bluuebunny/crossref_metadata_2025 huggingface dataset:
Population coding strategies in human tactile afferents
Authors: Corniani Giulia , Casal Miguel A , Panzeri Stefano , Saal Hannes P
Published: May 2022

Sensory information is conveyed by populations of neurons, and coding strategies cannot always be deduced when considering individual neurons. Moreover, information coding depends on the number of neurons available and on the composition of the population when multiple classes with different response properties are available. Here, we study population coding in human tactile afferents by employing a recently developed simulator of mechanoreceptor firing activity. First, we demonstrate that the optimal afferent density for conveying maximal information depends on the tactile feature under consideration and the afferent class coding this feature. Second, we find that information is spread across different classes for all tactile features, such that combining information from multiple afferent classes improves information transmission, and is often more efficient than increasing the density of afferents from the same class. Finally, we test the importance of timing precision and afferent identity in the population code to probe whether temporal and spatial information can be traded against each other. Destroying temporal information turns out to be more destructive than removing spatial information, and the contribution of either cannot be completely recovered from the other. Overall, our results suggest that both optimal afferent innervation densities and the composition of the population depend in complex ways on the tactile features in question, potentially accounting for the variety in which tactile peripheral populations are assembled in different regions across the body.
SARS-CoV-2 Omicron subvariants evolved to promote further escape from MHC-I recognition
Authors: Moriyama Miyu , Lucas Carolina , Monteiro Valter Silva ,   Yale SARS-CoV-2 Genomic Surveillance Initiative, Iwasaki Akiko
Published: May 2022

SARS-CoV-2 variants of concern (VOCs) possess mutations that confer resistance to neutralizing antibodies within the Spike protein and are associated with breakthrough infection and reinfection. By contrast, less is known about the escape from CD8+T cell-mediated immunity by VOC. Here, we demonstrated that all SARS-CoV-2 VOCs possess the ability to suppress MHC I expression. We identified several viral genes that contribute to the suppression of MHC I expression. Notably, MHC-I upregulation was strongly inhibited after SARS-CoV-2 infectionin vivo. While earlier VOCs possess similar capacity as the ancestral strain to suppress MHC I, Omicron subvariants exhibit a greater ability to suppress surface MHC-I expressions. Collectively, our data suggest that, in addition to escape from neutralizing antibodies, the success of Omicron subvariants to cause breakthrough infection and reinfection may in part be due to its optimized evasion from T cell recognition.

Significance

Numerous pathogenic viruses have developed strategies to evade host CD8+T cell-mediated clearance. Here, we demonstrated that SARS-CoV-2 encodes multiple viral factors that can modulate MHC-I expression in the host cells. We found that MHC-I upregulation was strongly suppressed during SARS-CoV-2 infectionin vivo. Notably, the Omicron subvariants showed an enhanced ability to suppress MHC-I compared to the original strain and the earlier SARS-CoV-2 variants of concern (VOCs). Our results point to the inherently strong ability of SARS-CoV-2 to hinder MHC-I expression and demonstrated that Omicron subvariants have evolved an even more optimized capacity to evade CD8 T cell recognition.
A Proximity-Dependent Biosensor System for Visualizing Cell-Cell Interactions Induced by Therapeutic Antibodies
Authors: Tang Yu , Cao Yanguang
Published: May 2022

Background and Purpose

Despite the promising results of therapeutic antibodies in engaging the immune system to eliminate malignant cells, many aspects of the complex interplay between immune cells and cancer cells during antibody therapy remain incompletely understood. This study aimed to develop a biosensor system that can evaluate direct cell-cell contact and interactions between immune effector and target cells induced by therapeutic antibodies in physiologically relevant environments.

Experimental Approach

The system uses two structural complementary luciferase units (SmBit and LgBit) expressed on the respective membranes of immune effector and target cells. Upon cell-cell contact, the two subunits form active NanoLuc, generating a luminescent signal, allowing for real-time monitoring of cell-cell interactions and quantitatively assessing the pharmacological effects of therapeutic antibodies.

Key Results

We optimized the system to ensure selectivity by adjusting the spacer lengths between two luciferase units to minimize interference from nonspecific intercellular contact. The system was able to quantitatively and longitudinally monitor cell-cell interactions between NK and target cells induced by rituximab and between T and target cells induced by blinatumomab in a three-dimensional cell culture system. The observation that NK cells exhibited faster interactions with target cells compared to T cells is intriguing and suggests potential differences in the mechanisms or kinetics of cell-cell interactions between different types of effector cells and tumor cells.

Conclusions and Implications

The biosensor system has the potential for broad applications to optimize antibody pharmacology and efficacy in various therapeutic areas through a deeper understanding of antibody-mediated cell-cell interactions.

What is already known

Therapeutic antibodies can activate the immune system to elicit cytotoxicity through inducing cell-cell interactions between immune and tumor cells.

Approaches for longitudinally evaluating cell-cell interaction induced by therapeutic antibodies remain limited.

What does this study add

This study develops a biosensor system for detecting cell-cell interactions induced by therapeutic antibodies in a longitudinal manner.

The system is able to monitor cell-cell interactions between NK and target cells, as well as between T and target cells, in a three-dimensional cell culture system.

