bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transient cell-in-cell formation underlies tumor resistance to immunotherapy
Authors: Gutwillig Amit , Santana-Magal Nadine , Farhat-Younis Leen , Rasoulouniriana Diana , Madi Asaf , Luxenburg Chen , Cohen Jonathan , Padmanabhan Krishnanand , Shomron Noam , Shapira Guy , Feinmesser Meora , Zlotnik Oran , Debets Reno , Reticker-Flynn Nathan E. , Rider Peleg , Carmi Yaron 
Published: September 2020

AbstractDespite the remarkable success of immunotherapy in cancer, most patients will develop resistant tumors. While the main conceptual paradigm suggests that relapsed clones emerge through a process of clonal selection and immunoediting, currently little evidence directly demonstrates this process in epithelial cancers.To study this process, we established several mouse models in which tumors drastically regress following immunotherapy, yet resistant tumors relapse within a few weeks of treatment cessation. Whole exome analyses indicated that relapsed tumors share hundreds of neo-antigens with the primary tumors and are comparably killed by reactive T cells. Examination of tumor cells that survive immunotherapies revealed that they structure a transient cell-in-cell formation, which is impenetrable to immune-derived cytotoxic compounds and to chemotherapies. This formation is mediated predominantly by a cell-membrane protein on activated T cells, which subsequently induces epidermal growth factor receptors and STAT3 phosphorylation in tumors cells. In contrast to previous reports on cell-in-cell formations, here both cells remain alive and can disseminate into single tumor cells once T cells are no longer present.Overall, this work highlights a powerful resistance mechanism which enable tumor cells to survive immune pressure and provides a new theoretical framework for combining chemotherapies and immunotherapies.
Susceptibility of domestic swine to experimental infection with SARS-CoV-2
Authors: Pickering Brad S. , Smith Greg , Pinette Mathieu M. , Embury-Hyatt Carissa , Moffat Estella , Marszal Peter , Lewis Charles E. 
Published: September 2020

AbstractSARS-CoV-2, the agent responsible for COVID-19 has been shown to infect a number of species. The role of domestic livestock and the risk associated for humans in close contact remains unknown for many production animals. Determination of the susceptibility of pigs to SARS-CoV-2 is critical towards a One Health approach to manage the potential risk of zoonotic transmission. Here, pigs undergoing experimental inoculation are susceptible to SARS-CoV-2 at low levels. Viral RNA was detected in group oral fluids and nasal wash from at least two animals while live virus was isolated from a pig. Further, antibodies could be detected in two animals at 11 and 13 days post infection, while oral fluid samples at 6 days post inoculation indicated the presence of secreted antibodies. These data highlight the need for additional livestock assessment to better determine the potential role domestic animals may contribute towards the SARS-CoV-2 pandemic.
Infrared thermography cannot be used to approximate core body temperature in wild primates
Authors: McFarland Richard , Barrett Louise , Fuller Andrea , Hetem Robyn S , Porter Warren , Young Christopher , Henzi S Peter 
Published: September 2020

ABSTRACTUnderstanding the physiological processes that underpin primate performance is key if we are to assess how a primate might respond when navigating new and changing environments. Given the connection between an animal’s ability to thermoregulate and the changing demands of its thermal environment, increasing attention is being devoted to the study of thermoregulatory processes as a means to assess primate performance. Infrared thermography can be used to record the body surface temperatures of free-ranging animals. However, some uncertainty remains as to how these measurements can be used to approximate core body temperature. Here, we use data collected from wild vervet monkeys (Chlorocebus pygerythrus) to examine the relationship between infrared body surface, core body, and local climate, to determine to what extent surface temperatures reflect core body temperature. While we report a positive association between surface and core body temperature – a finding that has previously been used to justify the use of surface temperature measurements as a proxy for core temperature regulation – when we controlled for the effect of the local climate in our analyses, this relationship was no longer observed. That is, body surface temperatures were solely predicted by local climate, and not core body temperatures, suggesting that surface temperatures tell us more about the environment a primate is in, and less about the thermal status of its body core in that environment. Despite the advantages of a non-invasive means to detect and record animal temperatures, infrared thermography alone cannot be used to approximate core body temperature in wild primates.
Development of a micro-CT mouse holder for a femur defect mouse model
Authors: Paul Graeme R. , Schwilch Peter , Wehrle Esther , Kuhn Gisela A. , Müller Ralph 
Published: September 2020

