was critical to the initial success of camp opening. Policies that were consistent and maintained among the camps helped prevent further spread.
Genome-wide association study identifies two new loci associated with anti-NMDAR encephalitis
Authors: Tietz Anja K , Angstwurm Klemens , Baumgartner Tobias , Doppler Kathrin , Eisenhut Katharina , Elišák Martin , Franke Andre , Golombeck Kristin S , Handreka Robert , Kaufmann Max , Kraemer Markus , Kraft Andrea , Lewerenz Jan , Lieb Wolfgang , Madlener Marie , Melzer Nico , Mojzisova Hana , Möller Peter , Pfefferkorn Thomas , Prüss Harald , Rostásy Kevin , Schnegelsberg Margret , Schröder Ina , Siebenbrodt Kai , Sühs Kurt-Wolfram , Wandinger Klaus-Peter , Wickel Jonathan , Leypoldt Frank , Kuhlenbäumer Gregor
Published: March 2021

Objective

To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis.

Methods

We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls followed by a colocalization analysis to identify putatively causal genes.

Results

We identified two independent risk loci harboring genome-wide significant variants (P < 5 × 10−8, OR ≤ 2.2), one on chromosome 15, harboring only the LRRK1 gene, and one on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage-disequilibrium. Colocalization signals with expression quantitative trait loci (eQTL) for different brain regions and immune cell types suggested ACP2, NR1H3, MADD, DDB2, and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1, encoding Leucine-Rich Repeat Kinase 1, a protein involved in B-cell development, and NR1H3 liver x receptor alpha, a transcription factor whose activation inhibits inflammatory processes.

Conclusion

This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the HLA-region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism.
A target HbA1c between 7 – 7.7% reduces macrovascular events in T2D regardless of duration of diabetes – a meta-analysis of randomized controlled trials
Authors: Sinha Binayak , Ghosal Samit
Published: March 2021

Introduction

The target glycosylated haemoglobin (HbA1c) at which macrovascular benefits may be derived in type 2 diabetes (T2D) has never been clearly outlined. This meta-analysis was conducted on fifteen randomized controlled trials to highlight the association of HbA1c range with macrovascular events.

Methods

The association of different HbA1c clusters (intention to treat (ITT) and end-of-study [EOS]) range (less or equal than 6.5%, 6.6%–7.0%, 7.1%–7.7%) with macrovascular complications and also the combined effect of duration of T2D (< 10 years or ≥ 10 years) and HbA1c levels was assessed.

Results

Intensive glucose-lowering strategy resulted in a significant 13% reduction in non-fatal myocardial infarction (NFMI) (P=0.006). Based on HbA1c achieved, a significant 36% reduction in non-fatal stroke (P=0.008) and a 22% reduction in all-cause mortality (P=0.02) were observed in the group with HbA1c between 7.1% – 7.7% irrespective of diabetes duration. In the cohort, with diabetes duration <10 years, reduction of HbA1c in the range7.1% - 7.7% resulted in a significant 36% reduction in non-fatal stroke (NFS) (P<0.001).

Conclusion

This is probably the first meta-analysis highlighting the importance of treating patients with T2D to a target HbA1C of 7 – 7.7%, as this target is associated with reduction in macrovascular events.
Early mechanisms of whisker development: Prdm1 and its regulation in whisker development and evolutionary loss
Authors: Manti Pierluigi Giuseppe , Darbellay Fabrice , Leleu Marion , Moret Bernard , Cuennet Julien , Droux Frederic , Stoudmann Magali , Mancini Gian-Filippo , Hautier Agnès , Barrandon Yann
Published: March 2021

