bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex andAPOEGenotype Influence Respiratory Function Under Hypoxic and Hypoxic-Hypercapnic Conditions
Authors: Taylor Chase E. , Mendenhall Laura E. , Sunshine Michael D. , Wilson Jessica N. , Calulot Chris M. , Sun Ramon C. , Johnson Lance A. , Alilain Warren J.
Published: August 2022

The apolipoprotein(APOE)gene has been studied due to its influence on Alzheimer’s disease (AD) development and work in anAPOEmouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Individuals with AD often co-present with obstructive sleep apnea (OSA) characterized by cessations in breathing during sleep. Despite the prominence ofAPOEgenotype and sex as factors in AD progression, little is known about the impact of these variables on respiratory control. Ventilation is tightly regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to chemoreception. Alterations within these modulatory systems may result in disruptions of appropriate respiratory control and ultimately, disease. Using mice expressing two different humanizedAPOEalleles, we characterized how sex and the presence ofAPOE3orAPOE4influences ventilation during baseline breathing (normoxia) and during respiratory challenge. We show that sex andAPOEgenotype influence breathing during hypoxic challenge, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing.
High-frequency quantitative ultrasound to assess the acoustic properties of engineered tissues in vitro
Authors: Sebastian Joseph A. , Strohm Eric M. , Chérin Emmanuel , Mirani Bahram , Démoré Christine , Kolios Michael C. , Simmons Craig A.
Published: August 2022

Acoustic properties of biomaterials and engineered tissues reflect their structure and cellularity. High-frequency ultrasound (US) can non-invasively characterize and monitor these properties with sub-millimetre resolution. We present an approach to estimate the acoustic properties of cell-laden hydrogels that accounts for frequency-dependent effects of attenuation in coupling media, hydrogel thickness, and interfacial transmission/reflection coefficients of US waves, all of which can bias attenuation estimates. Cell-seeded fibrin hydrogel disks were raster-scanned using a 40 MHz US transducer. Thickness, speed of sound, acoustic impedance, and acoustic attenuation coefficients were determined from the difference in the time-of-flight and ratios of the magnitudes of US signals, interfacial transmission/reflection coefficients, and acoustic properties of the coupling media. With this approach, hydrogel thickness was accurately measured by US, with excellent agreement to confocal microscopy (r2 = 0.97). Accurate thickness measurement enabled acoustic property measurements that were independent of hydrogel thickness, despite up to 60% reduction in thickness due to cell-mediated contraction. Notably, acoustic attenuation coefficients increased with increasing cell concentration (p<0.001), reflecting hydrogel cellularity independent of contracted hydrogel thickness. This approach enables accurate measurement of the intrinsic acoustic properties of biomaterials and engineered tissues to provide new insights into their structure and cellularity.
Bacterial phylogenetic markers in lake sediments as evidence for historical hemp retting
Authors: Rull Valentí , Sacristán-Soriano Oriol , Sànchez-Melsió Alexandre , Borrego Carles M. , Vegas-Vilarrúbia Teresa
Published: August 2022

Documenting prehistoric and historical hemp retting for fiber extraction is important in the study of human uses of this iconic plant and its cultural implications. In paleoecology, hemp retting is usually inferred from indirect proxies, notably anomalously high percentages of Cannabis pollen in lake sediments, but some recent studies have also used specific molecular biomarkers (cannabinol, Cannabis DNA) as a more straightforward evidence. Here we provide direct evidence of hemp retting by identifying phylogenetic signatures (16S rRNA genes) from pectinolytic bacteria actually responsible for the fermentation process that separates the fiber from the stalk, namely Bacillus, Clostridium, Escherichia, Massilia, Methylobacterium, Pseusomonas, Rhizobium and Rhodobacter. These analyses have been performed in the sediments from an Iberian lake previously considered as an important hemp retting site during the last five centuries, on the basis of Cannabis pollen abundances. The good match between biomarker and pollen evidence, in the context of the recent historical development of hemp industry in Spain, can be useful to interpret paleoecological records from other similar lakes in the way toward a more regional view on the introduction, spreading, uses and associated cultural connotations of Cannabis in the Iberian Peninsula within European and Mediterranean contexts.
Identification and functional prediction of sugar beet circRNAs involved in drought responses
Authors: Zou Chun-Lei , Guo Zhiqiang , Zhao Shanshan , Chen Jishuai , Zhang Chunlai
Published: August 2022