What is the clinical significance

The biosensor system has the potential for broad applications in the field of antibody pharmacology by providing a deeper understanding of antibody-mediated cell-cell interactions and their dynamics.
Polaramycin B, and not physical interaction, is the signal that rewires fungal metabolism in the Streptomyces – Aspergillus interaction
Authors: Berger Harald , Bacher Markus , Labuda Roman , Eppel Isabel Maria , Bayer Florentina , Sulyok Michael , Gasparotto Erika , Zehetbauer Franz , Doppler Maria , Gratzl Hannes , Strauss Joseph
Published: May 2022

Co-culturing the bacterium Streptomyces rapamycinicus and the ascomycete Aspergillus nidulans has previously been shown to trigger the production of orsellinic acid (ORS) and its derivates in the fungal cells. Based on these studies it was assumed that direct physical contact is a prerequisite for the metabolic reaction that involves a fungal amino acid starvation response and activating chromatin modifications at the biosynthetic gene cluster (BGC). Here we show that not physical contact, but a guanidine containing macrolide, named polaramycin B, triggers the response. The substance is produced constitutively by the bacterium and provokes the production of ORS above a certain concentration. In addition, several other secondary metabolites were induced by polaramycin B. Our genome-wide transcriptome analysis showed that polaramycin B treatment causes down-regulation of fungal genes necessary for membrane stability, general metabolism and growth. A compensatory genetic response can be observed in the fungus that included up-regulation of BGCs and genes necessary for ribosome biogenesis, translation and membrane stability. Our work discovered a novel chemical communication, in which the antifungal bacterial metabolite polaramycin B leads to the production of antibacterial defence chemicals and to the up-regulation of genes necessary to compensate for the cellular damage caused by polaramycin B.
Curation of BIDS (CuBIDS): a workflow and software package for streamlining reproducible curation of large BIDS datasets
Authors: Covitz Sydney , Tapera Tinashe M. , Adebimpe Azeez , Alexander-Bloch Aaron , Bertolero Maxwell A. , Feczko Eric , Franco Alexandre R. , Gur Raquel E. , Gur Ruben C. , Hendrickson Timothy , Houghton Audrey , Mehta Kahini , Murtha Kristin , Perrone Anders J. , Robert-Fitzgerald Tim , Schabdach Jenna M. , Shinohara Russell T , Vogel Jacob W. , Zhao Chenying , Fair Damien A. , Milham Michael P. , Cieslak Matthew , Satterthwaite Theodore D.
Published: May 2022

The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions that result in inconsistent processing across sessions. Additionally, in large-scale, heterogeneous neuroimaging datasets, hidden variability in metadata is difficult to detect and classify. To address these challenges, we created a Python-based software package titled “Curation of BIDS” (CuBIDS), which provides an intuitive workflow that helps users validate and manage the curation of their neuroimaging datasets. CuBIDS includes a robust implementation of BIDS validation that scales to large samples and incorporates DataLad––a version control software package for data––to ensure reproducibility and provenance tracking throughout the entire curation process. CuBIDS provides tools to help users perform quality control on their images’ metadata and identify unique combinations of imaging parameters. Users can then execute BIDS Apps on a subset of participants that represent the full range of acquisition parameters that are present, accelerating pipeline testing on large datasets.

HIGHLIGHTS

CuBIDS is a workflow and software package for curating BIDS data.

CuBIDS summarizes the heterogeneity in a BIDS dataset.

CuBIDS prepares BIDS data for successful preprocessing pipeline runs.

CuBIDS helps users perform metadata-based quality control.
Inhibiting 5-lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signaling and insulin-like growth factor-1
Authors: Kim Hyunjun , Kim Seon-Wook , Lee Sang-Hoon , Jung Da-Woon , Williams Darren R.
Published: May 2022

Background

Skeletal muscle atrophy can occur in response to numerous factors, such as aging and certain medications, and produces a major socioeconomic burden. At present, there are no approved drugs for treating skeletal muscle atrophy. Arachidonate 5-lipoxygenase (Aox5) is a drug target for a number of diseases. However, pharmacological targeting of Alox5, and its role in skeletal muscle atrophy, is unclear.

Methods

The potential effects of gene knockdown and pharmacological targeting of Alox5 on skeletal muscle atrophy was investigated using cell-based models, animal models, and human skeletal muscle tissue cultures. Malotilate, a clinically safe drug developed for enhancing liver regeneration and Alox5 inhibitor, was investigated as a repurposing candidate. Mechanism(s) of action in skeletal muscle atrophy were assessed by measuring the expression level or activation status of key regulatory pathways, and validated using gene knockdown and RNA sequencing.

