bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydrogel injection molding to generate complex cell encapsulation geometries
Authors: Emerson Amy E. , McCall Alec B. , Brady Sarah R. , Slaby Emily M. , Weaver Jessica D. 
Published: November 2021

AbstractBiofabrication methods capable of generating complex, three-dimensional, cell-laden hydrogel geometries are often challenging technologies to implement in the clinic and scaled manufacturing processes. Hydrogel injection molding capitalizes on the reproducibility, efficiency, and scalability of the injection molding process, and we adapt this technique to biofabrication using a library of natural and synthetic hydrogels with varied crosslinking chemistries and kinetics. We use computational modeling to evaluate hydrogel library fluid dynamics within the injection molds in order to predict molding feasibility and cytocompatibility. We evaluate the reproducibility of hydrogel construct molding and extraction and establish criteria for the selection of hydrogels suitable for injection molding. We demonstrate that hydrogel injection molding is capable of generating complex three-dimensional cell-laden construct geometries using diverse hydrogel materials and that this platform is compatible with primary human islet encapsulation. We envision the application of this technique with primary cells via an off-the-shelf clinical kit that can be implemented at the patient bedside by a clinician or integrated with scaled, high-throughput automated cell manufacturing processes to generate encapsulated cell-based therapeutic products.Graphical Abstract
Reproducible Discovery of Cell-Binding Peptides “Lost” in Bulk Amplification via Emulsion Amplification in Phage Display Panning
Authors: Matochko Wadim L. , Deiss Frédérique , Yang Yang , Derda Ratmir 
Published: November 2021

AbstractMany pharmaceutically-relevant cell surface receptors are functional only in the context of intact cells. Phage display, while being a powerful method for the discovery of ligands for purified proteins often fails to identify a diverse set of ligands to receptors on a cell membrane mosaic. To understand this deficiency, we examined growth bias in naïve phage display libraries and observed that it fundamentally changes selection outcomes: The presence of growth-biased (parasite) phage clones in a phage library is detrimental to selection and cell-based panning of such biased libraries is poised to yield ligands from within a small parasite population. Importantly, amplification of phage libraries in water-oil emulsions suppressed the amplification of parasites and steered the selection of biased phage libraries away from parasite population. Attenuation of the growth bias through the use of emulsion amplification reproducibly discovers the ligands for cell-surface receptors that cannot be identified in screen that use conventional ‘bulk’ amplification.Abstract FigureFind Ligands in DropletsCanonical phage display selection of ligands for breast cancer cells, which uses bulk amplification (BA) of phage library, reproducibly identified peptide ligands from a ~0.0001% sub-population of the library, which harbors fast-growing phage. Replacing BA by emulsion-amplification (EmA) altered the selection landscape and yielded cell-binding ligands not accessible to conventional phage-display select
The Temporal Pattern of Synaptic Activation Determines the Longevity of Structural Plasticity at Single Dendritic Spines
Authors: Argunsah Ali Özgür , Israely Inbal 
Published: November 2021

SummaryIndividual synapses are the points at which information is passed between neurons, yet it is unknown how the diverse patterns of activity that are observed in vivo effect plasticity at the level of single inputs. Here, we aimed to determine what are the structural plasticity consequences of naturalistic patterns of activity at single spines, as these reflect changes in synaptic efficacy. Utilizing two- photon fluorescence imaging and glutamate uncaging, we studied structural plasticity of individual CA1 hippocampal dendritic spines using activation patterns sampled from a Poisson distribution, which resemble endogenous firing patterns from their CA3 inputs. We found that while the majority of inputs initially undergo structural changes, the robustness of this plasticity is determined by the timing structure of the Poisson sampled naturalistic stimulation patterns. Further, we found that structural plasticity elicited by these naturalistic patterns is both NMDAR and protein synthesis dependent, consistent with requirements for other forms of plasticity. Lastly, we found that during the delivery of naturalistic activity patterns, spines underwent rapid and dynamic structural growth that predicted the longevity of plasticity, which was not the case during non-naturalistic stimulation protocols. These data suggest that dendritic spines are able to integrate incoming temporal information and accordingly modulate the longevity of plasticity that is induced.HighlightsNaturalistic stimulation of single dendritic spines of CA1 hippocampal neurons induces long lasting structural plasticity that depends on the temporal distribution of the synaptic events.Structural plasticity induced by naturalistic stimulation patterns requires NMDA receptor activation and new protein-synthesis.Rapid spine structural dynamics during naturalistic activity, but not regular patterns, predict the longevity of subsequent structural plasticity.
A prior exposure to Serratia marcescens or xenobiotics primes Drosophila enterocytes against a recurring cytoplasmic purge
Authors: Terreri Simone , Sina-Rahme Bechara , Pais Inês , Socha Catherine , Lestradet Matthieu , Yamba Miriam , Schirmeier Stefanie , Lee Kwang-Zin , Ferrandon Dominique 
Published: November 2021