Whiskers (vibrissae) are miniaturized organs that are designed for tactile sensing. Extremely conserved among mammals, they underwent a reduction in primates and disappeared in the human lineage. Furthermore, whiskers are highly innervated and their mechanoceptors signal to the primary somatosensory cortex, where a column of neurons called “barrel” represents each of them. This structure, known as barrel cortex, occupies a large portion of the somatosensory cortex of the rodent brain. Strikingly,Prdm1conditional knockout mice are one of the rare transgenic strains that do not develop whisker hair follicles while still displaying a pelage (Robertson et al. 2007). Here we show thatPrdm1is expressed early on during whisker development, more precisely in clusters of mesenchymal cells before placode formation. Its conditional knockout leads to the loss of expression ofBmp2, Shh, Bmp4, Krt17, Edar, Gli1though leaving the β-catenin driven first dermal signal intact. Furthermore, we prove thatPrdm1expressing cells not only act as a signaling center but also as a multipotent progenitor population contributing to the formation of the dermal papilla, dermal sheath and pericytes of the vascular sinuses of vibrissae. We confirm by genetic ablation experiments that the absence of motile vibrissae (macro vibrissae) formation reverberates on the organization of nerve wiring in the mystacial pads and organization of the barrel cortex. We prove thatLef1acts upstream ofPrdm1and identify a potential enhancer (named Leaf) that might be involved in the evolutionary process that led to the progressive reduction of snout size and vibrissae in primates.
Systems-level network modeling deciphers the master regulators of phenotypic plasticity and heterogeneity in melanoma
Authors: Pillai Maalavika , Jolly Mohit Kumar
Published: March 2021

Phenotypic (i.e. non-genetic) heterogeneity in melanoma drives dedifferentiation, recalcitrance to targeted therapy and immunotherapy, and consequent tumor relapse and metastasis. Various markers or regulators associated with distinct phenotypes in melanoma have been identified, but, how does a network of interactions among these regulators give rise to multiple “attractor” states and phenotypic switching remains elusive. Here, we inferred a network of transcription factors (TFs) that act as master regulators for gene signatures of diverse cell-states in melanoma. Dynamical simulations of this network predicted how this network can settle into different “attractors” (TF expression patterns), suggesting that TF network dynamics drives the emergence of phenotypic heterogeneity. These simulations can recapitulate major phenotypes observed in melanoma and explain de-differentiation trajectory observed upon BRAF inhibition. Our systems-level modeling framework offers a platform to understand trajectories of phenotypic transitions in the landscape of a regulatory TF network and identify novel therapeutic strategies targeting melanoma plasticity.
Protocol-dependence of middle cerebral artery dilation to modest hypercapnia
Authors: Al-Khazraji Baraa K. , Buch Sagar , Kadem Mason , Matushewski Brad J. , Norozi Kambiz , Menon Ravi S. , Shoemaker J. Kevin
Published: March 2021

There is a need for improved understanding of how different cerebrovascular reactivity (CVR) protocols affect vascular cross-sectional area (CSA) when measures of vascular CSA are not feasible. In human participants, we delivered ~±4mmHg end-tidal partial pressure of CO2(PETCO2) relative to baseline through controlled delivery, and measured changes in middle cerebral artery (MCA) cross-sectional area (CSA; magnetic resonance imaging (7 Tesla MRI)), blood velocity (transcranial Doppler and Phase contrast MRI), and calculated CVR based on steady-state versus a ramp protocol during two protocols: a 3-minute steady-state (+4mmHg PETCO2) and a ramp (delta of −3 to +4mmHg of PETCO2). We observed that 1) the MCA did not dilate during the ramp protocol, but did dilate during steady-state hypercapnia, and 2) MCA blood velocity CVR was similar between ramp and steady-state hypercapnia protocols, although calculated MCA blood flow CVR was greater during steady-state hypercapnia than during ramp, the discrepancy due to MCA CSA changes during steady-state hypercapnia. Due to the ability to achieve similar levels of MCA blood velocity CVR as steady-state hypercapnia, the lack of change in MCA cross-sectional area, and the minimal expected change in blood pressure, we propose that a ramp model, across a delta of ~−3 to +4mmHg PETCO2, may provide one alternative approach to collecting CVR measures in young adults with TCD when CSA measures are not feasible.
REPRODUCTIVE SENESCENCE IMPAIRS THE ENERGY METABOLISM OF HUMAN GRANULOSA CELLS
Authors: Cecchino Gustavo Nardini , García-Velasco Juan A. , Rial Eduardo
Published: March 2021

