bluuebunny/crossref_metadata_2025_split huggingface dataset:
Widespread reorganisation of the regulatory chromatin landscape facilitates resistance to inhibition of oncogenic ERBB2 signalling
Authors: Ogden Samuel , Carys Kashmala , Bruce Jason ,   the OCCAMS consortium, Sharrocks Andrew D. 
Published: April 2021

AbstractOesophageal adenocarcinoma (OAC) patients show poor survival rates and there are few targeted molecular therapies available. However, components of the receptor tyrosine kinase (RTK) driven pathways are commonly mutated in OAC, typified by high frequency amplifications of the RTKERRB2. ERBB2 can be therapeutically targeted, but this has limited clinical benefit due to the acquisition of drug resistance. Here we examined how OAC cells respond to ERBB2 inhibition through altering their regulatory chromatin landscapes and rewiring their gene regulatory networks to acquire a reversible resistant state. ERBB2 inhibition triggers widespread remodelling of the accessible chromatin landscape. This remodelling is accompanied by the activation of the transcriptional regulators HNF4A and PPARGC1A. Initially, inhibition of cell cycle associated gene expression programmes is observed, with compensatory increases in the programmes driving changes in metabolic activity. PPARGC1A is instrumental in promoting a switch to dependency on oxidative phosphorylation and both PPARGC1A and HNF4A are required for the acquisition of resistance to ERBB2 inhibition. Our work therefore reveals the molecular pathways that support the acquisition of a resistant state and points to potential new therapeutic strategies to combat drug resistance.
Loss ofSmad4promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation
Authors: Tan Xiaohong , Tong Lu , Li Lin , Xu Jinjin , Xie Shaofang , Ji Lei , Fu Jujiang , Liu Qingwu , Shen Shihui , Liu Yun , Xiao Yanhui , Gao Feiran , Moses Robb E. , Bardeesy Nabeel , Wang Yanxiao , Zhang Jishuai , Wong Kwok-kin , Tang Longying , Li Lei , Song Dianwen , Yang Xiao , Liu Jian , Li Xiaotao 
Published: April 2021

AbstractOver 85% of lung cancer patients harbor overt or subclinical metastases at diagnosis, and therefore most patients die of progressive metastatic disease despite aggressive local and systemic therapies. Somatic mutations in theSmad4gene have been found in non-small-cell lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generated a highly aggressive lung cancer mouse model bearing conditionalKrasG12D,p53fl/flLOF and/orSmad4fl/flLOF mutations. TheSmad4fl/fl;p53fl/fl; KrasG12D(SPK) mutant mice manifested a much higher incidence of tumor metastases than thep53fl/fl; KrasG12D(PK) mice. Molecularly, PAK3 was identified as a novel downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice was achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3’UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components suggests clinical use of Smad4 LOF as a potential marker for prognosis in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
Why does Δ9-Tetrahydrocannabinol act as a partial agonist of cannabinoid receptors?
Authors: Dutta Soumajit , Selvam Balaji , Das Aditi , Shukla Diwakar 
Published: April 2021

AbstractCannabinoid receptor 1 (CB1) is a therapeutically relevant drug target for controlling pain, obesity, and other central nervous system disorders. However, full agonists and antagonists of CB1have been reported to cause serious side effects in patients. Therefore, partial agonists have emerged as a viable alternative to full agonists and antagonists as they avoid overstimulation and side effects. One of the key bottlenecks in the design of partial agonists is the lack of understanding of the molecular mechanism of partial agonism. In this study, we examine two mechanistic hypotheses for the origin of partial agonism in cannabinoid receptors and explain the mechanistic basis of partial agonism exhibited by Δ9-Tetrahydrocannabinol (THC). In particular, we inspect whether partial agonism emerges from the ability of THC to bind in both agonist and antagonist binding pose or from its ability to only partially activate the receptor. Extensive molecular dynamics simulations and the Markov state model capture the THC binding in both antagonist, and agonist binding poses in CB1receptor. Furthermore, we observe that binding of THC in the agonist binding pose leads to rotation of toggle switch residues and causes partial outward movement of intracellular transmembrane helix 6 (TM6). Our simulations also suggest that the alkyl side chain of THC plays a crucial role in determining partial agonism by stabilizing the ligand in the agonist and antagonist-like poses within the pocket. This study provides us fundamental insights into the mechanistic origin of the partial agonism of THC.
Metabolic adaptation to progressive mitochondrial dysfunction in aging POLGD257Amice
Authors: Lim Esther W. , Handzlik Michal K. , Trefts Elijah , Gengatharan Jivani M. , Shaw Reuben J. , Metallo Christian M. 
Published: April 2021