Drought is one of the most common abiotic constraints on the quality and productivity of crops on a global scale. Despite the rapidly updating information on circRNAs (circular RNAs), their roles in the anti-drought regulation of sugar beet are least understood. As a newly recognized class of non-coding RNAs, circRNAs exert crucial effects on miRNA (microRNA) functionality, as well as on transcriptional regulation. To clarify the mechanism of how circRNAs of sugar beet respond to drought stress, deep sequencing was employed to characterize these circRNAs in a genome-wide manner under drought treatment. Our results identify a total of 17 differentially expressed circRNAs. As revealed by the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology outcomes, circRNAs were found capable and involved in drought-responsive events. Utilizing the target genes exhibiting direct/indirect associations with drought resistance, we established a circRNA–miRNA–mRNA meshwork based on the circRNAs that were expressed differentially. The probable sponge functions of novel_circ_0000442 and novel_circ_0000443 were exerted by targeting ath-miR157d. This helped regulate the expression of relevant target genes, including BVRB_1 g004570, BVRB_1 g005450, and BVRB_1 g005790, that were involved in drought response. Apart from offering novel understandings of anti-drought mechanisms, our findings lay a basis for probing deeper into the intricate regulatory networks of sugar beet genes.
Optimal Cancer Evasion in a Dynamic Immune Microenvironment
Authors: George Jason T. , Levine Herbert
Published: August 2022

The failure of cancer treatments, including immunotherapy, continues to be a major obstacle in preventing durable remission. This failure often results from tumor evolution, both genotypic and phenotypic, away from sensitive cell states. Here, we propose a mathematical framework for studying the dynamics of adaptive immune evasion that tracks the number of tumor-associated antigens available for immune targeting. We solve for the unique optimal cancer evasion strategy using stochastic dynamic programming and demonstrate that this policy results in increased cancer evasion rates when compared to a passive, fixed strategy. Our foundational model relates the likelihood and temporal dynamics of cancer evasion to features of the immune microenvironment, where tumor immunogenicity reflects a balance between cancer adaptation and host recognition. In contrast with a passive strategy, optimally adaptive evaders navigating varying selective environments result in substantially heterogeneous post-escape tumor antigenicity, giving rise to immunogenically hot and cold tumors.
Characterization of network hierarchy reflects cell-state specificity in genome organization
Authors: Wang Jingyao , Xue Yue , He Yueying , Quan Hui , Zhang Jun , Gao Yi Qin
Published: August 2022

Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C datasets and derived the chromatin contact networks (CCNs). We discovered significant decreases in information transmission efficiencies in CCNs of colorectal cancer (CRC) and T-lineage acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Through network embedding in Poincaré disk, the hierarchy depths of CCNs from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of CCN change was observed for the transition from embryo to differentiated primary tissues. During early embryo developments of both human and mouse, the hierarchy of embedded chromatin structure gradually establishes. Additionally, we found tissue-specific conservation of hierarchy order in normal CCNs, which was disturbed in tumor. Our findings uncover the cell-state related hierarchical characteristics in chromatin structure, which reveal chromatin loci that play important roles in stabilizing the cellular conditions.
Gemini calling! First occurrence of successful twinning in wild, endangered lion-tailed macaques Macaca silenus in the Anamalai hills of the Western Ghats, India
Authors: Dhawale Ashni Kumar , Sinha Anindya
Published: August 2022

We recorded the first occurrence of surviving twins in lion-tailed macaques Macaca silenus from the Anamalai hills of the Western Ghats, India. The Puthuthottam population of liontailed macaques has historically been restricted to a rainforest fragment measuring 92ha, situated adjacent to human settlements, however, direct interactions between macaques and humans have been observed only in the last ten years. The population now visit settlements at a rate of 0.52/ day, and exploits anthropogenic foods. We recorded two sets of twins from the Puthuthottam population within a six-month period. Two previous cases of twins have been observed in this population since 2000, however, in both cases the twins did not survive beyond a few weeks. We followed and opportunistically collected ad libitum behavioural data on both sets of twins for a year between March 2019 to March 2020. Both mothers carrying the twins used the ground substrate extensively, however the mother with the younger set of twins also used the canopy and other precarious substrates such as cable wires. Our report shows that twinning occurs in lion-tailed macaques and twins are able to survive successfully. This report also supports previous evidence that twinning may occur in higher frequencies as a direct response to provisioning, with the mothers’ behaviour contributing to the successful survival of both twins.
The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern
Authors: Graham Carl , Lechmere Thomas , Rehman Aisha , Seow Jeffrey , Kurshan Ashwini , Huettner Isabella , Maguire Thomas J.A. , Tam Jerry , Cox Daniel , Ward Christopher , Racz Mariusz , Waters Anele , Mant Christine , Malim Michael H. , Fox Julie , Doores Katie J.
Published: August 2022