Female age is the single greatest factor influencing reproductive performance. It is widely known that mitochondrial dysfunction plays a key role in reproductive senescence. Ovarian bioenergetics includes a sophisticated metabolic synergism between oocytes and human mural granulosa cells (GCs), which is crucial for oocyte maturation during follicular growth. These cells are believed to be potential biomarkers of oocyte quality. It has been proposed that alterations in their energy metabolism could lead to infertility. We investigated if there is an age-related effect on the energy metabolism of human mural granulosa cells. We performed an observational prospective cohort and experimental study including 127 women that underwent in vitro fertilization cycles allocated to two groups: a control group comprising oocyte donors aged less than 35 years and a group of infertile women aged over 38 years. The bioenergetics of cumulus cells and purified mural GCs were determined from oxidative phosphorylation parameters, aerobic glycolysis and adenine nucleotide levels. We have found that human mural GCs and cumulus cells present a high glycolytic profile and that the follicular fluid is critical to sustain their energy metabolism. GCs from older women present lower mitochondrial respiration and glycolysis than those from young donors which is not accompanied by a lower respiratory capacity. The diminished energy metabolism leads to a decrease in the total cellular energy charge. We conclude that, as women age, mural granulosa cells exhibit a reduction in their energy metabolism that is likely to influence female reproductive potential.
Refget: standardised access to reference sequences
Authors: Yates Andrew D , Adams Jeremy , Chaturvedi Somesh , Davies Robert M. , Laird Matthew , Leinonen Rasko , Nag Rishi , Sheffield Nathan C. , Hofmann Oliver , Keane Thomas
Published: March 2021

Reference sequences are essential in creating a baseline of knowledge for many common bioinformatics methods, especially those using genomic sequencing. We have created refget, a Global Alliance for Genomics and Health API specification to access reference sequences and sub-sequences using an identifier derived from the sequence itself. We present four reference implementations across in-house and cloud infrastructure, a compliance suite and a web report used to ensure specification conformity across implementations.https://w3id.org/ga4gh/refget.
Chronic exercise protects against the progression of renal cyst growth and dysfunction in rats with polycystic kidney disease
Authors: Qiu Jiahe , Sato Yoichi , Xu Lusi , Miura Takahiro , Kohzuki Masahiro , Ito Osamu
Published: March 2021

Introduction

Polycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model.

Methods

Six-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 weeks (28 m/min, 60 min/day, 5 days/week). After 12 weeks, kidney function and histology were examined, protein expressions were analyzed, and signaling cascades of PKD were examined.

Results

Chronic exercise reduced the excretion of urinary protein, liver-type fatty acid-binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary arginine vasopressin (AVP) excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis, and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6.

Conclusion

Chronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with down-regulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.
Adipocyte Tribbles1 Regulates Plasma Adiponectin and Plasma Lipids in Mice
Authors: Ha Elizabeth E. , Quartuccia Gabriella I. , Ling Ruifeng , Xue Chenyi , Hernandez-Ono Antonio , Imam Rami , Cui Jian , Soni Rajesh K. , Bauer Robert C.
Published: March 2021

