bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus
Authors: Li Thomas M. , Zyulina Victoria , Seltzer Ethan S. , Dacic Marija , Chinenov Yurii , Daamen Andrea R. , Veiga Keila R. , Schwartz Noa , Oliver David J. , Lora Jose , Jabbari Ali , Liu Yong , Shipman William D. , Ambler William G. , Taber Sarah F. , Onel Karen B. , Zippin Jonathan H. , Rashighi Mehdi , Krueger James G. , Anandasabapathy Niroshana , Rogatsky Inez , Blobel Carl P. , Lipsky Peter E. , Lu Theresa T. 
Published: August 2021

ABSTRACTBackgroundThe autoimmune disease lupus erythematosus (lupus) is characterized by photosensitivity, where even ambient ultraviolet radiation (UVR) exposure inflames skin. Beneficial effects of anifrolumab (anti-interferon α/breceptor (anti-IFNAR)) on lupus skin disease support a pathogenic role for IFN-I, but mechanistic understanding is limited. We have shown that Langerhans cell (LC) dysfunction contributes to photosensitivity. Healthy LCs act via a disintegrin and metalloprotease 17 (ADAM17) to release epidermal growth factor receptor (EGFR) ligands that limit UVR-induced keratinocyte apoptosis and photosensitivity. However, LC ADAM17 activity is reduced in non-lesional lupus model skin, and data point to reduced LC-mediated protection in human lupus. Here, we asked about the role of the IFN-rich lupus skin environment in LC dysfunction and the implications of this regulation for photosensitivity.MethodsGene expression patterns in non-lesional skin from human lupus and multiple murine models were examined. We used MRL/lpr, B6.Sle1yaa, and imiquimod models of lupus inin vivostudies to assess the role of IFN-I in LC ADAM17 dysfunction and photosensitivity.ResultsWe show a shared IFN-rich environment in non-lesional skin across human and murine model systems, that IFN-I inhibits LC ADAM17 activity, and that anti-IFNAR in lupus models restores LC ADAM17 function and reduces photosensitivity in EGFR and LC ADAM17-dependent manners. Reactive oxygen species (ROS) can mediate ADAM17 activity, and we show reduced LC ROS expression in lupus models that is restored by anti-IFNAR.ConclusionsOur findings suggest that IFN-I promotes photosensitivity by causing LC ADAM17 dysfunction and that anifrolumab ameliorates lupus skin disease at least in part by restoring LC function. This work provides insight into IFN-I-mediated disease mechanisms, LC regulation, and a mechanism of action for anifrolumab in lupus.
TGF-β1 drives Th9 but not Treg cells upon allergen exposure
Authors: Musiol Stephanie , Alessandrini Francesca , Jakwerth Constanze A. , Chaker Adam M. , Schneider Evelyn , Guerth Ferdinand , Ghiordanescu Ileana , Ullmann Julia T. , Kau Josephine , Plaschke Mirjam , Haak Stefan , Buch Thorsten , Schmidt-Weber Carsten B. , Zissler. Ulrich M. 
Published: August 2021

AbstractTGF-β1 is known to have a pro-inflammatory impact by inducing Th9 cells, while it also induces anti-inflammatory Treg cells (Tregs). In the context of allergic airway inflammation (AAI) its dual role can be of critical importance in influencing the outcome of the disease. Here we demonstrate that TGF-β acts in AAI by driving effector T cells into Th9 cells, while Tregs differentiate independently. Induction of experimental AAI and airway hyperreactivity in a mouse model with inducible genetic ablation of the TGFβ-receptor 2 (TGFBR2) on CD4+T cells significantly reduced the disease phenotype. Further, it blocked the induction of Th9 cell frequencies, but increased Treg cells. To translate these findings into a human clinically relevant context, Th9 and Treg cells were quantified both locally in induced sputum and systemically in blood of allergic rhinitis and asthma patients with or without allergen-specific immunotherapy (AIT). Natural allergen exposure induced local and systemic Th2, Th9 cell and reduced Tregs, while therapeutic allergen exposure by AIT suppressed Th2 and Th9 cell frequencies along with TGF-β and IL-9 secretion. Altogether, these findings support that neutralization of TGF-β represents a viable therapeutic option in allergy and asthma, not posing the risk of immune dysregulation by impacting Tregs.
Quantitative Phosphoproteomic Analyses Identify STK11IP as a Lysosome-Specific Substrate of mTORC1 that Regulates Lysosomal Acidification
Authors: Zi Zhenzhen , Zhang Zhuzhen , Feng Qiang , Kim Chiho , Scherer Philipp E. , Gao Jinming , Levine Beth , Yu Yonghao 
Published: August 2021