COVID-19 vaccines are playing a vital role in controlling the COVID-19 pandemic. As SARS-CoV-2 variants encoding mutations in the surface glycoprotein, Spike, continue to emerge, there is increased need to identify immunogens and vaccination regimens that provide the broadest and most durable immune responses. We compared the magnitude and breadth of the neutralizing antibody response, as well as levels of Spike-reactive memory B cells, in individuals receiving a second dose of BNT126b2 at a short (3-4 week) or extended interval (8-12 weeks) and following a third vaccination approximately 6-8 months later. We show that whilst an extended interval between the first two vaccinations can greatly increase the breadth of the immune response and generate a higher proportion of Spike reactive memory B cells, a third vaccination leads to similar levels between the two groups. Furthermore, we show that the third vaccine dose enhances neutralization activity against omicron lineage members BA.1, BA.2 and BA.4/BA.5 and this is further increased following breakthrough infection during the UK omicron wave. These findings are relevant for vaccination strategies in populations where COVID-19 vaccine coverage remains low.
Finding a Needle in a Haystack: Design and Implementation of a Digital Site-less Clinical Study of Serial Rapid Antigen Testing to Identify Asymptomatic SARS-CoV-2 Infection
Authors: Soni Apurv , Herbert Carly , Pretz Caitlin , Stamegna Pamela , Filippaios Andreas , Shi Qiming , Suvarna Thejas , Harman Emma , Schrader Summer , Nowak Chris , Schramm Eric , Kheterpal Vik , Behar Stephanie , Tarrant Seanan , Ferranto Julia , Hafer Nathaniel , Robinson Matthew , Achenbach Chad , Murphy Robert L. , Manabe Yukari C. , Gibson Laura , Barton Bruce , O’Connor Laurel , Fahey Nisha , Orvek Elizabeth , Lazar Peter , Ayturk Didem , Wong Steven , Zai Adrian , Cashman Lisa , Rao Lokinendi V , Luzuriaga Katherine , Lemon Stephenie , Blodgett Allison , Trippe Elizabeth , Barcus Mary , Goldberg Brittany , Roth Kristian , Stenzel Timothy , Heetderks William , Broach John , McManus David
Published: August 2022

Background

Rapid antigen tests (Ag-RDT) for SARS-CoV-2 with Emergency Use Authorization generally include a condition of authorization to evaluate the test’s performance in asymptomatic individuals when used serially.

Objective

To describe a novel study design to generate regulatory-quality data to evaluate serial use of Ag-RDT in detecting SARS-CoV-2 virus among asymptomatic individuals.

Design

Prospective cohort study using a decentralized approach. Participants were asked to test using Ag-RDT and molecular comparators every 48 hours for 15 days.

Setting

Participants throughout the mainland United States were enrolled through a digital platform between October 18, 2021 and February 15, 2022. Ag-RDTs were completed at home, and molecular comparators were shipped to a central laboratory.

Participants

Individuals over 2 years old from across the U.S. with no reported COVID-19 symptoms in the 14 days prior to study enrollment were eligible to enroll in this study.

Measurements

Enrollment demographics, geographic distribution, and SARS-CoV-2 infection rates are reported.

Key Results

A total of 7,361 participants enrolled in the study, and 492 participants tested positive for SARS-CoV-2, including 154 who were asymptomatic and tested negative to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 U.S. states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide.

Limitations

New, complex workflows required significant operational and data team support. Conclusions: The digital site-less approach employed in the ‘Test Us At Home’ study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19, and can be adapted across research disciplines to optimize study enrollment and accessibility.
Multi-ancestry meta-analysis and fine-mapping in Alzheimer’s Disease
Authors: Lake Julie , Solsberg Caroline Warly , Kim Jonggeol Jeffrey , Acosta-Uribe Juliana , Makarious Mary B. , Li Zizheng , Levine Kristin , Heutink Peter , Alvarado Chelsea , Vitale Dan , Kang Sarang , Gim Jungsoo , Lee Kun Ho , Pina-Escudero Stefanie D. , Ferrucci Luigi , Singleton Andrew B. , Blauwendraat Cornelis , Nalls Mike A. , Yokoyama Jennifer S. , Leonard Hampton L.
Published: August 2022

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published and de novo GWAS from European, East Asian, African American, and Caribbean Hispanic populations to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to Alzheimer’s disease risk.
Hypoxia Sensing in Resident Cardiac Macrophages Regulates the Arg1 Macrophage Lineage During Ischemic Heart Injury
Authors: Kadyrov Farid F. , Koenig Andrew L. , Amrute Junedh M. , Dun Hao , Li Wenjun , Weinheimer Carla J. , Nigro Jessica M. , Kovacs Attila , Bredemeyer Andrea L. , Lai Lulu , Kopecky Benjamin J. , Penna Vinay , Kreisel Daniel , Lavine Kory J.
Published: August 2022

