bluuebunny/crossref_metadata_2025_split huggingface dataset:
SASH1 interacts with TNKS2 and promotes human melanocyte stem cell maintenance
Authors: Lambert Karoline A. , Clements Christopher M. , Mukherjee Nabanita , Pacheco Theresa R. , Shellman Samantha X. , Henen Morkos A. , Vögeli Beat , Goldstein Nathaniel B. , Birlea Stanca , Hintzsche Jennifer , Tan Aik-Choon , Zhao Rui , Norris David A. , Robinson William A. , Wang Yizhou , VanTreeck Jillian G , Shellman Yiqun G. 
Published: September 2023

ABSTRACTBoth aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1S519Nvariant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1S519Nwas defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1’s promotion of stem-like function. Further, the SASH1S519Nvariant is in abona fideTankyrase-binding motif, and SASH1S519Nalters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.
Pan tissue analysis of humanNUMBalternative splicing
Authors: Zhang Yangjing , McGlade C. Jane 
Published: September 2023

AbstractAlternative splicing (AS) of pre-mRNA generates multiple protein isoforms from a single gene. It is developmentally regulated and mis-regulation is associated with many diseases. Previous studies that examined AS of the cell fate determinantNUMBdemonstrated that it undergoes a regulated switch in the inclusion of protein coding exons 3 and 9 during rodent development and the differentiation of human cell lines. Here we extend this work by comparing exon 9 and exon 3 inclusion levels of the humanNUMBgene across different normal human tissues by analysis of RNA sequencing data deposited in the Genotype-Tissue Expression (GTEx) and the Vertebrate Alternative Splicing and Transcription (VastDB) databases. Our results support earlier studies and reveal specific Numb isoform expression patterns in previously unexamined tissue and cell types, suggesting that Numb isoform expression is regulated in the normal development of a broad range of tissue types throughout the body.
Novel Epidermal Oxysterols Function as Alarm Substances in Zebrafish
Authors: Li Yaxi , Yan Zhi , Lin Ainuo , Yang Xiao , Li Xiaodong , Yin Xiuli , Li Weiming , Li Ke 
Published: September 2023

AbstractAquatic animals often use chemical cues to signal predation risk. When injured, shoaling fish skins release alarm substances that induce intense fear and a suite of anti-predator behaviors in other shoal members. However, the chemical nature of alarm substances remains largely unknown. Here we show that zebrafish alarm substance comprises 24-methyl-5α-cholestane-3α,7α,12α,24,28-pentahydroxy 28-sulfate, a novel oxysterol sulfate, and 5α-cyprinol sulfate. These compounds are present in zebrafish skin extract and, at concentrations of less than one nanomolar, each induces anti-predator behaviors and increases cortisol levels. Their mixture, at its natural ratio, replicates the skin extract in eliciting the full suite of anti-predator behavior patterns. Our findings reveal a molecular-level mechanism whereby fish signal predation danger.
Substrate promiscuity of xenobiotic-transforming hydrolases from stream biofilms impacted by treated wastewater
Authors: Yu Yaochun , Trottmann Niklas Ferenc , Schärer Milo R. , Fenner Kathrin , Robinson Serina L. 
Published: September 2023

AbstractOrganic contaminants enter aquatic ecosystems from various sources, including wastewater treatment plant effluent. Freshwater biofilms play a major role in the removal of organic contaminants from receiving water bodies, but knowledge of the molecular mechanisms driving contaminant biotransformations in complex stream biofilm (periphyton) communities remains limited. Previously, we demonstrated that biofilms in experimental flume systems grown at higher ratios of treated wastewater (WW) to stream water displayed an increased biotransformation potential for a number of organic contaminants. We identified a positive correlation between WW percentage and biofilm biotransformation rates for the widely-used insect repellent,N,N-diethyl-meta-toluamide (DEET). Here, we conducted deep shotgun sequencing of flume biofilms and identified a positive correlation between WW percentage and metagenomic read abundances of DEET hydrolase (DH) homologs. To test the causality of this association, we constructed a targeted metagenomic library of DH homologs from flume biofilms. We screened our complete metagenomic library for activity with four different substrates and a subset thereof with 183 WW-related organic compounds. The majority of active hydrolases in our library preferred aliphatic and aromatic ester substrates while, remarkably, only a single reference enzyme was capable of DEET hydrolysis. Of the 626 total enzyme-substrate combinations tested, approximately 5% were active enzyme-substrate pairs. Metagenomic DH family homologs revealed a broad substrate promiscuity spanning 22 different compounds when summed across all enzymes tested. We biochemically characterized the most promiscuous and active enzymes identified based on metagenomic analysis from uncultivatedRhodospirillaceaeandPlanctomycetaceae. In addition to characterizing new DH family enzymes, we exemplified a framework for linking metagenome-guided hypothesis generation with experimental validation. Overall, this study expands the scope of known enzymatic contaminant biotransformations for metagenomic hydrolases from WW-receiving stream biofilm communities.Graphical abstractHighlightsMetagenomic DEET hydrolase abundances higher in biofilms grown in treated wastewater.Eleven out of 64 metagenomic hydrolases tested exhibited hydrolysis activity.Related enzymes in a single family of DEET hydrolases biotransform 20+ contaminants.Reference DEET hydrolase shows a substrate preference for benzamide moieties.‘True’ DEET hydrolases are in low abundance even in biofilms that degrade DEET.
HybriSeq: Probe-based Device-free Single-cell RNA Profiling
Authors: Foyt Daniel , Brown David , Zhou Shuqin , Huang Bo 
Published: September 2023

