bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estrogen for the Treatment and Prevention of Breast Cancer
Authors: Abderrahman Balkees , Jordan V. Craig 
Published: May 2022

Abstract
In 1971, Sir Alexander Haddow et al. delivered the inaugural David A. Karnofsky lecture at the American Society for Clinical Oncology. This award was designated American Society for Clinical Oncology’s highest, as he had used translational research to identify the first clinical therapy, that is, synthetic estrogens to treat breast cancer. His lecture was entitled “Thoughts on Chemical Therapy.” For 40 years, high-dose synthetic estrogens were used as palliative therapy, for some advanced breast cancer patients 5 years following menopause. Mechanisms were unknown. Tamoxifen, a failed “morning-after pill,” is an antiestrogen in estrogen receptor–positive breast cancer, which was subsequently used to treat all stages of breast cancer and to prevent breast cancer. In 2008, Jordan was selected to present the 38th Karnofsky lecture entitled: “The Paradoxical Action of Estrogen in Breast Cancer—Survival or Death?” Unexpectedly, through a study of acquired resistance to long-term tamoxifen therapy, estrogen-induced apoptosis in long-term estrogen-deprived breast cancer was deciphered in Jordan’s laboratory. These data and the biological rules established under laboratory conditions provided molecular mechanisms to aid in the interpretation of the Women's Health initiative in the United States and the Million Women Study in the United Kingdom. In addition, by establishing laboratory models to understand mechanisms of estrogen-induced apoptosis, new estrogen derivatives were successfully evaluated in the laboratory and tested as candidates for women after the therapeutic failure of antiestrogenic strategies to treat breast cancer. For the future, the knowledge obtained about estrogen-induced apoptosis in cancer holds the promise of discovering new therapies to control or cure cancer in general.
Decreased spontaneous brain activity in the dorsal visual pathway in age-related macular degeneration patients revealed by fractional amplitude of low-frequency fluctuation
Authors: Lai Ping-Hong , Cai Yue-Hong , Zhong Yu-Lin , Huang Xin 
Published: May 2022

Background
Age-related macular degeneration (AMD) is the leading cause of visual loss in the developed world and damages the central retina. Growing evidences demonstrated that AMD patients were associated with brain structure changes in visual pathway. However, it remains unknown whether alterations of spontaneous brain activity changes occur in AMD patients.

Purpose
The purpose of this study was to investigate the effect of central vision loss on spontaneous brain activity in AMD patients.

Material and methods
Seventeen AMD patients and 17 healthy controls (HCs) underwent resting-state MRI scans. The fractional amplitude of low-frequency fluctuations (fALFFs) was applied to investigate the spontaneous brain activity changes in AMD patients.

Results
Compared with HC group, AMD patients showed significant decreased fALFF values in the right calcarine/cuneus (brodmann area 17,8) and right superior parietal lobule (brodmann area 7).

Conclusion
Our results showed that AMD patients had decreased brain activities in the dorsal visual pathway, which offer important insights into the neural mechanisms of central visual field defect in AMD patients.
Anti-SARS-Cov-2 S-RBD IgG formed after BNT162b2 vaccination can bind C1q and activate complement
Authors: Abu-Humaidan Anas H. A. , Ahmad Fatima M. , Awajan Dima , Jarrar Raba’a F. , Alaridah Nader 
Published: May 2022