Myocardial infarction initiates cardiac remodeling and is central to heart failure pathogenesis. Following myocardial ischemia reperfusion injury, monocytes enter the heart and differentiate into diverse subpopulations of macrophages. The mechanisms and dynamics of monocyte differentiation within this context are unknown. We investigated the role of macrophage hypoxia sensing on monocyte differentiation following reperfused myocardial infarction. We show that deletion ofHif1α, a hypoxia response transcription factor, in resident cardiac macrophages led to increased remodeling and overrepresentation of a macrophage subset marked by arginase 1 (Arg1) expression. Arg1+macrophages displayed an inflammatory gene signature and were predicted to represent an intermediate state within the monocyte differentiation cascade. Lineage tracing of Arg1+macrophages revealed the existence of a monocyte differentiation trajectory consisting of multiple transcriptionally distinct macrophage states. We further showed that deletion ofHif1αin resident cardiac macrophages resulted in arrested progression through this trajectory and accumulation of an inflammatory intermediate state marked by persistentArg1expression. Collectively, our findings unveil distinct trajectories of monocyte differentiation and identify hypoxia sensing as an important determinant of monocyte differentiation following myocardial infarction.
Proteostasis governs differential temperature sensitivity across embryonic cell types
Authors: Dorrity Michael W. , Saunders Lauren M. , Duran Madeleine , Srivatsan Sanjay R. , Ewing Brent , Queitsch Christine , Shendure Jay , Raible David W. , Kimelman David , Trapnell Cole
Published: August 2022

The genetic program of embryonic development is remarkably robust, but temperature stress can degrade its ability to generate animals with invariant anatomy. While the stereotyped, consistent phenotypes associated with environmental stress during vertebrate development suggest that some cell types are more sensitive to stress than others, the basis of this sensitivity is unknown. Here, we characterize hundreds of individual zebrafish embryos under temperature stress using whole-animal single cell RNA-seq to identify cell types and molecular programs within them that drive phenotypic variability. We find that temperature perturbs the normal proportions and gene expression programs of numerous cell types and also introduces asynchrony in their development. The notochord is particularly sensitive to temperature stress, which we show is due to a specialized cell type, sheath cells. Further analyses show that sheath cells accumulate misfolded protein at elevated temperature, leading to a cascading structural failure of the notochord and irreversible anatomic defects in the embryo. Our study demonstrates that whole-animal single cell RNA-seq can characterize mechanisms important for developmental robustness and pinpoint molecular programs within specific cell types that constitute key failure points.
The dietary fiber guar gum ameliorates experimental autoimmune encephalomyelitis via attenuated Th1 activation and differentiation
Authors: Fettig Naomi M , Robinson Hannah G , Allanach Jessica R , Davis Katherine M , Simister Rachel L , Wang Elsie J , Sharon Andrew J , Jiayu Ye , Popple Sarah J , Seo Jung Hee , Gibson Deanna L , Crowe Sean A , Horwitz Marc S , Osborne Lisa C
Published: August 2022

Dietary fibers are potent modulators of immune responses that can restrain inflammation in multiple disease contexts. However, dietary fibers encompass a biochemically diverse family of carbohydrates, and it remains unknown how different fiber sources influence immunity. In a head-to-head comparison of four different high-fiber diets, we demonstrate a unique and potent ability of guar gum to reduce neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a T cell-mediated mouse model of multiple sclerosis. CD4+ T cells from guar gum-fed mice have blunted Th1-skewing, reduced migratory capacity, and limited activation and proliferative capabilities. These changes are not explained by guar gum-specific alterations to the microbiota at the 16S rRNA level, nor by specific alterations in short chain fatty acids. These findings demonstrate specificity in the host response to fiber sources, and define a new pathway of fiber-induced CD4+ T cell immunomodulation that protects against pathologic neuroinflammation.
Dissecting the contributions of tumor heterogeneity on metastasis at single-cell resolution
Authors: Winkler Juliane , Tan Weilun , Diadhiou Catherine M. M. , McGinnis Christopher S. , Abbasi Aamna , Hasnain Saad , Durney Sophia , Atamaniuc Elena , Superville Daphne , Awni Leena , Lee Joyce V. , Hinrichs Johanna H. , Hein Marco Y. , Borja Michael , Detweiler Angela , Liu Su-Yang , Nanjaraj Ankitha , Sitarama Vaishnavi , Rugo Hope S. , Neff Norma , Gartner Zev J. , Pisco Angela Oliveira , Goga Andrei , Darmanis Spyros , Werb Zena
Published: August 2022

Metastasis is the leading cause of cancer-related deaths, but metastasis research is challenged by limited access to patient material and a lack of experimental models that appropriately recapitulate tumor heterogeneity. Here, we analyzed single-cell transcriptomes of matched primary tumor and metastasis from patient-derived xenograft models of breast cancer, demonstrating that primary tumor and metastatic cells show profound transcriptional differences across heterogeneous tumors. While primary tumor cells upregulated several metabolic genes, metastatic cells displayed a motility phenotype in micrometastatic lesions and increased stress response signaling during metastatic progression. Additionally, we identified gene signatures that are associated with the metastatic potential and correlated with patient outcomes. Poorly metastatic primary tumors showed increased immune-regulatory control that may prevent metastasis, whereas highly metastatic primary tumors upregulated markers of epithelial-mesenchymal transition (EMT). We found that intra-tumor heterogeneity is dominated by epithelial-mesenchymal plasticity (EMP) which presented as a dynamic continuum with intermediate cell states that were characterized by novel, specific markers. These intermediate EMP markers correlated with worse patient outcomes and could serve as potential new therapeutic targets to block metastatic development.
Motile Living Biobots Self-Construct from Adult Human Somatic Progenitor Seed Cells
Authors: Gumuskaya Gizem , Srivastava Pranjal , Cooper Ben G. , Lesser Hannah , Semegran Ben , Garnier Simon , Levin Michael
Published: August 2022