AbstractWe have developed the HybriSeq method for single-cell RNA profiling, which utilizes in situ hybridization of multiple probes for targeted transcripts, followed by split-pool barcoding and sequencing analysis of the probes. We have shown that HybriSeq can achieve high sensitivity for RNA detection with multiple probes and profile differential splicing. The utility of HybriSeq is demonstrated in characterizing cell-to-cell heterogeneities of a panel of 95 cell-cycle-related genes and the detection of misannotated transcripts.
Coevolution of larval signalling and worker response can trigger developmental caste determination in social insects
Authors: Lagos-Oviedo Juan J. , Pen Ido , Kreider Jan J. 
Published: September 2023

AbstractEusocial insects belong to distinct queen and worker castes, which, in turn, can be divided into several morphologically specialised castes of workers. Caste determination typically occurs by differential nutrition of developing larvae. We present a model for the coevolution of larval signalling and worker task allocation – both modelled by flexible smooth reaction norms – to investigate the evolution of caste determination mechanisms and worker polymorphism. In our model, larvae evolve to signal their nutritional state to workers. The workers evolve to allocate time to foraging for resources versus feeding the brood, conditional on the larval signals and their body size. Worker polymorphism evolves under accelerating foraging returns of increasing body size, which causes selection to favour large foraging and small nursing workers. Worker castes emerge because larvae evolve to amplify their signals after obtaining some food, which causes them to receive more food, while the other larvae remain unfed. This leads to symmetry-breaking among the larvae who either are well-nourished or malnourished; thus, emerging as small or large workers. Our model demonstrates the evolution of nutrition-dependent caste determination and worker polymorphism by a self-reinforcement mechanism that evolves from the interplay of larval signalling and worker response to the signals.
Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration
Authors: Liu Jian , Copland David A. , Clare Alison J. , Gorski Mathias , Richards Burt T. , Scott Louis , Theodoropoulou Sofia , Greferath Ursula , Cox Katherine , Bell Oliver H. , Ou Kepeng , Le Brun Powell Jenna , Wu Jiahui , Robles Luis Martinez , Li Yingxin , Nicholson Lindsay B. , Coffey Peter J. , Fletcher Erica L. , Guymer Robyn , Radeke Monte J. , Heid Iris M. , Hageman Gregory S. , Chan Ying Kai , Dick Andrew D. 
Published: September 2023

AbstractUnchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration.One Sentence SummaryIRAK-M is a protective molecule and promising therapeutic target for macular degeneration
Phylogenomics reveals an island as a genetic reservoir of a continental population
Authors: Aoki Daisuke , Senzaki Masayuki , Ando Haruko , Odaya Yoshiya , Heim Wieland , Kitazawa Munehiro , Tom Wulf , Trense Daronja , Bastardot Mark , Fukuda Atsunori , Takahashi Masao , Kondo Natsuko 
Published: September 2023