AbstractThe cytoplasmic extrusion of enterocytes is a fast response to an exposure to pore-forming toxin (PFT)-producing bacteria whereby their apical cytoplasm is extruded into the intestinal lumen. As a result of this purge, the intestinal epithelium becomes thin prior to a subsequent recovery. We report here that the ingestion of ethanol or caffeine induces a similar response, which suggests that a common purging process is triggered by bacterial toxins and abiotic toxicants. We also delineate an additional mechanism that is initiated by these stimuli that we refer to as priming. The initial exposure of the intestinal epithelium to either PFT or xenobiotics protects enterocytes against a further round of purging upon a second bacterial infection. Priming prevents the epithelium from being persistently thin in the context of chronic intestinal infections. We have identified the upper part of the p38b MAPK pathway as well as the homeobox-containing transcription factors E5/EMS as being required for priming and not for the regrowth of enterocytes after the cytoplasmic purge. Unexpectedly, the priming process appears to function cell-nonautonomously. Our findings suggest that the cytoplasmic purge extrusion has been selected because it constitutes a fast reaction to accidental exposure to bacterial toxins or toxicants.
ClinGen CDH1 specifications for the ACMG/AMP guidelines: improvement of germline variant clinical assertions and updated curation guidelines
Authors: Luo Xi , Maciaszek Jamie L. , Thompson Bryony A. , Leong Huei San , Dixon Katherine , Sousa Sónia , Anderson Michael , Roberts Maegan E. , Lee Kristy , Spurdle Amanda B. , Mensenkamp Arjen R. , Brannan Terra , Pardo Carolina , Zhang Liying , Pesaran Tina , Wei Sainan , Fasaye Grace-Ann , Kesserwan Chimene , Shirts Brian H. , Davis Jeremy L. , Oliveira Carla , Plon Sharon E. , Schrader Kasmintan A. , Karam Rachid 
Published: November 2021

AbstractPurposeThe Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations for effective medical care. In addition, the CDH1 VCEP continues to update these specifications in keeping with evolving clinical practice and variant interpretation guidelines.MethodsCDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen, and expert knowledge from ongoing CDH1 variant curations. Trained biocurators curated 273 variants using updated CDH1 interpretation guidelines and incorporated published and unpublished data provided by diagnostic laboratories. All variants were reviewed by the ClinGen VCEP and classifications submitted to ClinVar.ResultsUpdated CDH1-specific variant interpretation guidelines include eleven major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36/37) of variants with ClinVar conflicting interpretations were resolved into benign, likely benign, likely pathogenic, or pathogenic, and 35% (15/43) of VUS were resolved into benign or likely benign. Overall, 88% (239/273) of curated variants had non-VUS classifications.ConclusionThe development and evolution of CDH1-specific criteria by the expert panel results in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene.
Transcriptional integration of distinct microbial and nutritional signals by the small intestinal epithelium
Authors: Lickwar Colin R. , Davison James M. , Kelly Cecelia , Mercado Gilberto Padilla , Wen Jia , Davis Briana R. , Tillman Matthew C. , Semova Ivana , Andres Sarah F. , Vale Goncalo , McDonald Jeffrey G. , Rawls John F. 
Published: November 2021

AbstractTo preserve its physiologic functions, the intestine must interpret and adapt to complex combinations of stimuli from dietary and microbial sources. However, the transcriptional strategies by which the intestinal epithelium integrates and adapts to dietary and microbial information remains unresolved. We compared adult mice reared germ free (GF) or conventionalized with a microbiota (CV) either fed normally or after a single high-fat meal (HFM). Jejunal epithelium preparations were queried using genomewide assays for RNA-seq, the activating histone mark H3K27ac ChIP-seq, and ChIP-seq of the microbially-responsive transcription factor HNF4A. We identified distinct nutritional and microbial responses at certain genes, but also apparent simultaneous influence of both stimuli at many other loci and regulatory regions. Increased expression levels and H3K27ac enrichment following HFM at a subset of these sites was dependent on microbial status. H3K27ac sites that were preferentially increased by HFM in the presence of microbes neighbor lipid anabolism and proliferation genes as well as intestinal stem cell (ISC) markers, were usually active only in ISCs, and were not HNF4A targets. In contrast, H3K27ac sites that were preferentially increased by HFM in the absence of microbes neighbored targets of the nuclear receptor and energy homeostasis regulator PPARA, were frequently accessible only in enterocytes, and were HNF4A bound. These results reveal that HNF4A supports a differentiated enterocyte and FAO program in GF, and that suppression of HNF4A by the combination of microbes and HFM may result in preferential activation of IEC proliferation programs. Microbial and nutritional responses are therefore integrated with some of the same transcriptional programs that regulate intestinal proliferation and differentiation.
Dorsal striatum coding for the timely execution of action sequences
Authors: Martinez María Cecilia , Zold Camila Lidia , Coletti Marcos Antonio , Murer Mario Gustavo , Belluscio Mariano Andrés 
Published: November 2021