Results

Myotubes treated with the atrophy-inducing glucocorticoid, dexamethasone, were protected from catabolic responses by treatment with malotilate (+41.29%, P < 0.01). Similar anti-atrophy effects were achieved by gene knockdown of Alox5 (+30.4%, P < 0.05). Malotilate produced anti-atrophy effects without affecting the myogenic differentiation program. In an in vivo model of skeletal muscle atrophy, malotilate treatment enhanced muscle performance (Grip strength: +35.72%, Latency to fall: +553.1%, P < 0.05), increased mass and fiber cross sectional area (Quadriceps: +23.72%, Soleus: +33.3%, P < 0.01), and down-regulated atrogene expression (Atrogin-1: -61.58%, Murf-1: -66.06%, P < 0.01). Similar, beneficial effects of malotilate treatment were observed in an aging muscle, which also showed the preservation of fast twitch fibers (Type 2a: +56.48%, Type 2b: +37.32%, P < 0.01). Leukotrine B4, a product of Alox5 activity with inflammatory and catabolic functions, was found to be elevated in skeletal muscle undergoing atrophy (Quadriceps: +224.4%, P < 0.001). Cellular transcriptome analysis showed that targeting Alox5 upregulated biological processes regulating organogenesis and increased the expression of insulin-like growth factor-1, a key anti-atrophy hormone (+226.5%, P < 0.05). Interestingly, these effects were restricted to the atrophy condition and not observed in normal skeletal muscle cultures with Alox5 inhibition. Human skeletal muscle tissue was also protected from atrophy by pharmacological targeting of Alox5 (+23.68%, P < 0.05).

Conclusion

These results shed new light on novel drug targets and mechanisms underpinning skeletal muscle atrophy. Alox5 is a regulator and drug target for muscle atrophy, and malotilate is an attractive compound for repurposing studies to treat this disease.
Nrf1 is an indispensable redox-determining factor for mitochondrial homeostasis by integrating multi-hierarchical regulatory networks
Authors: Hu Shaofan , Feng Jing , Wang Meng , Wufuer Reziyamu , Liu Keli , Zhang Zhengwen , Zhang Yiguo
Published: May 2022

To defend a vast variety of challenges in the oxygenated environments, all life forms have been evolutionally established a set of antioxidant, detoxification and cytoprotective systems during natural selection and adaptive survival, in order to maintain cell redox homeostasis and organ integrity in the healthy development and growth. Such antioxidant defense systems are predominantly regulated by two key transcription factors Nrf1 and Nrf2, but the underlying mechanism(s) for their coordinated redox control remains elusive. Here, we found that loss of full-length Nrf1 led to a dramatic increase in reactive oxygen species (ROS) and oxidative damages in Nrf1α-/- cells, and this increase was not eliminated by drastic elevation of Nrf2, even though the antioxidant systems were also substantially enhanced by hyperactive Nrf2. Further studies revealed that the increased ROS production in Nrf1α-/- resulted from a striking impairment in the mitochondrial oxidative respiratory chain and its gene expression regulated by nuclear respiratory factors, called αPalNRF1 and GABPNRF2. In addition to antioxidant capacity of cells, glycolysis was greatly augmented by aberrantly-elevated Nrf2, so to partially relieve the cellular energy demands, but aggravate its mitochondrial stress. The generation of ROS was also differentially regulated by Nrf1 and Nrf2 through miR-195 and/or mIR-497-mediated UCP2 pathway. Consequently, the epithelial-mesenchymal transformation (EMT) of Nrf1α-/- cells was activated by putative ROS-stimulated signaling via MAPK, HIF1α, NF-kB, PI3K and AKT, all players involved in cancer development and progression. Taken together, it is inferable that Nrf1 acts as a potent integrator of redox regulation by multi-hierarchical networks.
High-throughput single-cell sequencing for retroviral reservoir characterization
Authors: Droske Lauren E , Shank Stephen D. , Cash Melanie N , Pond Sergei L Kosakovsky , Salemi Marco , Magalis Brittany Rife
Published: May 2022

During the course of infection, human immunodeficiency virus (HIV) maintains a stably integrated reservoir of replication-competent proviruses within the host genome that are unaffected by antiretroviral therapy. Curative advancements rely heavily on targeting the reservoir, though determinants of its evolutionary origins remain ill-supported through current strategies and are often limited by sample variety. Here, we describe a single-cell deoxyribonucleic acid sequencing (scDNA-seq) method, optimized for sequencing of proviral and host DNA from a treatment-interrupted HIV animal model. We report its benefits for improving viral reservoir resolution to support critical evolutionary events otherwise considered unreliable using traditional viral envelope gene signal alone, as well as comparative advantages to existing near-full-length genome sequencing methods. Given the variety of proviral characteristics that may influence viral rebound, scDNA-seq holds immense value in its ability to streamline many of the present-day applications available in viral reservoir studies, such as integration status and putative replication competency.
Network Thermodynamics of Biological Systems: A Bond Graph Approach
Authors: Gawthrop Peter J. , Pan Michael
Published: May 2022

Edmund Crampin (1973-2021) was at the forefront of Systems Biology research and his work will influence the field for years to come. This paper brings together and summarises the seminal work of his group in applying energy-based bond graph methods to biological systems. In particular, this paper: (a) motivates the need to consider energy in modelling biology; (b) introduces bond graphs as a methodology for achieving this; (c) describes extensions to modelling electrochemical transduction; (d) outlines how bond graph models can be constructed in a modular manner and (e) describes stoichiometric approaches to deriving fundamental properties of reaction networks. These concepts are illustrated using a new bond graph model of photosynthesis in chloroplasts.
Introgression of the Triticum timopheevii genome into wheat detected by chromosome-specific KASP markers
Authors: King Julie , Grewal Surbhi , Othmeni Manel , Coombes Benedict , Yang Cai-yun , Walter Nicola , Ashling Stephen , Scholefield Duncan , Walker Jack , Hubbart-Edwards Stella , Hall Anthony , King Ian
Published: May 2022