SummaryA decline in mitochondrial function is associated with neurodegeneration and aging. Progressive mitochondrial defects have diverse metabolic consequences that could drive some of the pathophysiological changes that occur with aging. Here, we comprehensively characterized metabolic alterations in PolgD257Amitochondrial DNA mutator mice. Plasma alanine increased dramatically with time, with lactate and other organic acids accumulating to a lesser extent. These changes were reflective of increased glycolysis, rapid gluconeogenesis, and hypoglycemia. Tracing with [15N]ammonium revealed impairment of the urea cycle and diversion to purine catabolism. We also measured alterations in the lipidome, observing a general reduction in canonical lipids and the accumulation of 1-deoxysphingolipids, which are synthesized from alanine via promiscuous serine palmitoyltransferase activity. Consistent with 1-deoxysphingolipid’s association with peripheral neuropathy, PolgD257Amice exhibited thermal hypoalgesia. These results highlight the distinct changes that occur in carbon and nitrogen metabolism upon mitochondrial impairment and key metabolic mechanisms which can drive aging-associated neuropathy.
PTPRU, a quiescence-induced receptor tyrosine phosphatase negatively regulates osteogenic differentiation of human mesenchymal stem cells
Authors: Rumman Mohammad , Dhawan Jyotsna 
Published: April 2021

AbstractBone marrow mesenchymal stem cells (MSCs) are heterogeneous osteo-progenitors that are mainly responsible for bone regeneration and homeostasis. In vivo, a subpopulation of bone marrow MSCs persists in a quiescent state, providing a source of new cells for repair. Previously, we reported that induction of quiescence in hMSCs in vitro skews their differentiation potential in favour of osteogenesis while suppressing adipogenesis. Here, we uncover a new role for a protein tyrosine phosphatase, receptor type U (PTPRU) in repressing osteogenesis during quiescence. A 75 kD PTPRU protein isoform was found to be specifically induced during quiescence and down-regulated during cell cycle reactivation. Using siRNA-mediated knockdown, we report that in proliferating hMSC, PTPRU preserves self-renewal, while in quiescent hMSC, PTPRU not only maintains reversibility of cell cycle arrest but also suppresses expression of osteogenic lineage genes. Knockdown of PTPRU in proliferating or quiescent hMSC de-represses osteogenic markers, and enhances induced osteogenic differentiation. We also show that PTPRU positively regulates a β-catenin-TCF transcriptional reporter. Taken together, our study suggests a role for a quiescence-induced 75kD PTPRU isoform in modulating bone differentiation in hMSC, potentially involving the Wnt pathway.
Unraveling the stepwise maturation of the yeast telomerase
Authors: Hirsch Anna Greta , Becker Daniel , Lamping Jan-Philipp , Krebber Heike 
Published: April 2021

AbstractTelomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organismSaccharomyces cerevisiaewe defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA,TLC1is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est- and the Pop-proteins. This partly matured telomerase is re-import into the nucleus via Mtr10 and a novelTLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation inCSE1bypasses this defect and become Type I like survivors. Interestingly, both import receptors contact the Sm-ring for nuclear import, which therefore resembles a quality control step in the maturation process of the telomerase. The re-imported immatureTLC1is finally trimmed into the ~1150 nucleotide long mature form. TMG-capping ofTLC1finalizes maturation, leading to mature telomerase.
Evolution and function of nitrogen fixation gene clusters in sugarcane associated Bradyrhizobium strains
Authors: de Matos Gustavo Feitosa , Rouws Luc Felicianus Marie , Simões‐Araújo Jean Luiz , Baldani José Ivo 
Published: April 2021