AbstractThe evolutionarily conserved serine/threonine kinase mTORC1 is a central regulator of cell growth and proliferation. mTORC1 is activated on the lysosome surface. However, once mTORC1 is activated, it is unclear whether mTORC1 phosphorylates local lysosomal proteins to regulate specific aspects of lysosomal biology. Through cross-reference analyses of lysosome proteomic with mTORC1-regulated phosphoproteomic, we identified STK11IP as a novel lysosome-specific substrate of mTORC1. mTORC1 directly phosphorylates STK11IP at S404. Knockout of STK11IP led to a robust increase of autophagosome-lysosome fusion and autophagy flux. Dephosphorylation of STK11IP at S404 represses the role of STK11IP as an autophagy inhibitor. Mechanistically, STK11IP binds to V-ATPase, and regulates the activity of V-ATPase. Knockout of STK11IP protects mice from fasting and Methionine and Choline-Deficient Diet (MCD) diet induced fatty liver. Thus, our study demonstrates that STK11IP phosphorylation represents a novel mechanism for mTORC1 to regulate lysosomal acidification, and points to STK11IP as a promising therapeutic target for the amelioration of diseases with aberrant autophagy signaling.
Prefrontal cortex neural compensation during an operant devaluation task
Authors: Fisher Hayley , Lin Hongyu , May Jensen , McLean Caitlin , Pickens Charles L. 
Published: August 2021

AbstractDeficits in goal-directed action are reported in multiple neuropsychiatric conditions, including schizophrenia. However, dysfunction is not always apparent in early stages of schizophrenia, possibly due to neural compensation. We designed a novel devaluation task in which goal-directed action could be guided by stimulus-outcome (S-O) [presumably orbitofrontal cortex (OFC)-mediated] or response-outcome (R-O) associations [presumably prelimbic cortex (PL)-mediated]. We previously found suggestive evidence that OFC and PL could compensate for each other in this task, and we more directly assessed this potential compensation here. In Experiment 1, rats received OFC, PL, combined OFC+PL, or sham lesions and then completed our devaluation task. The OFC+PL lesion group exhibited impaired devaluation. In Experiment 2, rats received cholera-toxin-b (CTb) into OFC and either neurotoxic or sham PL lesions. Rats were then sacrificed on the last training day to double-label for Arc and CTb. We found increased Arc+CTb in mediodorsal thalamus (MD) and increased Arc+ neurons in OFC when PL was lesioned, suggesting that PL lesions lead to a compensatory increased activation of the MD→OFC circuit. Our results suggest that our devaluation task can model neural compensation between OFC and PL and this compensation may be regulated by MD.Significance StatementTo detect compensatory responses, behavioral models that use different strategies must be developed to determine if the strategies shift when a brain area or circuit is incapacitated. Neural compensation is commonly observed in human research but only a few models of neural compensation exist, and few identify compensation within the prefrontal cortex. This research is among the first to show neural compensation between prefrontal cortex regions and implicate a thalamocortical circuit in modulating this compensation. Not only will this model provide a way to behaviorally identify subtle neurological shifts, it can also elucidate basic neurological mechanisms that mediate how circuits interact with each other and how dysfunction in one circuit can affect connectivity in other brain areas.
Thought Extramission: The Eyes Project Conceptual Maps at Close Distance
Authors: Dumitru Magda L. , Joergensen Gitte H. 
Published: August 2021