SummaryThe automatic initiation of actions can be highly functional. But occasionally these actions cannot be withheld and are released at inappropriate times, impulsively. Striatal activity has been shown to participate in the timing of action sequence initiation and it has been linked to impulsivity. Using a self-initiated task, we trained adult male rats to withhold a rewarded action sequence until a waiting time interval has elapsed. By analyzing neuronal activity we show that the striatal response preceding the initiation of the learned sequence is strongly modulated by the time subjects wait before eliciting the sequence. Interestingly, the modulation is steeper in adolescent rats, which show a strong prevalence of impulsive responses compared to adults. We hypothesize this anticipatory striatal activity reflects the animals’ subjective reward expectation, based on the elapsed waiting time, while the steeper waiting modulation in adolescence reflects age-related differences in temporal discounting, internal urgency states or explore-exploit balance.
Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury
Authors: Wasserman Aaron H. , Huang Amanda R. , Lewis-Israeli Yonatan R. , Dooley McKenna D. , Mitchell Allison L. , Venkatesan Manigandan , Aguirre Aitor 
Published: November 2021

ABSTRACTCardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature. Critical work in the last two decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development. Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardial-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells. In mammals, this process alone is insufficient for significant regeneration, but it might be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function. Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and migration in a model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells. In addition, we demonstrate that OXT is produced after cardiac cryoinjury in zebrafish, and that it elicits significant epicardial activation promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium development in zebrafish embryos. The above processes are significantly impaired when OXT signaling is inhibited chemically or genetically through RNA interference. RNA sequencing data suggests that the transforming growth factor beta (TGF-β) pathway is the primary mediator of OXT-induced epicardial activation. Our research reveals for the first time an evolutionary conserved brain-controlled mechanism inducing cellular reprogramming and regeneration of the injured mammalian and zebrafish heart, a finding that could contribute to translational advances for the treatment of cardiac injuries.
Concerted cellular responses to type I interferon propel memory impairment associated with amyloid β plaques
Authors: Roy Ethan R. , Chiu Gabriel , Li Sanming , Propson Nicholas E. , Zheng Hui , Cao Wei 
Published: November 2021

AbstractDespite well-documented maladaptive neuroinflammation in Alzheimer’s disease (AD), the principal signal that drives memory and cognitive impairment remains elusive. Here, we reveal robust, age-dependent cellular reactions to type I interferon (IFN), an innate immune cytokine aberrantly elicited by β amyloid plaques, and examine their role in cognition and neuropathology relevant to AD in a murine amyloidosis model. Long-term blockade of IFN receptor rescued both memory and synaptic deficits, and also resulted in reduced microgliosis, inflammation, and neuritic pathology. Interestingly, microglia-specific IFN receptor ablation attenuated the loss of post-synaptic terminals, whereas IFN signaling in neural cells contributed to pre-synaptic alteration and plaque accumulation. Intriguingly, IFN pathway activation displayed a strong inverse correlation with cognitive performance, promoting selective synapse engulfment by microglia rather than amyloid plaques. Overall, IFN signaling represents a critical module within the neuroinflammatory network of AD and prompts a concerted cellular state that is detrimental to memory and cognition.
A low-resource reliable pipeline to democratize multi-modal connectome estimation and analysis
Authors: Chung Jaewon , Lawrence Ross , Loftus Alex , Pisner Derek , Kiar Gregory , Bridgeford Eric W. , Roncal William Gray ,   Consortium for Reliability and Reproducibility (CoRR), Chandrashekhar Vikram , Mhembere Disa , Ryman Sephira , Zuo Xi-Nian , Margulies Daniel S. , Craddock R. Cameron , Priebe Carey E. , Jung Rex , Calhoun Vince D. , Caffo Brian , Burns Randal , Milham Michael P. , Vogelstein Joshua T. 
Published: November 2021