Fundamental knowledge gaps exist with respect to the plasticity of cells from adult soma and the potential diversity of body shape and behavior in living constructs derived from such genetically wild-type cells. Here we introduce Anthrobots, a spheroid-shaped multicellular biological robot (biobot) platform with diameters ranging from 30 to 500 microns. Anthrobots have an inherent capacity for motility in aqueous environments, via cilia covering their surface. Each Anthrobot starts out as a single cell, derived from the adult human lung, and self-constructs into a multicellular motile biobot after having been cultured in extra cellular matrix for 2 weeks and transferred into a minimally viscous habitat. Anthrobots exhibit a wide range of behaviors with motility patterns ranging from tight loops to straight lines and speeds ranging from 5-50 microns/second. Our anatomical investigations reveal that this behavioral diversity is significantly correlated with their morphological diversity. Anthrobots can assume diverse morphologies from fully polarized to wholly ciliated bodies with spherical or ellipsoidal shapes, each correlating with a distinct movement type. Remarkably, as a function of these different movement types, Anthrobots were found to be capable of traversing live human tissues in various ways. Furthermore, Anthrobots were able to induce rapid repair of wounds in human neural cell sheets in vitro. By controlling microenvironmental cues in bulk, entirely novel structure, behavior, and biomedically-relevant capabilities can be discovered in morphogenetic processes without direct genetic editing or manual sculpting.

Significance Statement

We demonstrate that normal, non-genetically-modified human tracheal cells can be induced to form a new proto-organism - Anthrobots - which exhibit spontaneous behavior, swimming around in one of several patterns, demonstrating plasticity for novel form and function inherent in even elderly human somatic cells. Moreover, Anthrobots are able to traverse over cultured neurons, settling down and causing repair under them: the nerves knit together across the wound gap due to the presence of the Anthrobot. A patient’s own cells can be harnessed to make a motile biological robot that can traverse human tissue and induce repair. In the future, this platform can deliver pro-regenerative therapeutics for a range of biomedical applications that will not trigger rejection or require immune suppression.
Predicting regional somatic mutation rates using DNA motifs
Authors: Liu Cong , Wang Zengmiao , Wang Jun , Liu Chengyu , Wang Mengchi , Ngo Vu , Wang Wei
Published: August 2022

How the locus-specificity of epigenetic modifications is regulated remains an unanswered question. A contributing mechanism is that epigenetic enzymes are recruited to specific loci by DNA binding factors recognizing particular sequence motifs (referred to as epi-motifs). Using these motifs to predict biological outputs depending on local epigenetic state such as somatic mutation rates would confirm their functionality. Here, we used DNA motifs including known TF motifs and epi-motifs as a surrogate of epigenetic signals to predict somatic mutation rates in 13 cancers at an average 23kbp resolution. We implemented an interpretable neural network model, called contextual regression, to successfully learn the universal relationship between mutations and DNA motifs, and uncovered motifs that are most impactful on the regional mutation rates such as TP53 and epi-motifs associated with H3K9me3. Furthermore, we identified genomic regions with significantly higher mutation rates than the expected values in each individual tumor and demonstrated that such cancer-specific regions can accurately predict cancer types. (The code is available from https://github.com/Wang-lab-UCSD/SomaticMutation)

Significance Statement

The relationship between DNA motifs and somatic mutation rates in cancers is not fully understood, especially at high resolution. Here we developed an interpretable neural network model to successfully predict somatic mutation rates using DNA motifs in 13 diverse cancers and identified the most informative motifs. Furthermore, we showed that the genomic regions with significant higher mutation rates than the predicted values can be used for cancer classification.
Effect of contact pressure on porcine postmortem brain tissue impedance
Authors: Poßner Lucas , Wilhelmy Florian , Pliquett Uwe , Knösche Thomas R. , Weise Konstantin , Lindner Dirk
Published: August 2022

In this experimental study we demonstrate the influence of contact pressure on porcine postmortem brain tissue impedance using a movable electrode array and a load cell. We show that the variation of the contact pressure between the tissue and the measurement probe leads to a coefficient of variation in the measured impedance of under 3%. Its influence can therefore be neglected. Further, we fit the measured impedances to an equivalent circuit model and compare the resistance as well as the cell density of grey and white matter brain tissue based on the model parameters.
Improved inter-protein contact prediction using dimensional hybrid residual networks and protein language models
Authors: Si Yunda , Yan Chengfei
Published: August 2022