AbstractIntroductionActivation of the classical complement pathway through C1q binding to immunoglobulins (Ig) contributes to pathogen neutralization, thus, the ability of Ig produced after vaccination to bind C1q could affect vaccine efficacy. In this study, we investigated C1q binding and subsequent complement activation by anti-spike (S) protein receptor-binding domain (RBD) specific antibodies produced following vaccination with either the mRNA vaccine BNT162b2 or the inactivated vaccine BBIBP-CorV.MethodsSerum samples were collected in the period July 2021-March 2022. Participants’ demographic data, type of vaccine, date of vaccination, as well as adverse effects of the vaccine were recorded. The serum samples were incubated with S protein RBD-coated plates. Levels of human IgG, IgM, and C1q, that were bound to the plate, as well as formed C5b-9, were compared between different groups of participants.ResultsA total of 151 samples were collected from vaccinated (n=116) and non-vaccinated (n=35) participants. Participants who received either one or two doses of BNT162b2 formed higher levels of anti-RBD IgG than participants who received BBIBP-CorV. The anti-RBD IgG formed following either vaccine bound C1q, but significantly more C1q binding was observed in participants who received BNT162b2. Subsequently, C5b-9 formation was significantly higher in participants who received BNT162b2, while no significant difference in C5b-9 formation was found between the non-vaccinated and BBIBP-CorV groups. Formation of C5b-9 was strongly correlated to C1q binding, additionally, the ratio of formed C5b-9/ bound C1q was significantly higher in the BNT162b2 group.ConclusionAnti-RBD IgG formed following vaccination can bind C1q with subsequent complement activation, the degree of terminal complement pathway activation differed between vaccines, which could play a role in in the protection offered by COVID-19 vaccines. Further investigation into the correlation between vaccine protection and the ability of vaccine generated antibodies to activate complement is required.
Spatial Transcriptomics Prediction from Histology jointly through Transformer and Graph Neural Networks
Authors: Zeng Yuansong , Wei Zhuoyi , Yu Weijiang , Yin Rui , Li Bingling , Tang Zhonghui , Lu Yutong , Yang Yuedong 
Published: May 2022

ABSTRACTThe rapid development of spatial transcriptomics allows for the measurement of RNA abundance at a high spatial resolution, making it possible to simultaneously profile gene expression, spatial locations, and the corresponding hematoxylin and eosin-stained histology images. Since histology images are relatively easy and cheap to obtain, it is promising to leverage histology images for predicting gene expression. Though several methods have been devised to predict gene expression using histology images, they don’t simultaneously include the 2D vision features and the spatial dependency, limiting their performances. Here, we have developed Hist2ST, a deep learning-based model using histology images to predict RNA-seq expression. At each sequenced spot, the corresponding histology image is cropped into an image patch, from which 2D vision features are learned through convolutional operations. Meanwhile, the spatial relations with the whole image and neighbored patches are captured through Transformer and graph neural network modules, respectively. These learned features are then used to predict the gene expression by following the zero-inflated negative binomial (ZINB) distribution. To alleviate the impact by the small spatial transcriptomics data, a self-distillation mechanism is employed for efficient learning of the model. Hist2ST was tested on the HER2-positive breast cancer and the cutaneous squamous cell carcinoma datasets, and shown to outperform existing methods in terms of both gene expression prediction and following spatial region identification. Further pathway analyses indicated that our model could reserve biological information. Thus, Hist2ST enables generating spatial transcriptomics data from histology images for elucidating molecular signatures of tissues.
Sex-limited diversification of the eye in Heliconius butterflies
Authors: Buerkle Nathan P. , VanKuren Nicholas W. , Westerman Erica L. , Kronforst Marcus R. , Palmer Stephanie E. 
Published: May 2022

AbstractButterflies have evolved an immense diversity in eye organization to support a range of vision-based behaviors including courtship, oviposition, and foraging. This diversity has been surveyed extensively across the butterfly phylogeny, and here we take a complementary approach to characterize the eye within a group of closely related Heliconius butterflies. Using a combination of immunostaining for different opsins and eyeshine for determining the distribution of light-filtering screening pigments, we identified several sexually dimorphic features of eye organization where male eyes varied and female eyes did not. Ultraviolet (UV) sensitive photoreceptors varied in which of two UV opsins were expressed, including co-expression of both within single photoreceptors, and these differences were consistent with a role in courtship and conspecific identification. Additional differences across species and sex included the distribution of three ommatidial types defined by the expression pattern of UV and blue opsins, the distribution of a red screening pigment, and which ommatidial types expressed the red screening pigment. We hypothesize that female eyes are optimized for a dimorphic behavior such as oviposition, while male eyes adapt to other selective pressures such as the local light environment.
Real-time feeding behavior monitoring by electrical penetration graph rapidly reveals host plant susceptibility to crapemyrtle bark scale (Hemiptera: Eriococcidae)
Authors: Wu Bin , Chun Elizabeth , Xie Runshi , Knox Gary W. , Gu Mengmeng , Qin Hongmin 
Published: May 2022