AbstractLight extramission is a popular yet erroneous model of human vision positing that light projects through the eyes over surrounding objects, allowing them to become visible. However, light extramission research has failed to distinguish between light and other types of emissions coming from the eyes, thereby discounting the possibility that extramission mechanisms might hold true for phenomena other than light. Here, we explored the thought extramission model, which is the notion that thoughts emanate from the eyes in the form of visualized representations. We show that the eyes project thoughts a short distance away in the form of high-resolution conceptual maps whose structure collapses at great distances. We also demonstrate that sensory filtering of thought projection by reducing light contrast lowers the resolution of conceptual maps. Our results highlight the supporting role of the visual system for thought processes relying on contrast, luminance, and perspective formation.
Environment dependent benefits of inter-individual variation in honey bee recruitment
Authors: Rajagopal Supraja , Brockmann Axel , George Ebi Antony 
Published: August 2021

AbstractInter-individual differences in behaviour within the members of a social group can affect the group’s productivity. In eusocial insects, individual differences amongst workers in a colony play a central role division of labour and task allocation. Extensive empirical and theoretical work has highlighted variation in response thresholds as a proximate mechanism underlying individual behavioural differences and hence division of labour. However, other response parameters, like response probability and intensity, can affect these differences. In this study, we first extended a previously published agent-based model on honey bee foraging to understand the relative importance of response (dance) probability and response (dance) intensity in the task of recruitment. Comparing variation obtained from the simulations with previously published empirical data, we found that response intensity plays a more important role than probability in producing consistent inter-individual differences in recruitment behaviour. We then explored the benefits provided by this individual variation in recruitment behaviour to the colony’s collective foraging effort under different environmental conditions. Our results revealed that individual variation leads to a greater energetic yield per forager, but only when food is abundant. Our study highlights the need to consider all response parameters while studying division of labour and adds to the growing body of evidence linking individual variation in behavioural responses to the success of social groups.
Rhythmic clock gene expression in Atlantic salmon parr brain
Authors: Bolton Charlotte M , Bekaert Michaël , Eilertsen Mariann , Helvik Jon Vidar , Migaud Herve 
Published: August 2021

ABSTRACTTo better understand the complexity of clock genes in salmonids, a taxon with an additional whole genome duplication, an analysis was performed to identify and classify gene family members (clock, arntl, period, cryptochrome, nr1d, ror, and csnk1). The majority of clock genes, in zebrafish and Northern pike, appeared to be duplicated. In comparison to the 29 clock genes described in zebrafish, 48 clock genes were discovered in salmonid species. There was also evidence of species-specific reciprocal gene losses conserved to the Oncorhynchus sister clade. From the six period genes identified three were highly significantly rhythmic, and circadian in their expression patterns (per1a.1, per1a.2, per1b) and two was significantly rhythmically expressed (per2a, per2b). The transcriptomic study of juvenile Atlantic salmon (parr) brain tissues confirmed gene identification and revealed that there were 2,864 rhythmically expressed genes (p < 0.001), including 1,215 genes with a circadian expression pattern, of which 11 were clock genes. The majority of circadian expressed genes peaked two hours before and after daylight. These findings provide a foundation for further research into the function of clock genes circadian rhythmicity and the role of an enriched number of clock genes relating to seasonal driven life history in salmonids.
Divergent transcriptional and transforming properties of PAX3-FOXO1 and PAX7-FOXO1 paralogs
Authors: Manceau Line , Richard Albert Julien , Lollini Pier-Luigi , Greenberg Maxim V. C. , Gilardi-Hebenstreit Pascale , Ribes Vanessa 
Published: August 2021

AbstractThe hallmarks of the alveolar subclass of rhabdomyosarcoma are chromosomal translocations that generate chimeric PAX3-FOXO1 or PAX7-FOXO1 transcription factors. Both PAX-FOXO1s result in related cell transformation in animal models, but both mutations are associated with distinct pathological manifestations in patients. To assess the mechanisms underlying these differences, we generated isogenic fibroblast lines expressing either PAX-FOXO1 paralog. Mapping of their genomic recruitment using CUT&Tag revealed that the two chimeric proteins have distinct DNA binding preferences. In addition, PAX7-FOXO1 causes stronger de novo transactivation of its bound regions than PAX3-FOXO1, resulting in greater transcriptomic dynamics involving genes regulating cell shape and cycle. Consistently, PAX3-FOXO1 accentuates fibroblast cellular traits associated with contractility and surface adhesion and limits entry into M phase. In contrast, PAX7-FOXO1 drives cells to adopt an amoeboid shape, reduces entry into S phase, and causes more genomic instabilities. Altogether, our results argue that the diversity of rhabdomyosarcoma manifestation arises, in part, from the divergence between the transcriptional activities of PAX3-FOXO1 and PAX7-FOXO1. Furthermore, the identified pronounced deleterious effects of PAX7-FOXO1 provide an explanation for the low frequency of the translocation generating this factor in patients with rhabdomyosarcoma.
Sarcoptic mange outbreak decimates South American camelid populations in San Guillermo National Park, Argentina
Authors: Ferreyra Hebe , Rudd Jaime , Foley Janet , Vanstreels Ralph E. T. , Martín Ana M. , Donadio Emiliano , Uhart Marcela M. 
Published: August 2021