Triticum timopheevii (2n=28, AtAtGG) is a tetraploid wild relative species with great potential to increase the genetic diversity of hexaploid wheat Triticum aestivum (2n=42, AABBDD) for various important agronomic traits. A breeding scheme that propagated advanced backcrossed populations of wheat-T. timopheevii introgression lines through further backcrossing and self-fertilisation resulted in the generation of 99 introgression lines (ILs) that carried 309 homozygous segments from the At and G subgenomes of T. timopheevii. These introgressions contained 89 and 74 unique segments from the At and G subgenomes, respectively. These overlapping segments covered 98.9% of the T. timopheevii genome that has now been introgressed into bread wheat cv. Paragon including the entirety of all T. timopheevii chromosomes via varying sized segments except for chromosomes 3At, 4G and 6G. Homozygous ILs contained between one and eight of these introgressions with an average of three per introgression line. These homozygous introgressions were detected through the development of a set of 480 chromosome-specific Kompetitive allele specific PCR (KASP) markers that are well-distributed across the wheat genome. Of these, 149 were developed in this study based on single nucleotide polymorphisms (SNPs) discovered through whole genome sequencing of T. timopheevii. A majority of these KASP markers were also found to be T. timopheevii subgenome specific with 182 detecting At subgenome and 275 detecting G subgenome segments. These markers showed that 98% of the At segments had recombined with the A genome of wheat and 74% of the G genome segments had recombined with the B genome of wheat with the rest recombining with the D genome of wheat. These results were validated through multi-colour in situ hybridisation analysis. Together these homozygous wheat-T. timopheevii ILs and chromosome-specific KASP markers provide an invaluable resource to wheat breeders for trait discovery to combat biotic and abiotic stress factors affecting wheat production due to climate change.
Lipid droplets are a metabolic vulnerability in melanoma
Authors: Lumaquin Dianne , Montal Emily , Baggiolini Arianna , Ma Yilun , LaPlante Charlotte , Huang Ting-Hsiang , Suresh Shruthy , Studer Lorenz , White Richard M.
Published: May 2022

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the pigmented cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved in human melanoma specimens. This state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt oxidative metabolism and slow melanoma growth in vivo. Because the pigmented cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
Neutrophil-Mediated Stromal-Tumor IL-6/STAT-3 Signaling Underlies the Association between Neutrophil-to-Lymphocyte Ratio Dynamics and Chemotherapy Response in Localized Pancreatic Cancer: A Hybrid Clinical-Preclinical Study
Authors: De Castro Silva Iago , Sharma Prateek , Bianchi Anna , Deshpande Nilesh U. , Mehra Siddharth , England Jonathan , Hosein Peter J. , Kwon Deukwoo , Merchant Nipun B. , Datta Jashodeep
Published: May 2022

Background

Partial/complete pathologic response following neoadjuvant chemotherapy (NAC) in pancreatic cancer (PDAC) patients undergoing pancreatectomy is associated with improved survival. We sought to determine whether neutrophil-to-lymphocyte ratio (NLR) dynamics predict pathologic response following chemotherapy in PDAC, and if manipulating NLR impacts chemosensitivity in preclinical models and uncovers potential mechanistic underpinnings underlying these effects.

Methods

Pathologic response in PDAC patients (n=94) undergoing NAC and pancreatectomy (7/2015-12/2019) was dichotomized as partial/complete or poor/absent (case-cohort design). Bootstrap-validated multivariable models assessed associations between pre-chemotherapy NLR (%neutrophils÷%lymphocytes) or NLR dynamics during chemotherapy (ΔNLR=pre-surgery—pre-chemotherapy NLR) and pathologic response, disease-free survival (DFS), and overall survival (OS). To preclinically model effects of NLR attenuation on chemosensitivity, C57BL/6 mice (n=8-10/arm) were orthotopically injected with KrasG12D/+;Trp53fl/+;PdxCre(KPC)cells and randomized to vehicle, NLR-attenuating anti-Ly6G, gemcitabine/paclitaxel, or gemcitabine/paclitaxel+anti-Ly6G treatments.

Results

In 94 PDAC patients undergoing NAC (median:4 months), pre-chemotherapy NLR (P<0.001) and ΔNLR attenuation during NAC (P=0.002) were independently associated with partial/complete pathologic response. An NLR score=pre-chemotherapy NLR+ΔNLR correlated with DFS (P=0.006) and OS (P=0.002). Upon preclinical modeling, combining NLR-attenuating anti-Ly6G treatment with gemcitabine/paclitaxel—compared with gemcitabine/paclitaxel or anti-Ly6G alone—not only significantly reduced tumor burden and metastatic outgrowth, but also augmented tumor-infiltrating CD107a+-degranulating CD8+ T-cells (P<0.01) while dampening inflammatory cancer-associated fibroblast (CAF) polarization (P=0.006) and chemoresistant IL-6/STAT-3 signaling in vivo. Neutrophil-derived IL-1β emerged as a novel mediator of stromal inflammation, inducing inflammatory CAF polarization and CAF-tumor cell IL-6/STAT-3 signaling in ex vivo co-cultures.