AbstractCorrect fixation of an object is essential for accurate micro computed tomography scanning. In this document, we provide a motivation for, description of, and use cases for a mouse holder appropriate for holding an externally fixated mouse in femur fracture/defect healing experiments. In addition to rigid fixation, the holder provides heating and anaesthetic gas to ensure correct anaesthetic conditions for the animal. We provide the description and design files for a Scanco viva40 scanner, but with small changes, the holder can be used with other scanners.
Epigenetic clock and methylation study of oocytes from a bovine model of reproductive aging
Authors: Kordowitzki Paweł , Haghani Amin , Zoller Joseph A. , Li Caesar Z. , Raj Ken , Spangler Matthew L. , Horvath Steve 
Published: September 2020

ABSTRACTCattle are an attractive animal model of fertility in women due to their high degree of similarity relative to follicle selection, embryo cleavage, blastocyst formation, and gestation length. To facilitate future studies of the epigenetic underpinnings of aging effects in the female reproductive axis, several DNA methylation-based biomarkers of aging (epigenetic clocks) for bovine oocytes are presented. One such clock was germane to only oocytes, while a dual-tissue clock was highly predictive of age in both oocytes and blood. Dual species clocks that apply to both humans and cattle were also developed and evaluated. These epigenetic clocks can be used to accurately estimate the chronological age of the oocyte donor. Both epigenetic clock studies and epigenome wide association studies revealed that blood and oocytes differ substantially with respect aging and the underlying epigenetic signatures that potentially influence the aging process. The rate of epigenetic aging was found to be slower in oocytes compared to blood, however, oocytes appeared to begin at an older epigenetic age. The epigenetic clocks for oocytes are expected to address questions in the field of reproductive aging, including the central question: how to slow aging of oocytes.
Dissociable components of oscillatory activity underly information encoding in human perception
Authors: Vidaurre Diego , Cichy Radoslaw M. , Woolrich Mark W. 
Published: September 2020

AbstractBrain decoding can predict visual perception from non-invasive electrophysiological data by combining information across multiple channels. However, decoding methods typically confound together the multi-faceted and distributed neural processes underlying perception, so it is unclear what specific aspects of the neural computations involved in perception are reflected in this type of macroscale data. Using MEG data recorded while participants viewed a large number of naturalistic images, we analytically separated the brain signal into a slow 1/f drift (<5Hz) and a oscillatory response in the theta frequency band. Combined with a method for capturing between-trial variability in the way stimuli are processed, this analysis revealed that there are at least three dissociable components that contain distinct stimulus-specific information: a 1/f component, reflecting the temporally stable aspect of the stimulus representation; a global phase shift of the theta oscillation, related to differences in the speed of processing between the stimuli; and differential patterns of theta phase across channels, likely related to stimulus-specific computations. We demonstrate that common cognitive interpretations of decoding analysis can be flawed if the multicomponent nature of the signal is ignored, and suggest that, by acknowledging this fact, we can provide a more accurate interpretation of commonly observed phenomena in the study of perception.
Parvalbumin interneurons in the nucleus accumbens regulate impairment of risk avoidance inDISC1transgenic mice
Authors: Zhou Xinyi , Wu Bifeng , Xiao Qian , He Wei , Zhou Ying , Wei Pengfei , Zhang Xu , Liu Yue , Wang Jie , Li Weidong , Wang Liping , Tu Jie 
Published: September 2020

