bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma
Authors: Flesken-Nikitin Andrea , Ralston Coulter Q. , Fu Dah-Jiun , De Micheli Andrea J. , Phuong Daryl J. , Harlan Blaine A. , Armstrong Amanda P. , McKellar David , Ghuwalewala Sangeeta , Schimenti John C. , Cosgrove Benjamin D. , Nikitin Alexander Yu. 
Published: December 2023

AbstractThe distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell markerSlc1a3can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation ofTrp53andRb1, whose pathways are commonly altered in HGSC, leads to elimination of targetedSlc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+,Prom1+,Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a previously unrecognized cancer-prone cell state and point to pre-ciliation mechanisms as novel diagnostic and therapeutic targets.
Sex differences in responses to aggressive encounters among California mice
Authors: Kuske Jace X. , Godoy Alexandra Serna , Ramirez Alison V. , Trainor Brian C. 
Published: December 2023

AbstractDespite how widespread female aggression is across the animal kingdom, there remains much unknown about its neuroendocrine mechanisms, especially in females that engage in aggression outside the peripartum period. Although the impact of experience in aggressive encounters on steroid hormone responses have been described, little is known about the impact of these experiences on female behavior or their neuropeptide responses. In this study, we compared behavioral responses in both male and female adult California mice based on if they had 0, 1, or 3 aggressive encounters using a modified resident intruder paradigm. We measured how arginine vasopressin and oxytocin cells in the paraventricular nucleus responded to aggression using c-fos immunohistochemistry. We saw that both sexes disengaged with intruders with repeated aggressive encounters, but that on the final day of testing females were most likely to freeze when they encountered intruders compared to no aggression controls – which was not significant in males. Finally, we saw that percent of arginine vasopressin and c-fos co-localizations in the posterior region of the paraventricular nucleus increased in males who fought compared to no aggression controls. No difference was observed in females. Overall, there is evidence that engaging in aggression induces stress responses in both sexes, and that females may be more sensitive to the effects of fighting.
Variant Graph Craft (VGC): A Comprehensive Tool for Analyzing Genetic Variation and Identifying Disease-Causing Variants
Authors: Li Jennifer , Yang Andy , Carneiro Benedito A , Uzun Ece Gamsiz , Massingham Lauren , Uzun Alper 
Published: December 2023

AbstractThe Variant Call Format (VCF) file is providing a structured and comprehensive text file that contains essential information about variant positions in the genome, as well as other critical details, such as alleles, genotype calls, and quality scores. Due to its rich data and format, the VCF file has become an increasingly popular resource for researchers and clinicians alike, enabling them to interpret and understand genomic variation data. However, analyzing and visualizing these files poses significant challenges, demanding access to diverse resources and a robust set of features for in-depth exploration. We introduce Variant Graph Craft (VGC), a VCF file visualization and analysis tool offering a wide range of features for exploring genetic variations, including extraction of variant data, intuitive visualization of variants, and the provision of a graphical representation of samples, complete with genotype information. Furthermore, VGC seamlessly integrates with external resources to offer valuable insights into gene function and variant frequencies in sample data. VGC offers gene function and pathway information from Molecular Signatures Database (MSigDB) for GO terms, as well as KEGG, Biocarta, Pathway Interaction Database, and Reactome. Additionally, the tool also provides a dynamic link to gnomAD for variant information, and includes ClinVar data for pathogenic variant information. VGC operates locally, assuring users of data security and privacy by eliminating the need for cloud-based VCF uploads. It supports the Human Genome Assembly Hg37, ensuring compatibility with a wide range of data sets. With its versatility, VGC accommodates various approaches exploring genetic variation data, and can be tailored to the specific needs of the user by using optional phenotype input data. In conclusion, VGC is a useful resource for exploring genetic variation in a secure and user-friendly environment. With its user-tailored set of features, this tool enables researchers and clinicians to easily explore and understand genomic variation data in a comprehensive and accessible manner. From identifying specific genetic mutations to analyzing patterns of variation across the genome, the VCF file visualization and analysis tool is an essential tool for those working in the field of genomics. VGC is freely available athttps://sites.brown.edu/gmilab/variantgraphcraft/
Angiotensin II type 1 receptor activation facilitates pain hypersensitivity via dorsal horn pericyte mediated vasoconstriction
Authors: Hardowar Lydia D. , Sheavyn Matt , McTernan Philip G. , Bates Dave O. , Hulse Richard P. 
Published: December 2023