Conclusions

Therapeutic strategies to mitigate neutrophil-CAF-tumor cell IL-1β/IL-6/STAT-3 signaling during NAC may improve pathologic responses and/or survival in PDAC.
Structural basis for activation of Arf1 at the Golgi complex
Authors: Muccini Arnold J. , Gustafson Margaret A. , Fromme J. Christopher
Published: May 2022

The Golgi complex is the central sorting station of the eukaryotic secretory pathway. Traffic through the Golgi requires activation of Arf GTPases that orchestrate cargo sorting and vesicle formation by recruiting an array of effector proteins. Arf activation and Golgi membrane association is controlled by large guanine nucleotide exchange factors (GEFs) possessing multiple conserved regulatory domains. Here we present cryoEM structures of full-length Gea2, the yeast paralog of the human Arf-GEF GBF1, that reveal the organization of these regulatory domains and explain how Gea2 binds to the Golgi membrane surface. We find the GEF domain adopts two different conformations compatible with different stages of the Arf activation reaction. The structure of a Gea2-Arf1 activation intermediate suggests the movement of the GEF domain primes Arf1 for membrane insertion upon GTP binding. We propose that conformational switching of Gea2 during the nucleotide exchange reaction promotes membrane insertion of Arf1.
Airway Basal Cells Show Regionally Distinct Potential to Undergo Metaplastic Differentiation
Authors: Zhou Yizhuo , Yang Ying , Qian Jun , Ge Jian , Sinner Debora , Ding Hongxu , Califano Andrea , Cardoso Wellington V.
Published: May 2022

Basal cells are multipotent stem cells of a variety of organs, and in the lung are known as crucial components of the airway epithelium. However, it remains unclear how diverse basal cells are and whether distinct subpopulations respond differently to airway challenges. Using single cell RNA-sequencing and functional approaches, we report a significant and previously underappreciated degree of heterogeneity in the basal cell pool, leading to identification of six subpopulations in the murine trachea. Among these we found two major subpopulations comprising the most stem-like progenitor compartment, but with distinct signatures and ability to self-renew and differentiate. Notably, these occupy distinct ventral and dorsal tracheal niches and differ in their ability to initiate an aberrant program of differentiation in response to environmental perturbations in primary cultures and in injury mouse models in vivo. We found that such heterogeneity is acquired prenatally, when the basal cell pool and local niches are being established, and depends on the integrity of these niches, as supported by the altered basal cell phenotype of cartilage-deficient mouse mutants. Lastly, we show that key features that distinguish these progenitor subpopulations in murine airways are conserved in humans. Together, the data provide critical insights into the origin and impact of basal cell heterogeneity on the establishment of regionally distinct responses of the airway epithelium during injury-repair and in disease conditions.
Cirrhosis and Inflammation Regulates CYP3A4 Mediated Chemoresistance in Vascularized Hepatocellular Carcinoma-on-a-chip
Authors: Özkan Alican , Stolley Danielle L. , Cressman Erik N. K. , McMillin Matthew , Yankeelov Thomas E. , Rylander Marissa Nichole
Published: May 2022

Understanding the effects of inflammation and cirrhosis on the regulation of drug metabolism during the progression of hepatocellular carcinoma (HCC) is critical for developing patient-specific treatment strategies. In this work, we created novel three-dimensional vascularized HCC-on-a-chips (HCCoC), composed of HCC, endothelial, stellate, and Kupffer cells tuned to mimic normal or cirrhotic liver stiffness. HCC inflammation was controlled by tuning Kupffer macrophage numbers, and the impact of cytochrome P450-3A4 (CYP3A4) was investigated by culturing HepG2 HCC cells transfected with CYP3A4 to upregulate expression from baseline. This model allowed for the simulation of chemotherapeutic delivery methods such as intravenous injection and transcatheter arterial chemoembolization (TACE). We showed that upregulation of metabolic activity, incorporation of cirrhosis and inflammation, increase vascular permeability due to upregulated inflammatory cytokines leading to significant variability in chemotherapeutic treatment efficacy. Specifically, we show that further modulation of CYP3A4 activity of HCC cells by TACE delivery of doxorubicin provides an additional improvement to treatment response and reduces chemotherapy-associated endothelial porosity increase. The HCCoCs were shown to have utility in uncovering the impact of the tumor microenvironment (TME) during cancer progression on vascular properties, tumor response to therapeutics, and drug delivery strategies.

Statement of Significance

Regulation of drug metabolism during the cancer progression of hepatocellular carcinoma (HCC) can be influential to develop personalized treatment strategies. We created novel vascularized hepatocellular carcinoma-chip (HCCoC) composed of tunable collagen and four main liver-specific cell lines to be used as a preclinical tool. In this model, we found cancer evolution states such as inflammation and cirrhosis increases vascular permeability progressively as a result of increased inflammatory cytokines. Furthermore, delivery of doxorubicin only with embolization improved treatment efficacy by decreasing CYP3A4 activity, which can modulate treatment outcome. Overall, we found different disease states can be influential on CYP3A4, thus its targeting can improve HCC treatment outcome.
Biological age is increased by stress and restored upon recovery
Authors: Poganik Jesse R. , Zhang Bohan , Baht Gurpreet S. , Kerepesi Csaba , Yim Sun Hee , Lu Ake T. , Haghani Amin , Gong Tong , Hedman Anna M. , Andolf Ellika , Pershagen Göran , Almqvist Catarina , White James P. , Horvath Steve , Gladyshev Vadim N.
Published: May 2022

Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recentin vitrostudies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. By applying advanced epigenetic aging clocks, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment of animals. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. Elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
Thermal adaptation and fatty acid profiles of bone marrow and muscles in mammals: implications of a study of caribou (Rangifer tarandus caribou)
Authors: Morin Eugène , Soppela Päivi , Chouinard P. Yvan
Published: May 2022

Mammals have evolved several physiological mechanisms to cope with changes in ambient temperature. Particularly critical among them is the process of keeping cells in a fluid phase to prevent metabolic dysfunction. In this paper, we examine variation in the fatty acid composition of bone marrow and muscle tissues in the cold-adapted caribou (Rangifer tarandus caribou) to determine whether there are systematic differences in fatty acid profiles between anatomical regions that could potentially be explained by thermal adaptation. Our results indicate that the bone marrow and muscle tissues from the appendicular skeleton are more unsaturated than the same tissues in the axial skeleton, a finding that is consistent with physiological adaptation of the appendicular regions to thermal challenges. Because mechanisms of thermal adaptation appear to be widely shared among terrestrial mammals, we suggest that the same patterns may prevail in other species, possibly including humans.
Groundfish biodiversity change in northeastern Pacific waters under projected warming and deoxygenation
Authors: Thompson Patrick L. , Nephin Jessica , Davies Sarah C. , Park Ashley E. , Lyons Devin A. , Rooper Christopher N. , Peña M. Angelica , Christian James R. , Hunter Karen L. , Rubidge Emily , Holdsworth Amber M.
Published: May 2022

In the coming decades, warming and deoxygenation of marine waters are anticipated to result in shifts in the distribution and abundance of fishes, with consequences for the diversity and composition of fish communities. Here, we combine fisheries independent trawl survey data spanning the west coast of the USA and Canada with high resolution regional ocean models to make projections of how 34 groundfish species will be impacted by changes in temperature and oxygen in British Columbia (B.C.) and Washington. In this region, species that are projected to decrease in occurrence are roughly balanced by those that are projected to increase, resulting in considerable compositional turnover. Many, but not all, species are projected to shift to deeper depths as conditions warm, but low oxygen will limit how deep they can go. Thus, biodiversity will likely decrease in the shallowest waters (< 100 m) where warming will be greatest, increase at mid depths (100—600 m) as shallow species shift deeper, and decrease at depths where oxygen is limited (> 600 m). These results highlight the critical importance of accounting for the joint role of temperature, oxygen, and depth when projecting the impacts of climate change on marine biodiversity.
Net-shaped DNA nanostructure designed for rapid/sensitive detection and potential inhibition of SARS-CoV-2 virus
Authors: Chauhan Neha , Xiong Yanyu , Ren Shaokang , Dwivedy Abhisek , Magazine Nicholas , Zhou Lifeng , Lin Xiaohe , Zhang Tianyi , Cunningham Brian T. , Yao Sherwood , Huang Weishan , Wang Xing
Published: May 2022

We present a net-shaped DNA nanostructure (called “DNA Net” herein) design strategy for selective recognition and high-affinity capture of the intact SARS-CoV-2 virions through spatial pattern-matching and multivalent interactions between the aptamers (targeting wild type spike-RBD) positioned on the DNA Net and the trimeric spike glycoproteins displayed on the viral outer surface. Carrying a designer nanoswitch, the DNA Net-aptamers releases fluorescent signal upon virus binding that is easily read by a hand-held fluorimeter for a rapid (in 10 mins), simple (mix- and-read), sensitive (PCR equivalent), room temperature compatible, and inexpensive (∼ $1.26/test) COVID-19 test assay. The DNA Net-aptamers also impede authentic wild-type SARS-CoV-2 infection in cell culture with a near 1×103-fold enhancement of the monomeric aptamer. Furthermore, our DNA Net design principle and strategy can be customized to tackle other life-threatening and economically influential viruses like influenza and HIV, whose surfaces carry class-I viral envelope glycoproteins like the SARS-CoV-2 spikes in trimeric forms.
Modulation of huntingtin degradation by cAMP-dependent protein kinase A (PKA) phosphorylation of C-HEAT domain Ser2550
Authors: Lee Yejin , Kim Hyeongju , Barker Douglas , Vijayvargia Ravi , Atwal Ranjit Singh , Specht Harrison , Keshishian Hasmik , Carr Steven A , Lee Ramee , Kwak Seung , Hyun Kyung-gi , Loupe Jacob , MacDonald Marcy E. , Song Ji-Joon , Seong Ihn Sik
Published: May 2022