AbstractIslands as biodiversity sinks due to their small population size and low genetic variation are recently challenged by a phenomenon where a continental lineage originates from islands. This raises an important question about through what demographic processes insular genetic variation is introduced to the continent and its evolutionary consequences on the continent. We address this question by focusing on an Asian rail species, the Swinhoe’s RailCoturnicops exquisitus, where frequent trans-oceanic dispersal in a continent-island system is expected. We reconstructed a spatiotemporally explicit demographic history of this species in the continent-island system, using integrative phylogenomics. Multiple lines of evidence supported asymmetric gene flow from an island population to the continental population that once diverged around the Middle Pleistocene. This has possibly impacted the continental genetic variation because ancient genetic variation may have been preserved in the large island population. Re-establishment of the island by the continental population was also detected, suggesting that the insular genetic variation has been maintained also by receiving a part of continental genetic variation. These results indicated that the maintenance of insular genetic variation through dynamic continent-island metapopulation may have allowed the island to act as a genetic reservoir for continental genetic variation.Teaser textWhat process allows island populations that are small and at the “evolutionary dead-end” to become the source of continental colonization? Using a cutting-edge integrative phylogenomics approach, we disentangled the demographic history of the little-studied Swinhoe’s Rail in East Asia, where it has survived by maintaining a dynamic metapopulation across a continent-island system. Particularly, gene flow from the island impacted the contemporary genetic variation of the continental population, possibly facilitating its demographic expansion. We suggested that maintenance of metapopulation and asymmetric gene flow from islands are key for islands to introduce their genetic variation to the continent.
Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractility-driven strain that inhibits fibril degradation
Authors: Saini K. , Cho S. , Tewari M. , Jalil AA.R. , Wang M. , Kasznel A.J. , Yamamoto K. , Chenoweth D.M. , Discher D.E. 
Published: September 2023

AbstractPolymer network properties such as stiffness often exhibit characteristic power laws in polymer density and other parameters. However, it remains unclear whether diverse animal tissues, composed of many distinct polymers, exhibit such scaling. Here, we examined many diverse tissues from adult mouse and embryonic chick to determine if stiffness (Etissue) follows a power law in relation to the most abundant animal protein, Collagen-I, even with molecular perturbations. We quantified fibrillar collagen in intact tissue by second harmonic generation (SHG) imaging and from tissue extracts by mass spectrometry (MS), and collagenase-mediated decreases were also tracked. Pan-tissue power laws for tissue stiffness versus Collagen-I levels measured by SHG or MS exhibit sub-linear scaling that aligns with results from cellularized gels of Collagen-I but not acellular gels. Inhibition of cellular myosin-II based contraction fits the scaling, and combination with inhibitors of matrix metalloproteinases (MMPs) show collagenase activity is strain - not stress- suppressed in tissues, consistent with past studies of gels and fibrils. Beating embryonic hearts and tendons, which differ in both collagen levels and stiffness by >1000-fold, similarly suppressed collagenases at physiological strains of ∼5%, with fiber-orientation regulating degradation. Scaling ofEtissuebased on ‘use-it-or-lose-it’ kinetics provides insight into scaling of organ size, microgravity effects, and regeneration processes while suggesting contractility-driven therapeutics.
Clonal fitness decline in somatic differentiation hierarchies
Authors: Ahmed Iftikhar , Dingli David , Huang Weini , Werner Benjamin 
Published: September 2023

AbstractThe concept of clonal fitness is fundamental to describe the evolutionary dynamics in somatic tissues. It is now well established that otherwise healthy somatic tissues become increasingly populated by expanding clones with age. However, the dynamic properties and respective fitnesses of these clones are less well understood. Here we show, that in somatic tissues organised as a differentiation hierarchy, theory predicts a natural decline of effective clonal fitness over time in the absence of additional driver events. This decline is intrinsic to the tissue organisation and can be captured quantitatively by a simple heuristic equation that is proportional to 1/time. We also show that the expected fitness decline is directly observable in human haematopoiesis. The predicted short and long term dynamics agree within vivoobservations using data of Neutrophil recovery after bone marrow transplants and naturally progressing Chronic Lymphocyte Leukemia (CLL). We further show that theory predicts the existence of a long term equilibrium fitness. All CLL patients transition into a stable equilibrium fitness eventually. We find significant inter-patient variation of long term fitness and a strong correlation with disease aggressiveness. Interestingly, CLL long term fitness can be forecast based on the early stages of disease progression, suggesting a Big Bang like model for CLL evolution.
Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory
Authors: Alvero Ayesha B. , Fox Alexandra , Madina Bhaskara , Krady Marie , Gogoi Radhika , Chehade Hussein , Nakaar Valerian , Almassian Bijan , Yarovinsky Timur , Rutherford Thomas , Mor Gil 
Published: September 2023