AbstractSarcoptic mange epidemics can devastate wildlife populations. In 2014, mange was first detected in vicuña (Vicugna vicugna) and guanaco (Lama guanicoe) in San Guillermo National Park (SGNP), Argentina. This study characterized the potential source and the impacts of the outbreak in 2017–2019. Transect surveys indicated a sharp decrease in the density of live vicuña and guanaco by 68% and 77%, respectively, from May 2017 to June 2018. By April 2019 no vicuña or guanaco were recorded on transect surveys, suggesting a near-extinction at the local level. Clinical signs consistent with mange (e.g. intense pruritus, hyperkeratosis, alopecia) were observed in 24% of live vicuña (n = 478) and 33% of live guanaco (n = 12) during surveys, as well as in 94% of vicuña carcasses (n = 124) and 85% of guanaco carcasses (n = 20) opportunistically examined during the study period. Histological examination (n = 15) confirmed sarcoptic mange as the cause of the cutaneous lesions. Genetic characterization revealed thatSarcoptes scabieirecovered from seven vicuña (n = 13) and three guanaco (n = 11) shared the same genotype, which is consistent with a single source and recent origin of the epidemic. A governmental livestock incentive program introduced llama (Lama glama) in areas adjacent to SGNP in 2009, some of which reportedly had alopecic scaling consistent with sarcoptic mange. We hypothesize that the introduction of mange-infected llama may have triggered the outbreak in wild camelids which has now put them at a high risk of local extinction. This unprecedented event highlights that the accidental introduction of disease may be underestimated at the onset yet can have devastating effects on native ungulate populations with potentially profound effects at the community and ecosystem levels.
Flexible pri-miRNA structures enable tunable production of 5’ isomiRs
Authors: Bofill-De Ros Xavier , Hong Zhenyi , Birkenfeld Ben , Alamo-Ortiz Sarangelica , Yang Acong , Dai Lisheng , Gu Shuo 
Published: August 2021

SUMMARYDrosha cleavage of a pri-miRNA defines mature microRNA sequence. Drosha cleavage at alternative positions generates 5’ isoforms (isomiRs) which have distinctive functions. To understand how pri-miRNA structures influence Drosha cleavage, we performed a systematic analysis of the maturation of endogenous pri-miRNAs and their variants both in vitro and in vivo. We show that, in addition to previously known features, the overall structural flexibility of pri-miRNA impacts Drosha cleavage fidelity. Internal loops and nearby G·U wobble pairs on the pri-miRNA stem induce the use of non-canonical cleavage sites by Drosha, resulting in 5’ isomiR production. By analyzing patient data deposited in The Cancer Genome Atlas, we provide evidence that alternative Drosha cleavage of pri-miRNAs is a tunable process that responds to the level of pri-miRNA-associated RNA-binding proteins. Together, our findings reveal that Drosha cleavage fidelity can be modulated by altering pri-miRNA structure, a potential mechanism underlying 5’ isomiR biogenesis in tumors.HIGHLIGHTSFlexible pri-miRNA structures lead to 5’ isomiR productionInternal loops and G·U pairs of pri-miRNA contribute to alternative Drosha cleavagesAlternative Drosha cleavage results in 5’ isomiRs from both strands of pre-miRNAs5’ isomiR production is upregulated by pri-miRNA-associated RBPs in cancersGRAPHICAL ABSTRACT
Benchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2
Authors: Sangree Annabel K , Griffith Audrey L , Szegletes Zsofia M , Roy Priyanka , DeWeirdt Peter C , Hegde Mudra , McGee Abby V , Hanna Ruth E , Doench John G 
Published: August 2021