AbstractHost range confirmation of invasive hemipterans relies on the evaluation of plant susceptibility though greenhouse or field trials, which are inefficient and time-consuming. When the green industry faces the fast-spreading threat of invasive pests such as crapemyrtle bark scale (Acanthococcus lagerstroemiae), it is imperative to timely identify potential host plants and evaluate plant resistance/susceptibility to pest infestation. In this study, we developed an alternative technology to complement the conventional host confirmation methods. We used electrical penetration graph (EPG) based technology to monitor the A. lagerstroemiae stylet-tip position when it was feeding on different plant tissues in real-time. The frequency and relative amplitude of insect feeding waveforms (recorded by EPG) were extracted by an R programming-based software written to generate eleven feeding parameters for comparative analysis between plant species. The results demonstrated that the occurrences of phloem phase and xylem phase offered conclusive evidence for host plant evaluation. Furthermore, parameters including the percentage of insects capable of accessing phloem tissue, time duration spent on initiating phloem phase and ingesting phloem sap, provided insight into why host plant susceptibility differs among similar plant species. In summary, this study developed a novel real-time diagnostic tool for quick A. lagerstroemiae host confirmation, which laid the essential foundation for effective pest management.Simple SummaryCrapemyrtle bark scale (CMBS; Acanthococcus lagerstroemiae), an invasive polyphagous sap feeder in the United States, has spread across 16 U.S. states in less than two decades, posing potential risks to the Green Industry. Confirming the host range is crucial for effective pest management of invasive insects. However, host range confirmation relying on greenhouse or field trials is often inefficient and time-consuming. In this study, we used the electrical penetration graph (EPG) to monitor the stylet penetration of CMBS in plant tissue in real-time. An R programming-based application was developed to better characterize the insect feeding waveforms recorded by EPG. By analyzing EPG-based feeding parameters, we demonstrated that CMBS have difficulty accessing the phloem tissue (salivation and ingestion) of a resistant plant compared to a susceptible plant. Importantly, we hereby present CMBS typical feeding behaviors on susceptible and non-susceptible plants comparatively, which provides direct evidence for revealing unknown hosts rapidly.
The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import by enhancing assembly of the TOM complex
Authors: Rödl Saskia , Brave Fabian den , Räschle Markus , Lenhard Svenja , Groh Carina , Becker Hanna , Zimmermann Jannik , Morgan Bruce , Richling Elke , Becker Thomas , Herrmann Johannes M. 
Published: May 2022

AbstractMitochondria are essential organelles that play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenesis enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and stabilizes its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in a compromised protein import into mitochondria and a subsequent accumulation of mitochondrial precursor proteins in the cytosol. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery in order to improve mitochondrial protein import during phases of metabolic transition.
Mycobacterium tuberculosis transcriptional regulator Rv1019 is upregulated in hypoxia and negatively regulates Rv3230c-Rv3229c operon encoding enzymes in the oleic acid biosynthetic pathway
Authors: Pushparajan Akhil Raj , Edison Lekshmi K , Kumar Ramakrishnan Ajay 
Published: May 2022

AbstractThe main obstacle in eradicating tuberculosis is the ability of Mycobacterium tuberculosis to remain dormant in the host, and then to get reactivated even years later under immuno-compromised conditions. Transcriptional regulation in intracellular pathogens plays an important role in adapting to the challenging environment inside the host cells. Previously, we demonstrated that Rv1019, a putative transcriptional regulator of M. tuberculosis H37Rv, is an autorepressor. We showed that, Rv1019 is cotranscribed with Rv1020 (mfd) and Rv1021 (mazG) encoding DNA repair proteins and negatively regulates the expression of these genes. In the present study, we show that Rv1019 also regulates the expression of the genes Rv3230c and Rv3229c (desA3) which form a two-gene operon in M. tuberculosis. Constitutive expression of Rv1019 in M. tuberculosis significantly downregulated the expression of these genes. Employing Wayne’s hypoxia-induced dormancy model of M. tuberculosis, we show that Rv1019 is upregulated (3-fold) under hypoxia. Finally, by reporter assay, using M. smegmatis as a model, we validate that Rv1019 is recruited to the promoter of Rv3230c-Rv3229c during hypoxia and negatively regulates this operon which is involved in the biosynthesis of oleic acid.
The Drosophila Fab-7 boundary element modulates Abd-B gene activity in the genital disc by guiding an inversion of collinear chromatin organization and alternative promoter use
Authors: Moniot-Perron Laura , Moindrot Benoit , Manceau Line , Edouard Joanne , Jaszczyszyn Yan , Gilardi-Hebenstreit Pascale , Hernandez Céline , Bloyer Sébastien , Noordermeer Daan 
Published: May 2022