AbstractVascular disturbance is a key factor in the development of neurological disease, with reduced integrity of the capillary network in the dorsal horn implicated in activation of nociceptive neural circuits and induction of pain hypersensitivity. Pericytes regulate capillary health and tone, with pericyte dysfunction in cerebral tissue associated with neurodegenerative disorders. Our work demonstrates that nociceptive processing is influenced by angiotensin II type 1 (AT1) receptor mediated pericyte contractility in the dorsal horn. Intravital imaging of the mouse spinal cord demonstrated angiotensin II induced cessation of spinal cord capillary perfusion. Intrathecal administration of angiotensin II induced pericyte contractility and narrowing of capillary diameter, which was accompanied by mechanical allodynia and heat hyperalgesia. Angiotensin II mediated pericyte activation and reduction of spinal cord blood flow, was prevented by inhibition of AT1 receptor via losartan treatment. In addition, losartan either systemically or intrathecally administered, prevented angiotensin II induced pain in male and female adult mice. This was associated with protection of the dorsal horn capillary endothelium, with intrathecal co-treatment with losartan preventing loss of CD31 immunoreactivity in the dorsal horn following administration of angiotensin II. This investigation demonstrates that AT1 mediated pericyte regulation of the dorsal horn capillary network, is fundamental in modulating nociceptive processing and perception of pain. Here we identify a novel cellular and mechanistic target for the development of new analgesic.
Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change
Authors: Dehkordi Siavash Raeisi , Wong Ivy Tsz-Lo , Ni Jing , Luebeck Jens , Zhu Kaiyuan , Prasad Gino , Krockenberger Lena , Xu Guanghui , Chowdhury Biswanath , Rajkumar Utkrisht , Caplin Ann , Muliaditan Daniel , Coruh Ceyda , Jin Qiushi , Turner Kristen , Teo Shu Xian , Pang Andy Wing Chun , Alexandrov Ludmil B. , Chua Christelle En Lin , Furnari Frank B. , Paulson Thomas G. , Law Julie A. , Chang Howard Y. , Yue Feng , DasGupta Ramanuj , Zhao Jean , Mischel Paul S. , Bafna Vineet 
Published: December 2023

SUMMARYOncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.
Tandem MutSβ binding to long extruded DNA trinucleotide repeats underpins pathogenic expansions
Authors: Li Jun , Wang Huaibin , Yang Wei 
Published: December 2023

SummaryExpansion of trinucleotide repeats causes Huntington’s disease, Fragile X syndrome and over twenty other monogenic disorders1. How mismatch repair protein MutSβ and large repeats of CNG (N=A, T, C or G) cooperate to drive the expansion is poorly understood. Contrary to expectations, we find that MutSβ prefers to bind the stem of an extruded (CNG) hairpin rather than the hairpin end or hairpin-duplex junction. Structural analyses reveal that in the presence of MutSβ, CNG repeats with N:N mismatches adopt a B form-like pseudo-duplex, with one or two CNG repeats slipped out forming uneven bubbles that partly mimic insertion-deletion loops of mismatched DNA2. When the extruded hairpin exceeds 40-45 repeats, it can be bound by three or more MutSβ molecules, which are resistant to ATP-dependent dissociation. We envision that such MutSβ-CNG complexes recruit MutLγ endonuclease to nick DNA and initiate the repeat expansion process3,4. To develop drugs against the expansion diseases, we have identified lead compounds that prevent MutSβ binding to CNG repeats but not to mismatched DNA.
MBD2 couples DNA methylation to Transposable Elements silencing during male gametogenesis
Authors: Wang Shuya , Wang Ming , Ichino Lucia , Boone Brandon A. , Zhong Zhenhui , Papareddy Ranjith K. , Lin Evan K. , Yun Jaewon , Feng Suhua , Jacobsen Steven E. 
Published: December 2023

AbstractDNA methylation is an essential component of transposable element (TE) silencing, yet the mechanism by which methylation causes transcriptional repression remains poorly understood1–5. Here we study theArabidopsis thalianaMethyl-CpG Binding Domain (MBD) proteins MBD1, MBD2, and MBD4, and show that MBD2 acts as a transposable element (TE) repressor during male gametogenesis. MBD2 bound chromatin regions containing high levels of CG methylation, and MBD2 was capable of silencing theFWAgene when tethered to its promoter. MBD2 loss caused TE activation in the vegetative cell (VC) of mature pollen without affecting DNA methylation levels, demonstrating that MBD2-mediated silencing acts strictly downstream of DNA methylation. Loss of silencing inmbd2became more significant in thembd5 mbd6oradcp1mutant backgrounds, as well as in plants with chemically induced genome-wide DNA demethylation, suggesting that MBD2 acts redundantly with other silencing pathways to safeguard TEs from activation. Overall, our study identifies MBD2 as a novel methyl reader that acts downstream of DNA methylation to silence TEs during male gametogenesis.
Characterization of carotenoid-producingMuricaudasp. strains isolated from the reef-building coralGalaxea fascicularisand subtropical seawater
Authors: Endo Funa , Motone Keisuke , Kai Kenji , Kitakaze Tomoya , Nishikawa Yumi , Nishimura Yuna , Kitamura Ruriko , Takagi Toshiyuki , Ito Michihiro , Miura Natsuko , Kataoka Michihiko 
Published: December 2023