ABSTRACTNumerous rationally-designed and directed-evolution variants of SpCas9 have been reported to expand the utility of CRISPR technology. Here, we benchmark PAM preferences, on-target activity, and off-target susceptibility of 11 variants of SpCas9 in cell culture assays with thousands of guides targeting endogenous genes. To enhance the coverage and thus utility of base editing screens, we demonstrate that the SpCas9-NG and SpG variants are compatible with both A>G and C>T base editors, more than tripling the number of guides and assayable residues. We demonstrate the performance of these technologies by screening for loss-of-function mutations in BRCA1 and Venetoclax-resistant mutations in BCL2, identifying both known and new insights into these clinically-relevant genes. We anticipate that the tools and methodologies described here will facilitate the investigation of genetic variants at a finer and deeper resolution for any locus of interest.
Abnormal Neurite Density and Orientation Dispersion in Frontal Lobe Link to Elevated Hyperactive/Impulsive Behaviors in Young Adults with Traumatic Brain Injury
Authors: Cao Meng , Luo Yuyang , Wu Ziyan , Wu Kai , Li Xiaobo 
Published: August 2021

AbstractTraumatic brain injury is a major public health concern. A significant proportion of individuals experience post-traumatic brain injury behavioral impairments, especially in attention and inhibitory control domains. Traditional diffusion-weighted MRI techniques, such as diffusion tensor imaging, have provided tools to assess white matter structural disruptions reflecting the long-term brain tissue alterations associated with traumatic brain injury. The recently developed neurite orientation dispersion and density imaging is a more advanced diffusion-weighted MRI modality, which provides more refined characterization of brain tissue microstructures by assessing the neurite orientation dispersion and neurite density properties. In this study, we investigated the morphometrical and microstructural alterations at chronic brain injury stage and their relationships with the functional outcomes. Neurite orientation dispersion and density imaging data from 44 young adults with chronic traumatic brain injury (ranging from 18 27 years of age; 23 males/21 females) who had no prior-traumatic brain injury history of attention deficits and/or hyperactivity and 45 group-matched normal controls (23 males /22 females) were collected. Maps of fractional anisotropy, neurite orientation dispersion index, and neurite density index were calculated. Vertex-wise and voxel-wise analyses were conducted for gray matter and white matter, respectively. Post-hoc region of interest-based analyses were also performed. Compared to the controls, the group of traumatic brain injury showed significantly increased orientation dispersion index in various gray matter regions and significantly decreased orientation dispersion index in several white matter regions. Brain-behavioral association analyses indicated that the reduced neurite density index of left precentral gyrus and the reduced orientation dispersion index of left superior longitudinal fasciculus were significantly associated with elevated hyperactive/impulsive symptoms in the patients with traumatic brain injury. These findings suggest that traumatic brain injury-induced chronic neurite orientation dispersion alterations of left superior longitudinal fasciculus and left precentral may significantly contribute to post-traumatic brain injury hyperactive/impulsive behaviors in young adults with traumatic brain injury.
Nuclear Translocation of Vitellogenin in the Honey Bee (Apis mellifera)
Authors: Salmela Heli , Harwood Gyan , Münch Daniel , Elsik Christine , Herrero-Galán Elías , Vartiainen Maria K. , Amdam Gro 
Published: August 2021

AbstractVitellogenin (Vg) is a conserved protein used by nearly all oviparous animals to produce eggs. It is also pleiotropic and performs functions in oxidative stress resistance, immunity, and, in honey bees, behavioral development of the worker caste. It has remained enigmatic how Vg affects multiple traits. Here, we asked whether Vg enters the nucleus and acts via DNA-binding. We used immunohistology, cell fractionation and cell culturation to show that a structural subunit of honey bee Vg translocates into cell nuclei. We then demonstrated Vg-DNA binding theoretically and empirically with prediction software and chromatin immunoprecipitation with sequencing (ChIP-seq), finding binding sites at genes influencing immunity and behavior. Finally, we investigated the immunological and enzymatic conditions affecting Vg cleavage and nuclear translocation, and constructed a 3D structural model. Our data are the first to show Vg in the nucleus and suggests a new fundamental regulatory role for this ubiquitous protein.