Multiple GWAS have identified SNPs in the 8q24 locus near theTRIB1gene that significantly associate with plasma lipids and coronary artery disease. While subsequent studies have uncovered roles for hepatic and myeloidTrib1in contributing to either plasma lipids or atherosclerosis, the causal tissue for these GWAS associations remains unclear. The same 8q24 SNPs significantly associate with plasma adiponectin levels in humans as well, suggesting a role forTRIB1in adipose tissue. Here, we report that adipocyte-specificTrib1knockout mice (Trib1_ASKO) have increased plasma adiponectin levels and decreased plasma cholesterol and triglycerides. We demonstrate that loss ofTrib1increases adipocyte production and secretion of adiponectin independent of the known TRIB1 function of regulating proteasomal degradation. RNA-seq analysis of adipocytes and livers from Trib1_ASKO mice suggests that alterations in adipocyte function underlie the plasma lipid changes observed in these mice. Secretomics and RNA-seq analysis revealed that Trib1_ASKO mice have increased production of Lpl and decreased production of Angptl4 in adipose tissue, and fluorescent substrate assays confirm an increase in adipose tissue Lpl activity, which likely underlies the observed triglyceride phenotype. In summary, we demonstrate here a novel role for adipocyteTrib1in regulating plasma adiponectin, total cholesterol, and triglycerides in mice, confirming previous genetic associations observed in humans and providing a novel avenue through whichTrib1regulates plasma lipids and coronary artery disease.
Relevance of Circulating Hybrid Cells as a Non-Invasive Biomarker for Myriad Solid Tumors
Authors: Dietz Matthew S. , Sutton Thomas L. , Walker Brett S. , Gast Charles E. , Zarour Luai , Sengupta Sidharth K. , Swain John R. , Eng Jennifer , Parappilly Michael , Limbach Kristen , Sattler Ariana , Burlingame Erik , Chin Yuki , Gower Austin , Montoya Mira Jose L. , Sapre Ajay , Chiu Yu-Jui , Clayburgh Daniel R. , Pommier SuEllen J. , Cetnar Jeremy P. , Fischer Jared M. , Jaboin Jerry J. , Han Seunggu J. , Nazemi Kellie J. , Pommier Rodney F. , Billingsley Kevin G. , Sheppard Brett C. , Tsikitis V. Liana , Skalet Alison H. , Mayo Skye C. , Lopez Charles D. , Gray Joe W. , Mills Gordon B. , Mitri Zahi , Hwan Chang Young , Chin Koei , Wong Melissa H.
Published: March 2021

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the ability to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.

Simple Summary

There is an incomplete understanding of circulating neoplastic cell populations and the fundamental mechanisms that drive dissemination, immune evasion, and growth —all critical information to more effectively prevent and treat cancer progression. A novel disseminated tumor cell population, circulating hybrid cells, are detected across many cancer types and carry functional tumor-initiating properties. Additionally, circulating hybrid cells are found at significantly higher levels than conventionally defined circulating tumor cells. Our study demonstrates that neoplastic hybrid cells harbor phenotypic and genetic characteristics of tumor and immune cells, display stem features, and are a generalizable phenomenon in solid tumors. Circulating hybrid cells therefore have relevance as a novel biomarker and open a new field of study in malignancy.
The mutational signatures of formalin fixation on the human genome
Authors: Guo Qingli , Lakatos Eszter , Al Bakir Ibrahim , Curtius Kit , Graham Trevor A. , Mustonen Ville
Published: March 2021

Background

Formalin fixation and paraffin embedding (FFPE) of patient material remains standard practice in clinical pathology labs around the world. Clinical archives of patient material near-exclusively consist of FFPE blocks. The ability to perform high quality genome sequencing on FFPE-derived DNA would accelerate a broad spectrum of medical research. However, formalin is a recognised mutagen and sequencing of DNA derived from FFPE material is known to be riddled with artefactual mutations.

Results

Here we derive genome-wide mutational signatures caused by formalin fixation, and provide a computational method to correct mutational profiles for these formalin-induced artefacts. We show that the FFPE-signature is dominated by C>T transitions caused by cytosine deamination, and has very high similarity to COSMIC signature SBS30 (base excision repair deficiency due to inactivation mutations inNTHL1). Further, we demonstrate that chemical repair of formalin-induced DNA lesions, a process that is routinely performed as part of sequencing library preparation, leads to a signature highly similar to COSMIC signature SBS1 (spontaneous deamination of methylated cytosine). Next, we design FFPEsig, a computational method to remove the formalin-induced artefacts from mutational counts. We prove the efficacy of this method by generating synthetic FFPE samples using 2,780 cancer genomes from the Pan-Cancer Analysis of Whole Genome (PCAWG) project, and via analysis of FFPE-derived genome sequencing data from colorectal cancers.