ABSTRACTBacterial symbionts in corals and coral-associated zooxanthellae are attracting increasing attention as potential probiotics. Some members of the family Flavobacteriaceae are zooxanthellae-associated bacteria, which are known to protect zooxanthellae from stresses such as heat and light by producing carotenoids that reduce reactive oxygen species production. This study characterized two Flavobacteriaceae bacteria,Muricaudasp. strains ORYM1 (NBRC115792) and ORYM2 (NBRC115793), isolated from the reef-building coralGalaxea fascicularisand its surrounding seawater in Okinawa, Japan, respectively. TheMuricaudasp. strain ORYM2 was isolated from subtropical seawater, and carotenoid production was assessed using ORYM2 as well as ORYM1, which was previously isolated fromG. fascicularis. De novogenome sequencing revealed that both strains contain complete sets of zeaxanthin biosynthesis genes, similar to those found in otherMuricaudaspp. Thin-layer chromatography and high-performance liquid chromatography analyses demonstrated that ORYM1 and ORYM2 produce several carotenoids. The bacterial strains and carotenoids identified in this study provide insights into the biological roles of zooxanthellae-associated bacteria in protecting zooxanthellae and reef-building corals from environmental stresses.Statements and declarationsCompeting interests: The authors declare no competing interests.
The Role of Anthropogenic Roosting Ecology in Shaping Viral Outcomes in Bats
Authors: Betke Briana A , Gottdenker Nicole , Meyers Lauren Ancel , Becker Daniel J 
Published: December 2023

AbstractThe ability of some wildlife to live in anthropogenic structures in response to rapid land-use change is widely observed across mammals. However, the influence of this adaptation in shaping viral hosting ability and diversity are not well understood, especially for the order Chiroptera. Anthropogenic roosting may have important consequences for predicting virus spillover and spillback risk, particularly as the propensity of bats to roost in anthropogenic structures (e.g., buildings, bridges, homes, and tunnels, etc.) directly relates to human exposure. Here, we integrate novel roosting ecology data with a machine learning approach to assess the importance of anthropogenic roosting in predicting viral outcomes and evaluate if this novel trait improves prediction of undetected but likely host species. Our results show that the importance of anthropogenic roosting varies moderately across viral outcomes. Anthropogenic roosting is most important for predicting virus hosting ability across bats, followed by zoonotic hosting ability, viral richness, and the proportion of viruses that are zoonotic. Anthropogenic roosting status is less important than human population density but more important than most family, diet, and foraging traits of bat species, and models with anthropogenic roosting predict a narrowed list of undetected virus hosts compared to models excluding this trait. We identified 35 bat species likely to host a virus, 18 of which roost in anthropogenic structures. Additionally, we identified 51 undetected zoonotic host species, 30 of which are anthropogenic roosting. Maps of predicted virus host distributions show distinct spatial patterns between anthropogenic and exclusively natural-roosting bats. These findings suggest that anthropogenic roosting has a non-trivial role in shaping viral outcomes in bats, specifically virus hosting ability.
Does novelty influence foraging decision of a scavenger?
Authors: Bhattacharjee Debottam , Sau Shubhra , Das Jayjit , Bhadra Anindita 
Published: December 2023

AbstractAcquiring knowledge about the environment is crucial for survival. Animals, often driven by their explorative tendencies, gather valuable information regarding food resources, shelter, mating partners, etc. While neophilia, or the preference for novel environmental stimuli or objects, can promote exploratory behaviour, neophobia, or avoidance of novel environmental stimuli, can constrain such behaviour. Neophobia can reduce predation risk, yet decreased exploratory behaviour resulting from it may limit the ability to discover potentially highly rewarding resources. Dogs (Canis familiaris) living in semi-urban and urban environments as free-ranging populations are, although subject to various selection forces, typically have negligible predation pressure. These dogs are scavengers in human-dominated environments; thus, selection against object-neophobia can provide benefits when searching for novel food resources. Although pet and captive pack-living dogs are known to exhibit neophilia when provided with novel objects, little is known about free-ranging dogs’ behavioural responses to novel objects, particularly in foraging contexts. Using an object choice experiment, we tested 274 free-ranging dogs from two age classes, adult and juvenile, to investigate their object-neophobia in a scavenging context. We employed a betweensubject study design, providing dogs with a familiar and a potentially novel object, both baited with equal but (partially)hidden food rewards. Adult and juvenile dogs significantly inspected the novel object first compared to the familiar one, even when we reduced the visual obscurity of the familiar object, i.e., when the hidden food reward was partially visible. Furthermore, novel objects with varying strengths of olfactory cues (baited vs. false-baited) were inspected comparably by adults and juveniles. No significant differences were found in the latencies to inspect the objects. These results indicate that free-ranging dogs, evidently from an early ontogenic phase, do not show object-neophobia, as demonstrated by their preference for novel over familiar food sources. We conclude that little to no constraint of neophobia on exploratory behaviour, yet selection for object-neophilia in semi-urban and urban-dwelling animals can guide foraging decision-making processes, providing adaptive benefits.
Aerosolized ⍺1adrenoreceptor antagonism does not affect experimentally induced lung fibrosis in animal models
Authors: Ghincea Alexander , Perry Carrighan , Liu Angela , McGovern John , Yu Sheeline , Peng Xue-Yan , Ishikawa Genta , Barnthaler Thomas , Herzog Erica L. , Sun Huanxing 
Published: December 2023