The knowledge of contacting residue pairs between interacting proteins is very useful for structural characterization of protein-protein interactions (PPIs). However, accurately identifying the tens of contacting ones from hundreds of thousands of inter-protein residue pairs is extremely challenging, and performances of the state-of-the-art inter-protein contact prediction methods are still quite limited. In this study, we developed a deep learning method for inter-protein contact prediction, referred to as DRN-1D2D_Inter. Specifically, we employed pretrained protein language models to generate structural information enriched input features to residual networks formed by dimensional hybrid residual blocks to perform inter-protein contact prediction. Extensively benchmarked DRN-1D2D_Inter on multiple datasets including both heteromeric PPIs and homomeric PPIs, we show DRN-1D2D_Inter consistently and significantly outperformed two state-of-the-art inter-protein contact prediction methods including GLINTER and DeepHomo, although both the latter two methods leveraged native structures of interacting proteins in the prediction, and DRN-1D2D_Inter made the prediction purely from sequences.
Phase behaviour of C18-N-acyl sphingolipids, the prevalent species in human brain
Authors: González-Ramírez Emilio J. , Etxaniz Asier , Alonso Alicia , M. Goñi Félix
Published: August 2022

Lipidomic analysis of the N-acyl components of sphingolipids in different mammalian tissues had revealed that brain tissue differed from all the other samples in that SM contained mainly C18:0 and C24:1 N-acyl chains, and that the most abundant Cer species was C18:0. Only in the nervous system was C18:0 found in sizable proportions. The high levels of C18:0 and C16:0, respectively in brain and non-brain SM, were important because SM is by far the most abundant sphingolipid in the plasma membrane. In view of these observations, the present paper is devoted to a comparative study of the properties of C16:0 and C18:0 sphingolipids (SM and Cer) pure and in mixtures of increasing complexities, using differential scanning calorimetry, confocal microscopy of giant unilamellar vesicles, and correlative fluorescence microscopy and atomic force microscopy of supported lipid bilayers. Membrane rigidity was measured by force spectroscopy. It was found that in mixtures containing dioleoyl phosphatidylcholine, sphingomyelin and cholesterol, i.e. representing the lipids predominant in the outer monolayer of cell membranes, lateral inhomogeneities occurred, with the formation of rigid domains within a continuous fluid phase. Inclusion of saturated Cer in the system was always found to increase the rigidity of the segregated domains. C18:0-based sphingolipids exhibit hydrocarbon chain-length asymmetry, and some singularities observed with this N-acyl chain, e.g. complex calorimetric endotherms, could be attributed to this property. Moreover, C18:0-based sphingolipids, that are typical of the excitable cells, were less miscible with the fluid phase than their C16:0 counterparts. The results could be interpreted as suggesting that the predominance of C18:0 Cer in the nervous system would contribute to the tightness of its plasma membranes, thus facilitating maintenance of the ion gradients.
TXNIP loss expands Myc-dependent transcriptional programs by increasing Myc genomic binding
Authors: Lim Tian-Yeh , Wilde Blake R. , Thomas Mallory L. , Murphy Kristin E. , Vahrenkamp Jeffery M. , Conway Megan E. , Varley Katherine E. , Gertz Jason , Ayer Donald E.
Published: August 2022

c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To achieve this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters and represses the expression of Thioredoxin Interacting Protein (TXNIP), which is a potent negative regulator of glucose uptake. A Mychigh/TXNIPlow gene signature is clinically significant as it correlates with poor clinical prognosis in Triple-Negative Breast Cancer (TNBC) but not in other subtypes of breast cancer. To better understand how TXNIP function contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show here that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc’s intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the metabolic signals that control TXNIP expression.
ALOHA: AI-guided tool for the quantification of venom-induced haemorrhage in mice
Authors: Jenkins Timothy P. , Laprade William Michael , Sánchez Andrés , Tulika Tulika , O’Brien Carol , Sørensen Christoffer V. , Stewart Trenton K. , Fryer Thomas , Laustsen Andreas H. , Gutiérrez José María
Published: August 2022

Venom-induced haemorrhage constitutes a severe pathology in snakebite envenomings, especially those inflicted by viperid species. In order to both explore venom compositions accurately, and evaluate the efficacy of viperid antivenoms for the neutralisation of haemorrhagic activity it is essential to have available a precise, quantitative tool for empirically determining venom-induced haemorrhage. Thus, we have built on our prior approach and developed a new AI-guided tool (ALOHA) for the quantification of venom-induced haemorrhage in mice. Using a smartphone, it takes less than a minute to take a photo, upload the image, and receive accurate information on the magnitude of a venom-induced haemorrhagic lesion in mice. This substantially decreases analysis time, reduces human error, and does not require expert haemorrhage analysis skills. Furthermore, its open access web-based graphical user interface makes it easy to use and implement in laboratories across the globe. Together, this will reduce the resources required to preclinically assess and control the quality of antivenoms, whilst also expediting the profiling of hemorrhagic activity in venoms for the wider toxinology community.
Gene expression noise dynamics unveil functional heterogeneity of ageing hematopoietic stem cells
Authors: Rosales-Alvarez Reyna Edith , Rettkowski Jasmin , Herman Josip Stefan , Dumbović Gabrijela , Cabezas-Wallscheid Nina , Grün Dominic
Published: August 2022