Conclusions

Formalin fixation leaves a predictable mutational footprint across the genome. The application of our FFPEsig software corrects the mutational profile for the influence of formalin, enabling robust mutational signature analysis in FFPE-derived patient material.
A meta-analysis of effects of feeding seaweed on beef and dairy cattle performance and methane yield
Authors: Lean Ian J. , Golder Helen M. , Grant Tianna M. D. , Moate Peter J.
Published: March 2021

There has been considerable interest in the use of red seaweed, and in particularAsparagopsis taxiformis, to increase production of cattle and to reduce greenhouse gas emissions. We hypothesized that feeding seaweed or seaweed derived products would increase beef or dairy cattle performance as indicated by average daily gain (ADG), feed efficiency measures, milk production, and milk constituents, and reduce methane emissions. We used meta-analytical methods to evaluate these hypotheses. A comprehensive search of Google Scholar, Pubmed and ISI Web of Science produced 14 experiments from which 23 comparisons of treatment effects could be evaluated. Red seaweed (A. taxiformis) and brown seaweed (Ascophyllum nodosum) were the dominant seaweeds used. There were no effects of treatment on ADG or dry matter intake (DMI). There was an increase in efficiency for feed to gain by 0.41 ± 0.22 kg per kg [standardized mean difference (SMD) = 0.70 ± 0.35; P = 0.001], but not for gain to feed (P = 0.215), although the direction of the change was for improved efficiency. The type of seaweed used was not a significant covariable for ADG and DMI. Milk production was increased with treatment on weighted mean difference (WMD; 1.35 ± 0.44 kg/d; P <0.001); however, the SMD of 0.45 was not significant (P = 0.111). Extremely limited data suggest the possibility of increased percentages of milk fat (P = 0.040) and milk protein (P = 0.001) on DerSimonian and Laird (D&L) WMD evaluation. The limited data available indicate dietary supplementation with seaweed produced a significant and substantial reduction in methane yield by 5.28 ± 3.5 g/kg DMI (P = 0.003) on D&L WMD evaluation and a D&L SMD of −1.70 (P = 0.001); however, there was marked heterogeneity in the results (I2> 80%). In one comparison, methane yield was reduced by 97%. We conclude that while there was evidence of potential for benefit from seaweed use to improve production and reduce methane yield morein vivoexperiments are required to strengthen the evidence of effect and identify sources of heterogeneity in methane response, while practical applications and potential risks are evaluated for seaweed use.
Egocentric Asymmetric Coding in Sensory Cortical Border Cells
Authors: Long Xiaoyang , Deng Bin , Cai Jing , Chen Zhe Sage , Zhang Sheng-Jia
Published: March 2021

Both egocentric and allocentric representations of space are essential to spatial navigation. Although some studies of egocentric coding have been conducted within and around the hippocampal formation, externally anchored egocentric spatial representations have not yet been fully explored. Here we record and identify two subtypes of border cell in the rat primary somatosensory cortex (S1) and secondary visual cortex (V2). Subpopulations of S1 and V2 border cells exhibit rotation-selective asymmetric firing fields in an either clockwise (CW) or counterclockwise (CCW) manner. CW- and CCW-border cells increase their firing rates when animals move unidirectionally along environmental border(s). We demonstrate that both CW- and CCW-border cells fire in an egocentric reference frame relative to environmental borders, maintain preferred directional tunings in rotated, stretched, dark as well as novel arenas, and switch their directional firings in the presence of multi-layer concentric enclosures. These findings may provide rotation-selective egocentric reference frames within a larger spatial navigation system, and point to a common computational principle of spatial coding shared by multiple sensory cortical areas.