SummaryBradyrhizobium spp. are well known to mediate biological nitrogen fixation (BNF) as microsymbionts inhabiting nodules on leguminous plants. However, they may also contribute to plant growth via free‐living N2 fixation (FLNF) in association with non‐legumes. Notably, several Bradyrhizobium strains from sugarcane roots display FLNF activity. Among them, Bradyrhizobium sacchari is a legume symbiotic species, whereas strains AG48 and M12 are non‐symbiotic. In the present study, a phylogenomic approach was applied to study peculiarities of these and other Bradyrhizobium strains with respect to N fixation (nif) gene content in order to reveal genetic features that enable FNLF in Bradyrhizobium spp. All FLNF strains carry an ancestral ‘non‐symbiotic’ nif‐gene cluster (NSC). B. sacchari also contains a second ‘symbiotic’ nif‐gene cluster (SC), a characteristic observed in only three of 156 evaluated genomes. B. sacchari stood out and presented a high level of sequence divergence between individual nif‐gene homologues and we discuss scenarios for the evolutionary origin of these clusters. The transcript level of NSC nifH gene increased during FLNF, when compared to symbiotic conditions. The data suggest that sugarcane roots harbor diverse Bradyrhizobium spp. that are genetically adapted to a dynamic environment where leguminous and non‐leguminous host plants are alternately available.
Environmental hazards: The microgeography of land‐use negative externalities
Authors: Somerville Tsur , Wetzel Jake 
Published: April 2021

AbstractThe decisions on the siting of hazardous facilities and compensation for nearby landowners depend on an accurate estimation of the negative externalities these facilities place on proximate land uses, primarily residential properties. In this paper, we highlight the sensitivity of these estimates to the treatment of distance from the hazard and to the presence of other nearby externality generating land uses identified at a highly granular geographic level. We find that estimated spillovers are quite sensitive to highly localized treatment of other land uses and that naive parametric specifications yield misleading results. Unlike previous work, we find proximity to a major oil pipeline results in lower house prices: properties adjacent to a property with a pipeline easement transact for 2.2% ($C 15.8k) less and those one property further away 1.6% ($C 11k) less than more distant residential properties. These effects vary by the type of land use on which the pipeline easement lies. Difference‐in‐differences tests indicate that the price effects of proximity respond to information shocks that remind potential buyers of pipeline risks but not those shocks that merely remind them of the presence of the pipeline. However, the effects of an information shock, in this case a nearby spill on the pipeline, dissipate within 18 months.
Development of a rapid colorimetric strip method for determination of volatile bases in mahi‐mahi and tuna
Authors: Bai Jing , Baker Shirley M. , Goodrich‐Schneider Renee M. , Montazeri Naim , Sarnoski Paul J. 
Published: April 2021