AbstractOne strong survival instinct in animals is to approach things that are of benefit and avoid risk. In humans, a large portion of mental disorders are accompanied by cognition-related impairments including the inability to recognize potential risks. One of the most important genes involved in risk behavior is disrupted-in-schizophrenia-1 (DISC1), and animal models where this gene has some dysfunction show cognitive impairments. However, whetherDISC1mice models have an impairment in avoiding potential risks is still not fully understood. In the present study, we used DISC1-N terminal truncation (DISC1-NTM) mice to study cognitive abilities related to potential risks. We found thatDISC1-NTMmice were impaired in risk avoidance on the elevated plus maze (EPM) test, and showed impairment in social preference in a three-chamber social interaction test. Staining for c-Fos following the EPM indicated that the nucleus accumbens (NAc) was associated with risk avoidance behavior inDISC1-NTMmice. Meanwhile,in vivoelectrophysiological recordings showed that firing rates of fast spiking neurons (FS) in the NAc significantly decreased inDISC1-NTMmice following tamoxifen administration. In addition, theta band power was lower when mice shuttled from the safe (closed) arms to the risky (open) arms, an effect which disappeared after induction of the truncatedDISC1gene. Furthermore, we found throughin vitropatch clamp recording that the frequency of action potentials stimulated by current injection was lower in parvalbumin (PV) neurons in the NAc ofDISC1-NTMmice than their wild-type littermates. Risk-avoidance impairments inDISC1-NTMmice were rescued using optogenetic tools that activated NAcPVneurons. Finally, we inhibited activitiy of NAcPVneurons in PV-Cre mice, which mimicked the risk-avoidance impairment found in theDISC1-NTMmice during tests on the elevated zero maze. Taken together, our findings confirmed a cognitive impairment inDISC1-NTMmice related to risk recognition and suggests that reduced excitability of NAcPVneurons may be responsible.
A cAMP/PKA-dependent synaptically targeted lncRNA mediates structural plasticity in hippocampal neurons by functionally interacting with the Spectrin/Ankyrin Network
Authors: Grinman Eddie , Nakahata Yoshihisa , Avchalumov Yosef , Espadas Isabel , Swarnkar Supriya , Yasuda Ryohei , Puthanveettil Sathyanarayanan V. 
Published: September 2020

AbstractActivity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long-noncoding transcriptome remains elusive. Here we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—whose expression is upregulated and is synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independent of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators Ankyrin (AnkB) and Spectrin (Sptn1) and is required for their dendritic localization. Taken together, this study demonstrates that ADEPTR regulates the dendritic Spectrin-Ankyrin network for structural plasticity at the synapse and illuminates a novel role for lncRNAs at the synapse.One Sentence SummaryWe have uncovered an intronic long noncoding RNA that is synaptically transported in a cAMP-dependent manner and is linked to cytoskeletal components of structural plasticity in hippocampal neurons.
Quantitative analysis of tyrosine phosphorylation from FFPE tissues reveals patient specific signaling networks
Authors: Kohale Ishwar N. , Burgenske Danielle M. , Mladek Ann C. , Bakken Katrina K. , Kuang Jenevieve , Boughey Judy C. , Wang Liewei , Carter Jodi M. , Haura Eric B. , Goetz Matthew P. , Sarkaria Jann N. , White Forest M. 
Published: September 2020

AbstractFormalin fixed paraffin embedded (FFPE) tissues are an invaluable source of clinical specimens. Tyrosine phosphorylation (pTyr) plays a fundamental role in cellular processes and is commonly dysregulated in cancer but has not been studied to date in FFPE samples. We describe a method for quantitative analysis of pTyr signaling networks at an unprecedented sensitivity, with hundreds of sites quantified from 1-2 10-μm sections of FFPE tissue specimens. Phosphotyrosine profiles of flash frozen and FFPE tissues derived from the same tumors suggest that FFPE tissues preserve pTyr signaling characteristics in PDX tumors and archived clinical specimens. Differential activation of oncogenic proteins was observed in triple negative breast cancer tumors as well as lung cancer tumors, highlighting patient specific oncogenic driving kinases and indicating potential targeted therapies for each patient. These data highlight the capability for direct translational insight from pTyr analysis of small amounts of FFPE tumor tissue specimens.
Sex differences in the amplification of responding to an alcohol-predictive cue by an alcohol-associated context
Authors: Segal Diana , Valyear Milan , Chaudhri Nadia 
Published: September 2020