AbstractPulmonary Fibrosis is a progressive and incurable condition that complicates many disease states. Adrenergic hyperinnervation and accumulation of fibroblasts expressing ⍺1- adrenoreceptors have been implicated in this process. Previous studies have demonstrated that systemic treatment with an ⍺1-adrenoreceptors antagonist attenuates fibrotic endpoints in lung fibrosis models. In an attempt to develop a lung targeted therapy, we determined whether ⍺1- adrenoreceptors antagonism delivered via inhaled administration of terazosin exerts antifibrotic benefits in experimentally induced lung fibrosis. C57/BL6 mice treated with bleomycin, or a doxycycline inducible line of transgenic mice with lung specific overexpression of the bioactive form of the human TGFβ1 (TGFβ1-Tg+model), received nebulized terazosin at varying doses on a therapeutic schedule following the induction of fibrosis and were sacrificed at 21 days. Airway inflammation, fibrotic endpoints, and lung function were evaluated. ⍺1-adrenoreceptors antagonism delivered via this method did not impact airway inflammation as indicated by bronchoalveolar lavage cell counts, and there was no significant difference observed in soluble collagen content. There was similarly no significant difference in respiratory mechanics with terazosin administration. These data show that inhaled delivery of the ⍺1-adrenoreceptors antagonist terazosin by this method is ineffective at treating fibrosis in these models and suggest that alternative dosing schedules or delivery methods may be more fruitful avenues of investigation. Further exploration of these findings may provide new therapeutic options and illuminate mechanisms through which adrenergic innervation and ⍺1-adrenoreceptors mediate fibrosis in the adult mammalian lung.
Transgenic mice overexpressing Pitx2 in the atria develop tachycardia-bradycardia syndrome
Authors: Baba Shunsuke , Shinjo Satoko , Seya Daiki , Bochimoto Hiroki , Akaike Toru , Nakano Atsushi , Minamisawa Susumu 
Published: December 2023

AbstractSinoatrial node (SAN) dysfunction often accompanies supraventricular tachyarrhythmias such as atrial fibrillation (AF), which is referred to as tachycardia-bradycardia syndrome (TBS). Although there have been many studies on electrical remodeling in TBS, the regulatory mechanisms that cause electrical remodeling in the SAN and atrial muscles by chronic bradycardia or tachycardia have not yet been fully investigated. Here we hypothesized that Pitx2c, a transcription factor that plays a central role in the late aspects of left-right asymmetric morphogenesis, regulates an interrelationship between the SAN and the atrial muscles and is involved in TBS-like pathology. To test this hypothesis, we generated transgenic mice overexpressingPitx2cspecifically in the atria (OE mice). Although Pitx2c is normally expressed only in left atria, the expression levels of Pitx2c protein in the right atria were significantly increased to similar levels of those in the left atria of non-transgenic control mice (WT). We found that the heart rate of OE mice was significantly variable although the average heart rate was similar between WT and OE mice. Electrophysiological examination showed that OE mice exhibited prolonged SAN recovery time and higher AF inducibility. In addition, recording of the atrial monophasic action potential duration using a Langendorff perfusion system demonstrated shorter action potential duration in OE atria. Histological analysis revealed that SAN-specific ion channel HCN4-positive cells were hardly detected in the SAN of OE mice, along with ectopic expression in the right atria. Furthermore, transcription factors associated with sinus node formation were down-regulated in the right atria of OE mice. Therefore, SAN dysfunction by Pitx2 dysregulation predisposed OE mice to a TBS-like phenotype. We conclude that Pitx2c is a key regulator that defines SAN function in the atria.