AbstractConnectomics—the study of brain networks—provides a unique and valuable opportunity to study the brain. Research in human connectomics, leveraging functional and diffusion Magnetic Resonance Imaging (MRI), is a resource-intensive practice. Typical analysis routines require significant computational capabilities and subject matter expertise. Establishing a pipeline that is low-resource, easy to use, and off-the-shelf (can be applied across multifarious datasets without parameter tuning to reliably estimate plausible connectomes), would significantly lower the barrier to entry into connectomics, thereby democratizing the field by empowering a more diverse and inclusive community of connectomists. We therefore introduce ‘MRI to Graphs’ (m2g). To illustrate its properties, we usedm2gto process MRI data from 35 different studies (≈ 6,000 scans) from 15 sites without any manual intervention or parameter tuning. Every single scan yielded an estimated connectome that adhered to established properties, such as stronger ipsilateral than contralateral connections in structural connectomes, and stronger homotopic than heterotopic correlations in functional connectomes. Moreover, the connectomes estimated bym2gare more similar within individuals than between them, suggesting thatm2gpreserves biological variability.m2gis portable, and can run on a single CPU with 16 GB of RAM in less than a couple hours, or be deployed on the cloud using its docker container. All code is available onhttps://github.com/neurodata/m2gand documentation is available on docs.neurodata.io/m2g.
Antiviral activity of pacific oyster (Crassostrea gigas) hemolymph against a human coronavirus
Authors: Pedler Rebecca L. , Harris James O. , Speck Peter G. 
Published: November 2021

ABSTRACTCoronaviruses can cause severe respiratory infections in humans. In this study we assessed the antiviral activity of Pacific oyster (Crassostrea gigas) hemolymph against a human coronavirus, HCoV-229E. An eight-fold reduction in infectivity of HCoV-229E on Huh-7 cells was observed in the presence of 10% C. gigas hemolymph. Antiviral activity of C. gigas hemolymph positively correlated with its concentration and appears to be active during an intracellular stage of HCoV-229E infection.
Isomeric lipid signatures reveal compartmentalised fatty acid metabolism in cancer
Authors: Young Reuben S. E. , Bowman Andrew P. , Tousignant Kaylyn D. , Poad Berwyck L. J. , Gunter Jennifer H. , Philp Lisa K. , Nelson Colleen C. , Ellis Shane R. , Heeren Ron M. A. , Sadowski Martin C. , Blanksby Stephen J. 
Published: November 2021

1.0SummaryCellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular fatty acids (FA) and de novo synthesis. Given that oxidation of de novo synthesised FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates - however hitherto FAs were considered part of a common pool. To probe FA metabolic partitioning, cancer cells were supplemented with stable-isotope labelled FAs. Structural analysis of the resulting glycerophospholipids revealed that labelled FAs from uptake were largely incorporated to canonical (sn-)positions on the glycerol backbone. Surprisingly, labelled FA uptake disrupted canonical isomer patterns of the unlabelled lipidome and induced repartitioning of n-3 and n-6 polyunsaturated-FAs into glycerophospholipid classes. These structural changes evidence differences in the metabolic fate of FAs derived from uptake or de novo sources and demonstrate unique signalling and remodelling behaviours usually hidden to conventional lipidomics.HighlightsLipid isomers reveal discrete metabolic compartmentalisation in cancerFAs derived from uptake and de novo synthesis have different metabolic fatesStearate uptake signals for PUFA (n-3 and n-6) repartitioning between lipid classessn-positional isomers are a marker for aberrant lipid metabolism
Long-term forest monitoring unravels constant mortality rise in European forests
Authors: George Jan-Peter , Sanders Tanja GM , Neumann Mathias , Cammalleri Carmelo , Vogt Jürgen V. , Lang Mait 
Published: November 2021

Abstract⍰European forests are an important source for timber production, human welfare, income, protection and biodiversity. During the last two decades, Europe has experienced a number of droughts which were exceptionally within the last 500 years both in terms of duration and intensity and these droughts seem to left remarkable imprints in the mortality dynamics of European forests. However, systematic observations on tree decline with emphasis on single species together with high-resolution drought data has been scarce so far so that deeper insights into mortality dynamics and drought occurrence is still limiting our understanding at continental scale.⍰Here we make use of the ICP Forest crown defoliation dataset, permitting us to retrospectively monitor tree mortality for four major conifers, two major broadleaves as well as a pooled dataset of nearly all minor tree species in Europe. In total, we analysed more than 3 million observations gathered during the last 25 years and employed a high-resolution drought index which is able to assess soil moisture anomaly based on a hydrological water-balance and runoff model every ten days globally. ⍰We found significant overall and species-specific increasing trends in mortality rates accompanied by decreasing soil moisture. A generalized linear model identified previous-year soil moisture anomaly as the most important driver of mortality patterns in European forests. Significant interactions appeared between previous-year soil moisture and stand water regime in conifers, strongly suggesting that conifers growing at productive sites are more vulnerable under drought.⍰We conclude that mortality patterns in European forests are currently reaching a concerning upward trend which could be further accelerated by global change-type droughts.Key messageForest mortality has significantly increased over the last 25 years and remained above the long-term mean since 2012.