ABSTRACTBackgroundIn male rats, physical contexts that are associated with alcohol can invigorate responding to a discrete, alcohol-predictive conditioned stimulus (CS), and amplify priming-induced reinstatement. Here, we examined these effects as a function of biological sex.MethodsMale and female Long-Evans rats were acclimated to drinking ethanol (EtOH, 15% v/v) in their home cages. Next, they were trained to associate an auditory CS (10 s; white noise; 15 trials per session) with EtOH delivery (0.2 ml per CS; 3.0 ml per session) into a fluid port for oral intake. Training occurred in a distinctive context containing specific visual, olfactory, and tactile stimuli. During alternating sessions rats were exposed to a second context where they did not receive EtOH. At test, CS presentations occurred in both contexts without EtOH delivery. Rats then underwent extinction using repeated unreinforced presentations of the CS in both contexts. An alcohol-primed reinstatement test was then conducted, in which 0.2 ml of EtOH was presented both at the start of the session and during the first CS presentation, after which no EtOH was delivered for the remainder of the session.ResultsAt both test and reinstatement, male rats made significantly more CS port-entries in the context associated with alcohol delivery than in the context in which alcohol was never experienced. Unlike males, female rats made a similar number of CS port-entries at test in both the alcohol context and the neutral context. The reinstatement observed in female rats was not affected by context.ConclusionsThese findings identify novel sex differences in the capacity of an alcohol-associated context to modulate responding to a discrete, alcohol-predictive cue.
Population-based Carrier Screening and Prenatal Diagnosis of Fragile X Syndrome in East Asian Populations
Authors: Guo Qiwei , Chang Yih-Yuan , Huang Chien-Hao , Hsiao Yu-Shan , Hsiao Yu-Chiao , Chiu I-fan , Zhou Yulin , Zhang Haixia , Ko Tsang-Ming 
Published: September 2020

AbstractIdentification of carriers of fragile X syndrome (FXS) with the subsequent prenatal diagnosis, and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers. The prevalence of FXS carriers and incidence of full mutation fetuses in carrier pregnancies were found to be 1/556 and 11.0%, respectively. The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG repeats forFMR1categorization; the integral risks of full mutation expansion were approximately 6.0%, 43.8%, and 100% for premutation alleles with 55-74, 75-89, and ≥90 CGG repeats, respectively. The protective effect of AGG interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75-89 CGG repeats from full mutation expansion. Lastly, family history was shown not an effective indicator for FXS carrier screening in East Asian populations and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXS-associated genetic profiles of East Asian populations are delineated and population-based carrier screening is shown to be promising for FXS intervention.
The organosulfur compound dimethylsulfoniopropionate (DMSP) is utilized as an osmoprotectant byVibriospecies
Authors: Gregory Gwendolyn J. , Boas Katherine E. , Boyd E. Fidelma 
Published: September 2020