Highlights

Egocentric border cells are present in rat S1 and V2

Subtypes of border cells display egocentric asymmetric coding

Egocentric and allocentric streams coexist in sensory cortices

Rotation-selective asymmetric firing is robust with environmental manipulations
Optimal immune specificity at the intersection of host life history and parasite epidemiology
Authors: Downie A. E. , Mayer A. , Metcalf C. J. E. , Graham A. L.
Published: March 2021

Epidemiology and life history are commonly hypothesized to influence host immune strategy, and the pairwise relationships between immune strategy and each factor have been extensively investigated. But the interaction of these two is rarely considered, despite evidence that this interaction might produce emergent effects on optimal immune strategy. Here we investigate the confluence of epidemiology and life history as it affects immune strategy through a demographically-framed model of sensitivity and specificity in parasite recognition and response. We find that variation in several different life history traits associated with both reproduction and longevity alters optimal immune strategies – but the direction and magnitude of these effects depends on how epidemiological risks vary across life. Drawing on published life history data, we also find that our predictions apply across chordate taxa. Our results shed light on the complex interactions shaping immune strategy and may prove valuable in interpreting empirical results in ecoimmunology.
Combination adjuvants enhance recombinant protein vaccine protection against fungal infection
Authors: Wuethrich Marcel , Dobson Hannah E. , Taira Cleison Ledesma , Okaa Uju Joy , Petrovsky Nikolai , Klein Bruce S.
Published: March 2021

The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with TLR agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2, which itself harbors an immunodominant antigen and Dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8, containing TLR4 agonist, provided the best protection against pulmonary infection withBlastomyces dermatitidis, being more effective than Freund’s complete adjuvant or Adjuplex. Advax3 was most efficient in inducing IFN-γ and IL-17 producing antigen-specific T cells that migrated to the lung uponBlastomyces dermatitidisinfection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or IFN-γ+and IL-17+correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+T cells, partially reduced by depletion of CD8+T cells, and completely eliminated after depletion of both CD4+and CD8+T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+and also CD4+T cells producing IFN-γ and/or IL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines.

IMPORTANCE

Fungal disease remains a challenging clinical and public health problem. Despite medical advances, invasive fungal infections have skyrocketed over the last decade and pose a mounting health threat in immune-competent and -deficient hosts with worldwide mortality rates ranking 7th, even ahead of tuberculosis. The development of safe, effective vaccines remains a major hurdle for fungi. Critical barriers to progress include the lack of defined fungal antigens and suitable adjuvants. Our research is significant in identifying adjuvant combinations that elicit optimal vaccine-induced protection when formulated with a recombinant protective antigen and uncovering the mechanistic bases of the underlaying vaccine protection, which will foster the strategic development of anti-fungal vaccines.
Baseline power of theta oscillations predicts mystical-type experiences induced by DMT
Authors: Tagliazucchi Enzo , Zamberlan Federico , Cavanna Federico , de la Fuente Laura , Romero Celeste , Perl Yonatan Sanz , Pallavicini Carla
Published: March 2021

N,N-Dimethyltryptamine (DMT) is a classic psychedelic capable of inducing short-lasting but profound changes in consciousness. As with other psychedelics, the experience induced by DMT strongly depends upon contextual factors, yet the neurobiological determinants of this variability remain unknown. We combined wireless electroencephalography and source imaging to map changes in neural oscillations elicited by inhaled DMT. Furthermore, we found that the power of frontal and temporal theta oscillations was inversely correlated with scales indexing feelings of unity and transcendence, which are an integral part of the phenomenology of mystical-type experiences. Finally, we established the robustness of these results using a machine learning model for regression trained and tested following a cross-validation procedure. Our results are consistent with the observation that the state of mind prior to consuming a psychedelic drug influences the ensuing subjective experience of the user. We also suggest that priming subjects to reduce their theta power before administration of a serotonergic psychedelic could enhance the likelihood of inducing mystical-type experiences, leading to sustained positive effects in well-being and improving the outcome of therapeutic interventions.