SummaryHox genes encode transcription factors that specify segmental identities along the Antero-Posterior body axis. These genes are organized in clusters, where their order corresponds to their activity along the body axis, an evolutionary conserved feature known as collinearity. In Drosophila, the BX-C cluster contains the three most posterior Hox genes, where their collinear activation incorporates progressive replacement of histone modifications, reorganization of 3D chromatin architecture and sequential activation of boundary elements and cis-regulatory regions. To dissect functional hierarchies, we compared chromatin organization in larvae and in cell lines, with a focus on the Abd-B gene. Our work establishes the importance of the Fab-7 boundary element for insulation between 3D domains marked by different histone modifications. Interestingly, we detected a non-canonical inversion of collinear chromatin dynamics at the Abd-B gene, with the active histone domain decreasing in size. This chromatin organization differentially instructed alternative Abd-B promoter use, thereby expanding the possibilities to regulate transcriptional output.
Structural basis of human LRRK2 membrane recruitment and activation
Authors: Zhu Hanwen , Tonelli Francesca , Alessi Dario R. , Sun Ji 
Published: May 2022

SummaryMutations in LRRK2 are the most common genetic cause of late-onset Parkinson’s disease (PD). LRRK2 encodes the leucine-rich repeat kinase 2 (LRRK2), whose kinase activity is regulated by Rab29, a membrane-anchored GTPase. However, molecular mechanisms underlying Rab29-dependent recruitment and activation of LRRK2 remain unclear. Here we report cryo-EM structures of LRRK2–Rab29 complexes in three oligomeric states, illustrating snapshots of key steps during LRRK2 membrane recruitment and activation. Rab29 binds to the ARM domain of LRRK2, and disruption at the interface abrogates LRRK2 kinase activity. Activation of LRRK2 is underpinned by the formation of an unexpected Rab29-induced super-assembly containing two central kinase-active and two peripheral kinase-inactive LRRK2 protomers. Central protomers undergo pronounced oligomerization-associated rearrangements and adopt an active conformation. Our work reveals the structural mechanism for LRRK2’s spatial regulation controlled by Rab GTPases, provides mechanistic insights into pathogenic mutations and identifies new opportunities to design LRRK2 inhibitors for PD treatment.
Reinstatement of Pavlovian responses to alcohol cues by stress
Authors: Armstrong Anne , Rosenthal Hailey , Stout Nakura , Richard Jocelyn M. 
Published: May 2022

AbstractRationaleStress may contribute to relapse to alcohol use in part by enhancing reactivity to cues previously paired with alcohol. Yet, standard models of stress-induced reinstatement generally use contingent presentations of alcohol-paired cues to reinforce instrumental behaviors, making it difficult to isolate the ability of cues to invigorate alcohol-seeking.ObjectiveHere we sought to test the impact of stress on behavioral responses to alcohol-paired cues, using a model of stress-induced reinstatement of Pavlovian conditioned approach, inspired by Nadia Chaudhri’s work on context-induced reinstatement.MethodsLong Evans rats were trained to associate one auditory cue with delivery of alcohol or sucrose and an alternative auditory cue with no reward. Following extinction training, rats were exposed to a stressor prior to being re-exposed to the cues under extinction conditions. We assessed the effects of yohimbine, intermittent footshock and olfactory cues paired with social defeat on responses to alcohol-paired cues, and the effects of yohimbine on responses to sucrose-paired cues.ResultsThe pharmacological stressor, yohimbine, enhanced Pavlovian responses to both alcohol and sucrose cues, but intermittent footshock and social defeat cues did not.ConclusionsWhile yohimbine elicited reinstatement of Pavlovian conditioned responses, these effects may be unrelated to activation of stress systems.
The DNA replication protein Orc1 from the yeast Torulaspora delbrueckii is required for heterochromatin formation but not as a silencer-binding protein
Authors: Maria Haniam , Rusche Laura N. 
Published: May 2022