AbstractDimethylsulfoniopropionate (DMSP) is a key component of the global geochemical sulfur cycle that is a secondary metabolite produced in large quantities by marine phytoplankton and utilized as an osmoprotectant. Bacterial DMSP lyases convert DMSP to the climate active gas dimethylsulfide (DMS). Whether marine bacteria can also accumulate DMSP as an osmoprotectant to maintain the turgor pressure of the cell in response to changes in external osmolarity remains unknown. The marine halophileVibrio parahaemolyticus, contains at least six osmolyte transporters, four betaine carnitine choline transport (BCCT) carriers BccT1-BccT4 and two ABC-family ProU transporters. In this study, we showed that DMSP is used as an osmoprotectant byV. parahaemolyticusand several otherVibriospecies includingV. choleraeandV. vulnificus. Using aV. parahaemolyticus proUdouble mutant, we demonstrated that these ABC transporters are not required for DMSP uptake. However, abccTnull mutant lacking all four BCCTs had a growth defect compared to wild type in high salt media supplemented with DMSP. UsingbccTtriple mutants, possessing only one functional BCCT, in growth pattern assays, we identified two BCCT-family transporters, BccT1 and BccT2 are carriers of DMSP.Vibrio choleraeandV. vulnificus, only contain a homolog of BccT3 and functional complementation inEscherichia coliMKH13 showed onlyV. choleraeBccT3 could transport DMSP. InV. vulnificusstrains, we identified and characterized an additional BCCT transporter that was also a carrier for DMSP. Phylogenetic analysis uncovered at least 11 distinct BCCT transporters among members of the Harveyi clade, with some species having up to 9 BCCTs as exemplified byV. jasicida.ImportanceDMSP is present in the marine environment, produced in large quantities by marine phytoplankton as an osmoprotectant, and is an important component of the global geosulfur cycle. The bacterial familyVibrionaceaeis comprised of marine species, many of which are halophiles such asV. parahaemolyticus, which can utilize a wide range of osmolytes and possesses at least six transporters for the uptake of these compounds. Here, we demonstrated thatV. parahaemolyticusand otherVibriospecies can accumulate DMSP as an osmoprotectant and show that the BCCT family transporters were required. DMSP was transported by four different BCCT transporters; BccT1, BccT2, BccT3 and BccT5 depending on the species. Bioinformatics and phylogenetics demonstrated thatVibriospecies contain a large number of BCCTs and that many of these are associated with different metabolic pathways.
Establishing a Living Biobank of Patient-Derived Organoids of Intraductal Papillary Mucinous Neoplasms of the Pancreas
Authors: Beato Francisca , Reverón Dayana , Dezsi Kaleena B. , Ortiz Antonio , Johnson Joseph O. , Chen Dung-Tsa , Ali Karla , Yoder Sean J. , Jeong Daniel , Malafa Mokenge , Hodul Pamela , Jiang Kun , Centeno Barbara A. , Abdalah Mahmoud A. , Balasi Jodi A. , Tassielli Alexandra F. , Sarcar Bhaswati , Teer Jamie K. , DeNicola Gina M. , Permuth Jennifer B. , Fleming Jason B. 
Published: September 2020

AbstractPancreatic cancer (PaCa) is the third leading cause of cancer-related deaths in the United States. There is an unmet need to develop strategies to detect PaCa at an early, operable stage and prevent its progression. Intraductal papillary mucinous neoplasms (IPMNs) are cystic PaCa precursors that comprise nearly 50% of pancreatic cysts detected incidentally via cross-sectional imaging. Since IPMNs can progress from low- and moderate-grade dysplasia to high-grade dysplasia and invasion, the study of these lesions offers a prime opportunity to develop early detection and prevention strategies. Organoids are an ideal preclinical platform to study IPMNs, and the objective of the current investigation was to establish a living biobank of patient-derived organoids (PDO) from IPMNs. IPMN tumors and adjacent normal pancreatic tissues were successfully harvested from 15 patients with IPMNs undergoing pancreatic surgical resection at Moffitt Cancer Center & Research Institute (Tampa, FL) between May of 2017 and March of 2019. Organoid cultures were also generated from cryopreserved tissues. Organoid count and size were determined over time by both Image-Pro Premier 3D Version 9.1 digital platform and Matlab application of a Circular Hough Transform algorithm, and histologic and genomic characterization of a subset of the organoids was performed using immunohistochemistry and targeted sequencing, respectively. The success rates for organoid generation from IPMN tumor and adjacent normal pancreatic tissues were 81% and 87%, respectively. IPMN organoids derived from different epithelial subtypes showed different morphologiesin vitro, and organoids recapitulated histologic and genomic characteristics of the parental IPMN tumor. In summary, this pre-clinical model has the potential to provide new opportunities to unveil mechanisms of IPMN progression to invasion and to shed insight into novel biomarkers for early detection and targets for chemoprevention.