Huntington’s disease (HD) is a neurodegerative disorder caused by an inherited unstable HTT CAG repeat that expands further, thereby eliciting a disease process that may be initiated by polyglutamine-expanded huntingtin or a short polyglutamine-product. Phosphorylation of selected candidate residues is reported to mediate polyglutamine-fragment degradation and toxicity. Here to support the discovery of phospho-sites involved in the life-cycle of (full-length) huntingtin, we employed mass spectrometry-based phosphoproteomics to systematically identify sites in purified huntingtin and in the endogenous protein, by proteomic and phospho-proteomic analyses of members of an HD neuronal progenitor cell panel. Our results bring total huntingtin phospho-sites to 95, with more located in the N-HEAT domain relative to numbers in the Bridge and C-HEAT domains. Moreover, phosphorylation of C-HEAT Ser2550 by cAMP-dependent protein kinase (PKA), the top hit in kinase activity screens, was found to hasten huntingtin degradation, such that levels of the catalytic subunit (PRKACA) were inversely related to huntingtin levels. Taken together these findings highlight categories of phospho-sites that merit further study and provide a phospho-site kinase pair (pSer2550-PKA) with which to investigate the biological processes that regulate huntingtin degradation and thereby influence the steady state levels of huntingtin in HD cells.
A comprehensive analysis of Usutu virus (USUV) genomes revealed lineage-specific codon usage patterns and host adaptation
Authors: Zhou Jianglin , Xing Yaling , Zhou Zhe , Wang Shengqi
Published: May 2022

The Usutu virus (USUV) is an emerging arbovirus virus maintained in the environment of Afro-Eurasia via a bird-mosquito-bird enzootic cycle and sporadically infected other vertebrates. Despite primarily asymptomatic or mild symptoms, humans infected by USUV can develop severe neurological diseases such as meningoencephalitis. However, no detailed study has yet been conducted to investigate its evolution from the perspective of codon usage patterns. Codon usage choice of viruses reflects the genetic variations that enable them to reconcile their viability and fitness towards the external environment and new hosts. This study performed a comprehensive evolution and codon usage analysis in USUVs. Our reconstructed phylogenetic tree confirmed the circulation viruses belonging to eight distinct lineages, reaffirmed by principal component analysis based on codon usage patterns. We also found a relatively small codon usage bias and that natural selection, mutation pressure, and evolutionary processes collectively shaped the codon usage of the USUV, with natural selection predominating over the others. Additionally, a complex interaction of codon usage between the USUV and its host was observed. This process could have enabled USUVs to adapt to various hosts and vectors, including humans. Therefore, the USUV may possess a potential risk of cross-species transmission and subsequent outbreaks. In this respect, further epidemiologic surveys, diversity monitoring, and pathogenetic research are warranted.
Controls of SAR11 subclade abundance, diversity, and growth in two Mid-Atlantic estuaries
Authors: Campbell Barbara J. , Lim Shen Jean , Kirchman David L.
Published: May 2022

SAR11 is a dominant bacterial clade in marine oligotrophic ecosystems. SAR11 can also be dominant in estuarine systems, where they are not well-studied. We examined the effects of season, nutrient concentrations, and salinity in shaping SAR11 subclade abundance, diversity, function, and growth in two Mid-Atlantic estuaries, the Delaware and Chesapeake Bays. Using metagenome-assembled genomes, we identified twelve distinct genomospecies within the Ia, II, IIIa, and V subclades, which made up to 60% of the total bacterial community. The functional potential of all SAR11 genomospecies varied, especially in carbohydrate metabolism, transporters, and one-carbon metabolic pathways. Predicted growth rates, estimated by the Peak to Trough method, varied by season and genomospecies. SAR11 growth rates negatively correlated in the spring but positively correlated in the summer with chlorophyll a concentrations and bacterial production, as well as phosphate and ammonium concentrations. Genomospecies in Ia.1, IIIa.2, and IIIa.4 subclades had low growth rates, while genomospecies in Ia.3, Ia.5, Ia.6, II, and V subclades had higher and more variable growth rates that were positively correlated with phosphate concentrations and temperature. Growth rate variation between subclades was associated with carbohydrate metabolic gene repertoires, especially glycolysis and number of transporters. While total transcript to genome ratios generally mirrored growth rates, transcription of genes involved in phosphate and nitrogen transport were negatively associated with growth rates. These data suggest that SAR11 genomospecies abundance varies in these estuaries because of differences in growth rates and metabolic capacities in response to changes in environmental conditions.

Importance

The SAR11 clade is one of the most abundant bacterial groups in marine systems, including many estuaries. From the Delaware Bay and Chesapeake Bay environmental metagenomes, we reconstructed nearly complete SAR11 metagenome-assembled genomes representing ten genomospecies in four subclades, of which at least one is novel. Growth rate estimates of genomospecies correlated with functional gene repertoires of carbohydrate transporter and metabolism. Different SAR11 genomospecies dominated among the seasons, depending on their growth rates, biological productivity, and nutrient concentrations. Our RNAseq approach facilitated an understanding of the environmental controls on the abundance of SAR11 genomospecies in their natural habitat. This study is the first to combine multiple measures of diversity, abundance, functional potential, growth rates and activity of this important group, demonstrating a direct link between SAR11 genomospecies abundance and growth in the context of its environment.
An attempt to find the correlations between body weight and the composition of gut microbiota in Zhejiang and Shanghai
Authors: Xia Yihan , Jin Ziying
Published: May 2022