ABSTRACTTo understand the process by which new protein functions emerge, we examined how the yeast heterochromatin protein Sir3 arose through gene duplication from the conserved DNA replication protein Orc1. Orc1 is a subunit of the origin recognition complex (ORC), which marks origins of DNA replication. In Saccharomyces cerevisiae, Orc1 also promotes heterochromatin assembly by recruiting the structural proteins Sir1-4 to silencer DNA. In contrast, the paralog of Orc1, Sir3, is a nucleosome-binding protein that spreads across heterochromatic loci in conjunction with other Sir proteins. We previously found that a non-duplicated Orc1 from the yeast Kluyveromyces lactis behaved like ScSir3 but did not have a silencer-binding function like ScOrc1. Moreover, K. lactis lacks Sir1, the protein that interacts directly with ScOrc1. Here, we searched for the presumed intermediate state in which non-duplicated Orc1 possesses both the silencer-binding and spreading functions. In the non-duplicated species Torulaspora delbrueckii, which has an ortholog of Sir1 (TdKos3), we found that TdOrc1 spreads across heterochromatic loci independently of ORC, as ScSir3 and KlOrc1 do. This spreading is dependent on the nucleosome binding BAH domain of Orc1 and on Sir2 and Kos3. However, TdOrc1 does not have a silencer-binding function: T. delbrueckii silencers do not require ORC binding sites to function, and Orc1 and Kos3 do not appear to interact. Instead, Orc1 and Kos3 both spread across heterochromatic loci with other Sir proteins. Thus, Orc1 and Sir1/Kos3 originally had different roles in heterochromatin formation than they do now in S. cerevisiae.
Stem Cell Secretome Promotes Scarless Corneal Wound Healing and Rescues Corneal Sensory Nerves
Authors: Kumar Ajay , Li Yunshu , Mallick Shayshadri , Yang Enzhi , Dhaliwal Deepinder K. , Price Andrew , Xie Ting , Du Yiqin 
Published: May 2022

AbstractCorneal scarring is a leading cause of blindness in the world. In this study, we explored the therapeutic potential of corneal stromal stem cell (CSSC)-derived secretome in a mechanical debridement mouse model of corneal scarring. CSSC secretome was able to promote scarless corneal wound healing. The mechanisms include 1) dampening inflammation with reduced CD45+, CD11b+/GR1+, and CD11b+/F4/80+ inflammatory cells in the wounded corneas; 2) reducing fibrotic extracellular matrix deposition such as collagen IV, collagen 3A1, SPARC, and α-SMA; 3) rescuing sensory nerves. The proteomic analysis shows upregulated proteins related to wound healing and cell adhesion which boost scarless wound healing. It also shows upregulated neuroprotective proteins in CSSC secretome related to axon guidance, neurogenesis, neuron projection development, and neuron differentiation. Four unique complement inhibitory proteins CD59, vitronectin, SERPING1, and C1QBP found in CSSC secretome contribute to reducing a complement cascade mediating cell death and membrane attacking complex autoantibodies after corneal injury. This study provides novel insights into mechanisms of stem cell secretome induced scarless corneal wound healing and neuroprotection and identifies regenerative proteins in the CSSC secretome.Significance StatementIn this study, we report the therapeutic role of corneal stromal stem cell (CSSC) secretome for scarless corneal wound healing and corneal sensory nerve rescuing. We uncovered that CSSC secretome dampens inflammation, reduces fibrosis, induces sensory nerve regeneration, and rescues corneal cells by inhibiting the complement system in the wounded mouse corneas. This study provides pre-clinical evidence for the use of CSSC secretome as a biologic treatment for corneal scarring to prevent corneal blindness. We delineated a plethora of proteins in the CSSC secretome, which individually or in combination have the potential as future therapies for scarless corneal wound healing.