Variability of gene expression due to stochasticity of transcription or variation of extrinsic signals, termed biological noise, is a potential driving force of cellular differentiation. While unicellular organisms exploit noise as a bet-hedging strategy, its role during multilineage differentiation of stem cells is underexplored. Utilizing single-cell RNA-sequencing to reconstruct cell state manifolds, we developed VarID2, a method for the quantification of biological noise at single-cell resolution. VarID2 reveals enhanced nuclear versus cytoplasmic noise across cell types of the peripheral blood, and distinct regulatory modes stratified by correlation between noise, expression, and chromatin accessibility. Noise levels are minimal in murine hematopoietic stem cells and increase during both differentiation and ageing. Differential noise identified myeloid-biased Dlk1+ long-term-HSCs in aged mice with enhanced quiescence and self-renewal capacity. VarID2 reveals fundamental properties of noise across cellular compartments, during stem cell differentiation and ageing, and uncovers distinct cellular sub-states invisible to conventional gene expression analysis.
Uni-Fold: An Open-Source Platform for Developing Protein Folding Models beyond AlphaFold
Authors: Li Ziyao , Liu Xuyang , Chen Weijie , Shen Fan , Bi Hangrui , Ke Guolin , Zhang Linfeng
Published: August 2022

Recent breakthroughs on protein structure prediction, namely AlphaFold, have led to unprecedented new possibilities in related areas. However, the lack of training utilities in its current open-source code hinders the community from further developing or adapting the model. Here we present Uni-Fold as a thoroughly open-source platform for developing protein folding models beyond AlphaFold. We reimplemented AlphaFold and AlphaFold-Multimer in the PyTorch framework, and reproduced their from-scratch training processes with equivalent or better accuracy. Based on various optimizations, Uni-Fold achieves about 2.2 times training acceleration compared with AlphaFold under similar hardware configuration. On a benchmark of recently released multimeric protein structures, Uni-Fold outperforms AlphaFold-Multimer by approximately 2% on the TM-Score. Uni-Fold is currently the only open-source repository that supports both training and inference of multimeric protein models. The source code, model parameters, test data, and web server of Uni-Fold are publicly available3.
A molecular atlas of the human postmenopausal fallopian tube and ovary from single-cell RNA and ATAC sequencing
Authors: Lengyel Ernst , Li Yan , Weigert Melanie , Zhu Lisha , Eckart Heather , Javellana Melissa , Ackroyd Sarah , Xiao Jason , Olalekan Susan , Glass Dianne , Iyer Shilpa , Bilecz Agnes Julia , Lastra Ricardo , Chen Mengjie , Basu Anindita
Published: August 2022

As part of the Human Cell Atlas initiative, we generated transcriptomic (scRNA-seq; 86,708 cells) and regulatory (scATAC-seq; 59,118 cells) profiles of the normal postmenopausal ovary and fallopian tube (FT) at single-cell resolution. In the FT, 22 cell clusters integrated into 11 cell types, including ciliated and secretory epithelial cells, while the ovary had 17 distinct cell clusters defining 6 major cell types. The dominant cell type in both the postmenopausal ovary and FT was stromal cells, which expressed several genes associated with aging. The fimbrial end of the FT had a significant number and variety of immune cells and active communication with the ovary; the ovary contained mostly stromal cells but few immune cells. The epithelial cells of the normal FT expressed multiple ovarian cancer risk-associated genes (CCDC170, RND3, TACC2, STK33, and ADGB). By integrating paired single-cell transcriptomics and chromatin accessibility data we found that the regulatory landscape of the fimbriae was markedly different from the isthmus and ampulla. Intriguingly, several cell types in the FT had comparable gene expression but different transcriptional regulations. Our single-cell transcriptional and regulatory maps allowed us to disentangle the complex cellular makeup of the postmenopausal FT and ovary and will contribute to a better understanding of gynecologic diseases in menopause.
Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease
Authors: Chu Yaping , Hirst Warren D. , Federoff Howard J. , Harms Ashley S. , Stoessl A. Jon , Kordower Jeffrey H.
Published: August 2022