Previous studies showed that the human gut microbiota was associated with metabolic diseases, but the interaction and mechanism between the gut microbiota and metabolic disease are still unclear. In this study, the gut microbiota of 58 persons living in Zhejiang and Shanghai area will be analyzed. Then, the potential contribution of the human gut microbiota to obesity/high Body Mass Index (BMI) will be explored. The gut microbiota was studied by high throughput sequencing analysis of bacterial 16S rRNA gene fragments, and the gut microbiota samples with different BMI were compared. Meanwhile, some gut microorganisms from faeces of a healthy individual were cultivated and isolated, and the classification was identified by 16S rRNA sequencing. The main microbes in human gut microbiota were assigned to the phyla of Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Moreover, four strains were isolated from an individual fecal sample, of which one species was assigned to Escherichia fergusonii and the other three strains were assigned to Weissella cibaria. These four species belong to both abundant and low-abundant species revealed by high throughput sequencing. It was found that individuals with different BMI have different gut microbiota; while the differences are not significant. Also, the Firmicutes/Bacteroidetes ratio increases with the decrease of BMI, which is corresponding to previous results. In the future, more cohort gut microbiota in Zhejiang and Shanghai area will be collected and recovered, and the gut microbiota database of Zhejiang and Shanghai area will be built up in order to provide the basis for future gut microbiota modulation in this area.
Molecular basis of C9orf72 poly-PR interference with the β-karyopherin family of nuclear transport receptors
Authors: Jafarinia Hamidreza , Van der Giessen Erik , Onck Patrick R.
Published: May 2022

Nucleocytoplasmic transport (NCT) is affected in several neurodegenerative diseases including C9orf72-ALS. It has recently been found that arginine-containing dipeptide repeat proteins (R-DPRs), translated from C9orf72 repeat expansions, directly bind to several importins. To gain insight into how this can affect nucleocytoplasmic transport, we use coarse-grained molecular dynamics simulations to study the molecular interaction of poly-PR, the most toxic DPR, with several Kapβs (importins and exportins). We show that poly-PR–Kapβ binding depends on the net charge per residue (NCPR) of the Kapβ, salt concentration of the solvent, and poly-PR length. Poly-PR makes contact with the inner surface of most importins, which strongly interferes with Kapβ binding to cargo-NLS, IBB, and RanGTP in a poly-PR length-dependent manner. Longer poly-PRs at higher concentrations are also able to make contact with the outer surface of importins that contain several binding sites to FG-Nups. We also show that poly-PR binds to exportins, especially at lower salt concentrations, interacting with several RanGTP and FG-Nup binding sites. Overall, our results suggest that poly-PR might cause length-dependent defects in cargo loading, cargo release, Kapβ transport and Ran gradient across the nuclear envelope.
Availability of abundant thiamine determines efficiency of thermogenic activation in human neck area derived adipocytes
Authors: Arianti Rini , Vinnai Boglárka Ágnes , Győry Ferenc , Guba Andrea , Csősz Éva , Kristóf Endre , Fésüs László
Published: May 2022

Brown/beige adipocytes express uncoupling protein-1 (UCP1) that enables them to dissipate energy as heat. Systematic activation of this process can alleviate obesity. Human brown adipose tissues are interspersed in distinct anatomical regions including deep neck. We found that UCP1 enriched adipocytes differentiated from precursors of this depot highly expressed ThTr2 transporter of thiamine and consumed thiamine during thermogenic activation of these adipocytes by cAMP which mimics adrenergic stimulation. Inhibition of ThTr2 led to lower thiamine consumption with decreased proton leak respiration reflecting reduced uncoupling. In the absence of thiamine, cAMP-induced uncoupling was diminished but restored by thiamine addition reaching the highest levels at thiamine concentrations larger than present in human blood plasma. Thiamine is converted to thiamine pyrophosphate (TPP) in cells; the addition of TPP to permeabilized adipocytes increased uncoupling fueled by TPP-dependent pyruvate dehydrogenase. ThTr2 inhibition also hampered cAMP-dependent induction of UCP1, PGC1a, and other browning marker genes, and thermogenic induction of these genes was potentiated by thiamine in a concentration dependent manner. Our study reveals the importance of amply supplied thiamine during thermogenic activation in human adipocytes which provides TPP for TPP-dependent enzymes not fully saturated with this cofactor and by potentiating the induction of thermogenic genes.

Abstract Figure

Highlights

Abundant thiamine is required for efficient activation of UCP1 dependent thermogenesis in human deep neck derived adipocytes

Inhibition of thiamine transporters leads to decreased thermogenic response

In stimulated adipocytes, thiamine supply provides extra thiamine pyrophosphate for increasing pyruvate dehydrogenase activity to generate sufficient fuel of UCP1 dependent respiration

Adrenergic stimulation of thermogenic gene expression is potentiated by thiamine in a concentration dependent manner
The mechanism underlying redundant functions of the YTHDF proteins
Authors: Zou Zhongyu , Sepich-Poore Caraline , Zhou Xiaoming , Wei Jiangbo , He Chuan
Published: May 2022

The YTH N6-methyladenosine RNA binding proteins (YTHDFs) mediate the functional effects of N6-methyladenosine (m6A) on RNA. Recently, a report proposed that all YTHDFs work redundantly to facilitate RNA decay, raising questions about the exact functions of individual YTHDFs, especially YTHDF1 and YTHDF2. We show that YTHDF1 and YTHDF2 differ in their low-complexity domains (LCDs) and exhibit different behaviors in condensate formation and subsequent physiological functions. Biologically, we also find that the global stabilization of RNA after depletion of all YTHDFs is driven by increased P-body formation and is not strictly m6A dependent.