AbstractTuna (Thunnus albacares) and mahi‐mahi (Coryphaena hippurus) are two major fish species responsible for scombroid poisoning in the United States. The purpose of this research was to develop a low‐cost and easily operated colorimetric strip method for the rapid determination of spoilage degree via amine response in mahi‐mahi and tuna. The color strip method was developed by investigating different types of dyes, filter papers, sample volume, water bath temperature, and other parameters. Ultimately rose bengal and bromophenol blue (BPB) dyes were chosen. These two dyes produced standard curves with good linearity (0–50 mg/L for the total biogenic amines) and uniformity of color change. The r2 values for the standard curves of the rose Bengal and BPB were 0.9535 and 0.8883, respectively. Significant positive Pearson correlations coefficients (r) between the volatile biogenic amine levels detected by these two colorimetric strip methods with increasing spoilage grade of mahi‐mahi (rose bengal: r = 0.8907, p < 0.0001; BPB: r = 0.8711, p < 0.0001) and tuna (rose bengal: r = 0.8351, p < 0.0001; BPB: r = 0.7362, p = 0.0001) were observed. For mahi‐mahi, the volatile amines detected by the colorimetric strips correlated positively with increasing levels of eight biogenic amines, free alanine, four aldehydes, isoamyl alcohol, two ketones, and dimethyl disulfide. For tuna, the results determined by colorimetric strips positively correlated with three biogenic amines, three free amino acids, four aldehydes, and ethanol. The two validated colorimetric strips could rapidly monitor the spoilage degree of mahi‐mahi and tuna at low‐cost.Practical ApplicationRose bengal strips and BPB strips were developed as a rapid, objective, analytical method that can serve as an alternative to sensory grading methods. These two nonspecific colorimetric strip methods provided good linear response and uniformity of color change. Volatile amine levels in fish determined by these colorimetric strip methods were statistically significant and positively correlated with the spoilage grade of fish.
The serotonin 2C receptor agonist lorcaserin, alone and in combination with the opioid receptor antagonist naltrexone, attenuates binge‐like ethanol drinking
Authors: Tabbara Rayane I. , Li Zhaoxia , Fletcher Paul J. , Lê Anh D. 
Published: April 2021

AbstractThe serotonin (5‐HT) system has been implicated in the pathophysiology of alcohol (ethanol; EtOH) use disorders. Lorcaserin, a 5‐HT2C receptor agonist, attenuates drug self‐administration in animal models. We investigated the effects of lorcaserin on EtOH intake using the drinking‐in‐the‐dark (DID) procedure, an animal model of binge‐like drinking. We compared the effects of lorcaserin to those of the Food and Drug Administration (FDA)‐approved drug naltrexone and examined the effects of combining lorcaserin and naltrexone. To examine whether effects were specific for EtOH, we examined the effects of lorcaserin and naltrexone, administered alone and in combination, on saccharin intake. Adult male C57BL/6J mice received EtOH access (20% v/v) for 2 h in the home‐cage during the first 3 days of the DID procedure, beginning 3 h into the dark cycle. On day 4, mice were injected with lorcaserin, naltrexone, or a combination of lorcaserin and naltrexone prior to a 4‐h EtOH access. Intake was measured at 2 and 4 h. Lorcaserin reduced EtOH intake in a dose‐dependent fashion over the 2‐ and 4‐h measurement periods. Naltrexone also reduced EtOH intake when administered alone, with dose‐dependent effects being more pronounced over 2 h rather than the full 4‐h session. Combining lorcaserin and naltrexone reduced binge‐like EtOH drinking to a greater extent than either drug alone. A similar pattern of results was obtained for saccharin intake. These results suggest that lorcaserin and naltrexone can have additive effects on binge‐like EtOH drinking. They also support continued research into the therapeutic potential of lorcaserin for alcohol use disorders.
Vertical stratification and seasonal changes of the avian community in Mount Cameroon lowland rainforest
Authors: Chmel Kryštof , Kamga Solange Mekuate , Awa Taku , Ewome Francis Luma , Uceda‐Gómez Guillermo , Hořák David , Mlíkovský Jiří , Molua Lucas Lyonga , Riegert Jan , Janeček Štěpán 
Published: April 2021