AbstractCurrent immunotherapies have proven effective in strengthening anti-tumor immune responses but constant opposing signals from tumor cells and surrounding microenvironment eventually lead to immune escape. We hypothesize that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system will provide a robust and long-term anti-tumor effect by creating immunological memory against the tumor. To achieve this, we developed CARG-2020, a virus-like-vesicle (VLV). It is a genetically modified and self-amplifying RNA with oncolytic capacity and encodes immune regulatory genes. CARG-2020 carries three transgenes: 1) the pleiotropic antitumor cytokine IL-12 in which the subunits (p35 and p40) are tethered together; 2) the extracellular domain (ECD) of the pro-tumor IL-17RA, which can serve as a dominant negative antagonist; and 3) shRNA for PD-L1. Using a mouse model of ovarian cancer, we demonstrate the oncolytic effect and immune modulatory capacities of CARG-2020. By enhancing IL-12 and blocking IL-17 and PD-L1, CARG-2020 successfully reactivates immune surveillance by promoting M1 instead of M2 macrophage differentiation, inhibiting MDSC expansion, and establishing a potent CD8+ T cell mediated anti-tumoral response. Furthermore, we demonstrate that this therapeutic approach provides tumor-specific and long-term protection preventing the establishment of new tumors. Our results provide rationale for the further development of this platform as a therapeutic modality for ovarian cancer patients to enhance the anti-tumor response and to prevent recurrence.
Individual variation in male pheromone production inXylocopa sonorinacorrelates with size and gland color
Authors: Goffinet Andrew J. , Darragh Kathy , Saleh Nicholas , Ostwald Madeleine M. , Buchmann Stephen L. , Ramirez Santiago R. 
Published: September 2023

AbstractSex pheromones are species-specific chemical signals that facilitate the location, identification, and selection of mating partners. These pheromones can vary between individuals, and act as signals of mate quality. Here, we investigate the variation of male pheromones in the mesosomal glands of the large carpenter beeXylocopa sonorina, within a Northern California population. We tested the hypothesis that morphological traits are correlated with the observed variation in chemical blend composition of these bees. We also conducted behavioral assays to test whether these male pheromones act as long-range attractants to conspecifics. We found that larger males with darker mesosomal glands have a higher pheromone amount in their glands. Our analysis also shows initial evidence that this pheromone blend serves as a long-range attractant to both males and females. We show that both male body size and sexual maturation are important factors influencing pheromone abundance, and that this pheromone blend acts as a long-range attractant. We hypothesize that this recorded variation in male pheromone could be important for female choice.
Predictive Deep Learning Model for Neural Vessel Occlusion
Authors: Karlsberg Aaron , Kim Sandy , Zaghari Nima , Li Lu 
Published: September 2023

AbstractRecent advances in medical applications for clot removal have enabled physicians to unblock blood vessel occlusions that occur in extremely narrow regions of the brain along the Horizontal (M1) segment of the middle cerebral artery. FDA approved, clinical trials have proven the significant cerebral recovery that can be achieved for victims of ischemic stroke when they undergo swift surgical intervention for clot removal. That said, carrying out such a delicate operation simultaneously requires extreme surgical expertise, and the ability to quickly identify the site of occlusion from 2D x-ray images of the brain. Fortunately, recent efforts in object detection and classification within the fields of deep learning and computer vision have dramatically improved the predictive power of the computer. Accordingly, the goal of this research project is to develop a deep learning model capable of accurately predicting the site of occlusion from frontal view cerebral angiograms in real time. Our current model utilizes YOLOv3 architecture and identifies the site of occlusion in 94.4% of all cases given a minimum 25% confidence threshold. Furthermore, in 83.97% of cases, the occlusion region is detected with at least 50% average intersection over union between the predicted region and the ground truth region. Finally, distributed over the entire validation set, the average intersection over union between the predicted region and the ground truth region was 74.29%.
mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated non-degradative ubiquitination of eIF4A1
Authors: Jiao Dongyue , Sun Huiru , Zhao Xiaying , Chen Yingji , Lv Zeheng , Shi Qing , Li Yao , Wang Chenji , Gao Kun 
Published: September 2023

AbstractEnhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by CRL3IBTKcomplex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and tumor cell growth bothin vivoandin vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTKcomplex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.Statement of Significance:Overexpression of IBTK contributes to the process of tumorigenesis by amplifying translation, and represents a promising target for anti-cancer therapies.