While Parkinson’s disease (PD) remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that PD consists of multiple pathologies, but it is unclear which occurs first and which are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits (MMD). Motor deficits were determined on a modified and validated Unified Parkinson’s Disease Rating Scale III (UPDRS III), but they occur to a degree insufficient to diagnose PD. We consider this population to have prodromal PD. However, in past studies, cases in this cohort had a selection bias as both a clinical syndrome in between no motor deficits and PD, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in this study, we only based inclusion on a clinical phenotype intermediate between no motor impairment and PD. Then, we divided this group further based upon whether or not they had a synucleinopathy. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation, loss of TH-phenotype in the substantia nigra and putamen, and changes in axonal transport occur equally in groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8-expressing phospho-tau, a pathology not seen in the nigrostriatal system of aged-matched controls. These finding were confirmed with early (CP13) and late (PHF1) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and is likely tau mediated.
Differential processing of decision information in subregions of rodent medial prefrontal cortex
Authors: Diehl Geoffrey W , Redish A David
Published: August 2022

Decision-making involves multiple cognitive processes requiring different aspects of information about the situation at hand. The rodent medial prefrontal cortex (mPFC) has been hypothesized to be central to these abilities. Functional studies have sought to link specific processes to specific anatomical subregions, but past studies of mPFC have yielded controversial results, leaving the precise nature of mPFC function unclear. To settle this debate, we recorded from the full dorso-ventral extent of mPFC in each of 8 rats, as they performed a complex economic decision task. These data revealed four distinct functional domains within mPFC that closely mirrored anatomically-identified subregions, including novel evidence to divide prelimbic cortex into dorsal and ventral components. We found that dorsal aspects of mPFC (ACC, dPL) were more involved in processing information about active decisions, while ventral aspects (vPL, IL) were more engaged in motivational factors.

Impact Statement

Diehl and Redish describe how the rodent medial prefrontal cortex is composed of functionally distinct subregions that process economic decision information differentially along a dorso-ventral gradient.
Low-level tuning biases in higher visual cortex reflect the semantic informativeness of visual features
Authors: Henderson Margaret , Tarr Michael J. , Wehbe Leila
Published: August 2022

Representations of visual and semantic information can overlap in human visual cortex, with the same neural populations exhibiting sensitivity to low-level features (orientation, spatial frequency, retinotopic position), and high-level semantic categories (faces, scenes). It has been hypothesized that this relationship between low-level visual and high-level category neural selectivity reflects natural scene statistics, such that neurons in a given category-selective region are tuned for low-level features or spatial positions that are diagnostic of the region’s preferred category. To address the generality of this “natural scene statistics” hypothesis, as well as how well it can account for responses to complex naturalistic images across visual cortex, we performed two complementary analyses. First, across a large set of rich natural scene images, we demonstrated reliable associations between low-level (Gabor) features and high-level semantic dimensions (indoor-outdoor, animacy, real-world size), with these relationships varying spatially across the visual field. Second, we used a large-scale fMRI dataset (the Natural Scenes Dataset) and a voxelwise forward encoding model to estimate the feature and spatial selectivity of neural populations throughout visual cortex. We found that voxels in category-selective visual regions exhibit systematic biases in their feature and spatial selectivity which are consistent with their hypothesized roles in category processing. We further showed that these low-level tuning biases are largely independent of viewed image category. Together, our results are consistent with a framework in which low-level feature selectivity contributes to the computation of high-level semantic category information in the brain.
Novel transient cell clusters provide a possible link between early neural activity and angiogenesis in the neonatal mouse retina
Authors: de Montigny Jean , Thorne Courtney , Bhattacharya Diya , Sertedakis Dimitrios Bousoulas , Krishnamoorthy Vidhyasankar , Rozenblit Fernando , Gollisch Tim , Sernagor Evelyne
Published: August 2022

Developing neurons become spontaneously active while growing blood vessels begin to irrigate their surroundings. However, surprising little is known about early interactions between neural activity and angiogenesis. In the neonatal mouse retina, spontaneous waves of impulses sweep across the ganglion cell layer (GCL), just underneath the growing superficial vascular plexus. We discovered clusters of transient auto-fluorescent cells in the GCL, forming an annulus that co-localizes with the frontline of the growing plexus. Blood vessel density is highest within cluster areas, suggesting their involvement in angiogenesis. Once the clusters and blood vessels reach the retinal periphery by the end of the first postnatal week, the clusters disappear, eliminated by microglial phagocytosis. Electrical imaging suggests that they have their own electrophysiological signature. Blocking Pannexin1 (PANX1) hemi-channels with probenecid blocks the waves and the fluorescent clusters disappear following prolonged exposure to the drug. Spontaneous waves’ initiation points follow a developmental center-to-periphery progression similar to the cluster cells. We suggest that these transient cells are specialized, hyperactive neurons residing in the GCL. They generate spontaneous activity hotspots, thereby triggering waves through purinergic paracrine signaling via PANX1 hemi-channels. The strong activity generated around these hotspots triggers angiogenesis, attracting new blood vessels that provide local oxygen supply. Signaling through PANX-1 attracts microglia that establish contact with these cells, eventually leading to their elimination by phagocytosis. These cluster cells may provide the first evidence that specialized transient neuronal populations guide angiogenesis in the developing CNS through neural activity.