AbstractWhile birds are known to show preferences for distinct vertical strata in forests, detailed studies on the vertical distribution of whole communities are still scarce. Furthermore, of those conducted, most have used ground‐based methods, including in both tropical and temperate forest. Here, we utilised ground‐to‐canopy mist nets to explore the vertical distribution of birds within lowland forest of Mount Cameroon National Park in both dry and wet seasons. In total, 908 birds from 83 species were caught. Species richness was highest in the understory and decreased towards the canopy as did bird abundance. We sampled more species during the dry season, with some species showing substantial seasonal changes in overall abundance. No seasonally driven stratal shifts in abundance were observed, while species richness increased in denser strata in the wet season. Although frugivoro‐insectivorous birds represented the most species‐rich foraging guild, their total abundance was unrelated to height above the ground, season and vegetation cover. This was also applied to gleaning insectivores, the second most species‐rich foraging guild. Omnivores, insectivoro‐nectarivores, sallying insectivores and frugivores typically showed a preference for higher vertical strata, while ground‐foraging insectivores preferred low forest strata with dense vegetation. Seasonal variation was most profound in frugivores and sallying insectivores.
Ichthyosiform sarcoidosis: Report of a case and comprehensive review of the literature
Authors: Chen Henry W. , Vandergriff Travis 
Published: April 2021

AbstractSarcoidosis is a disease that can affect a multitude of organs and manifest as cutaneous disease. Cutaneous manifestations of sarcoidosis vary widely in morphology, earning the nickname of “great imitator,” and the diagnosis often requires clinicopathologic correlation and additional laboratory and radiographic workup. We present the case of a 42‐year‐old African American woman with ichthyosiform sarcoidosis on the bilateral lower extremities. As one of the rarest specific variants of cutaneous sarcoidosis, ichthyosiform is understudied and has been primarily documented in case reports and series. We undertake a comprehensive review of the literature to identify key clinicopathologic features including the characterization of sites of cutaneous and systemic involvement, as well as typical histopathological findings. Lower extremities were the most involved body site (85.7%). Extracutaneous organ involvement centered around pulmonary (65.7%), lymph node (57.1%), and ocular (31.4%) involvement. Of the histopathological features reported, hyperkeratosis (51.4%) and diminished stratum granulosum (62.9%) were most frequently reported in conjunction with dermal granulomas (100%). We hope that these findings will serve to aid clinicopathological correlation and accurate diagnosis of ichthyosiform sarcoidosis.
Perceptions of Using Multiple Mobile Health Devices to Support Self‐Management Among Adults With Type 2 Diabetes: A Qualitative Descriptive Study
Authors: Lewinski Allison A. , Vaughn Jacqueline , Diane Anna , Barnes Angel , Crowley Matthew J. , Steinberg Dori , Stevenson Janee , Yang Qing , Vorderstrasse Allison A. , Hatch Daniel , Jiang Meilin , Shaw Ryan J. 
Published: April 2021

AbstractPurposeThis study identified facilitators and barriers pertaining to the use of multiple mobile health (mHealth) devices (Fitbit Alta® fitness tracker, iHealth® glucometer, BodyTrace® scale) that support self‐management behaviors in individuals with type 2 diabetes mellitus (T2DM).DesignThis qualitative descriptive study presents study participants’ perceptions of using multiple mobile devices to support T2DM self‐management. Additionally, this study assessed whether participants found visualizations, generated from each participant’s health data as obtained from the three separate devices, useful and easy to interpret.MethodsSemistructured interviews were completed with a convenience sample of participants (n = 20) from a larger randomized control trial on T2DM self‐management. Interview questions focused on participants’ use of three devices to support T2DM self‐management. A study team member created data visualizations of each interview participant’s health data using RStudio.ResultsWe identified two themes from descriptions of study participants: feasibility and usability. We identified one theme about visualizations created from data obtained from the mobile devices. Despite some challenges, individuals with T2DM found it feasible to use multiple mobile devices to facilitate engagement in T2DM self‐management behaviors.DiscussionAs mHealth devices become increasingly popular for diabetes self‐management and are integrated into care delivery, we must address issues associated with the use of multiple mHealth devices and the use of aggregate data to support T2DM self‐management.Clinical RelevanceReal‐time patient‐generated health data that are easily accessible and readily available can assist T2DM self‐management and catalyze conversations, leading to better self‐management. Our findings lay an important groundwork for understanding how individuals with T2DM can use multiple mHealth devices simultaneously to support self‐management.