bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assisted reproductive technology and association with childhood cancer subtypes
Authors: Gulrajani Natalie B. , Montes Samuel , McGough Dan , Wimberly Courtney E. , Khattab Ameera , Semmes Eleanor C. , Towry Lisa , Cohen Jennifer L. , Hurst Jillian H. , Landi Daniel , Hill Sherika N. , Walsh Kyle M. 
Published: April 2021

ABSTRACTObjectivesUse of assisted reproductive technology (ART) may alter the typical course of fetal development. We sought to investigate the association between ART use and childhood cancer subtype.Study designWe surveyed 1701 parents of children with cancer about ART use, demographics, and gestational and perinatal factors. Multivariable logistic regression modeled the association between ART use and childhood cancer subtypes, birthweight and multiple gestation status.ResultsAmong childhood cancer patients, ART use was highest among children with osteosarcoma (OR=2.81; 95% CI=1.2-6.4; P=0.01). ART use was also elevated among children with hepatoblastoma, and this relationship appeared mediated by low birthweight. No specific type of ART appeared to drive these associations. Low birthweight was itself strongly associated with increased hepatoblastoma risk, even after adjustment for ART use, multiple gestation status, sex, and parental income (P<0.001). Birthweight was higher in patients with germ cell tumors (P=0.02) and with neuroblastoma (P=0.06). Multiple gestation status was associated with neuroblastoma among females (OR=3.6, 95% CI=1.2-10.5, P=0.02), but not among males (OR=0.97, 95% CI=0.27-3.4, P=0.96) (Pinteraction=0.02).ConclusionsAssociations between ART use and hepatoblastoma risk may be mediated by birthweight, a strong hepatoblastoma risk factor that was replicated in our study. ART use may also be associated with osteosarcoma independent of birthweight, an association not previously observed in studies limited to cancers diagnosed before adolescence. Evaluating long-term health outcomes in children conceived by ART, throughout adolescence and potentially into adulthood, appears warranted.
A fructo-oligosaccharide prebiotic is well-tolerated in adults undergoing allogeneic hematopoietic stem cell transplantation: a phase I dose-escalation trial
Authors: Andermann Tessa. M. , Fouladi Farnaz , Tamburini Fiona B. , Sahaf Bita , Tkachenko Ekaterina , Greene Courtney , Buckley Matthew T. , Brooks Erin F. , Hedlin Haley , Arai Sally , Mackall Crystal L. , Miklos David , Fodor Anthony A. , Rezvani Andrew R. , Bhatt Ami S. 
Published: April 2021

AbstractBackgroundAlterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOS) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate, and consequently induce proliferation of immunomodulatory CD4+ FOXP3+ T-regulatory cells (Tregs), that impact GVHD risk.MethodsWe conducted a pilot Phase I trial to assess the investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity (RIC) allo-HCT (n=15) compared to concurrent controls (n=16). We administered FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool SCFAs using LC-MS, and determined peripheral T-cell concentrations using CyTOF.ResultsWe found that FOS was safe and well-tolerated at 10g per day without significant adverse effects in patients undergoing reduced-intensity conditioning allo-HCT. Community-level gut microbiota composition was significantly different on the day of transplant (day 0) between patients receiving FOS compared to concurrent controls, however FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or in peripheral Tregs although Tregs trended higher in those patients who received FOS. Early alterations in gut microbiota composition in those receiving FOS are especially intriguing although it remains unclear what impact this has on outcomes following transplantation and larger studies are required to investigate the use of prebiotics in HCT recipients.ConclusionsFOS is well-tolerated at 10g per day in patients undergoing RIC allo-HCT.
ILK play a key role in partial bladder outler obstruction (PBOO) by regulation TLR4/NF-κB(p65) pathway
Authors: Zhou Yiduo , Huang Yi , Gao Jie , Shu Le , Zhang Sicong , Chen Zhengsen , Shen Baixin , Wei Zhongqing , Ding Liucheng 
Published: April 2021

AbstractAimThe purpose of this research was to discuss the effects and relative mechanisms of ILK in PBOO by vivo and vitro study.Materials and methodsThe SD rats were divided into Normal, Sham and Model groups. Collecting Bladder outlet tissue, observation pathology and fibrosis levels by H&E and Masson staining. Measuring cell apoptosis and cell viability by TUNEL and p-histone H3 staining, ILK protein were evaluated by WB and IHC assay in Bladder outlet tissue. Using TGF-β1 stimulating BSMC cell to make PBOO cell model. Measuring cell proliferation by CCK-8 assay; Relative gene and proteins expression were evaluated by immunofluorescence, WB and RT-qPCR assay.ResultsCompared with Normal group, bladder weight, collage fiber area, apoptosis cell number and cell viability were significantly difference with ILK protein significantly increasing in bladder outer tissues of Model group (P < 0.05, respectively). In vitro cell experiment, ILK overexpression had effects to stimulate cell proliferation via TLR4/NF-κB(p65) pathway; however, with ILK knockdown, the cell proliferation was significantly depressed via regulation TLR4/NF-κB(p65).ConclusionILK play an important role in PBOO induced cell proliferation, ILK knockdown had effects to improve PBOO induced cell hyper-proliferation via depressing TLR4/NF-κB(p65) pathway.
Gambogic acid and gambogenic acid induce a thiol-dependent heat shock response and disrupt the interaction between HSP90 and HSF1 or HSF2
Authors: Pesonen Linda , Svartsjö Sally , Bäck Viktor , de Thonel Aurélie , Mezger Valérie , Sabéran-Djoneidi Délara , Roos-Mattjus Pia 
Published: April 2021

AbstractCancer cells rely on heat shock proteins (HSPs) for growth and survival. Especially HSP90 has multiple client proteins and plays a critical role in malignant transformation, and therefore different types of HSP90 inhibitors are being developed. The bioactive natural compound gambogic acid (GB) is a prenylated xanthone with antitumor activity and it has been proposed to function as an HSP90 inhibitor. However, there are contradicting reports whether GB induces a heat shock response (HSR), which is cytoprotective for cancer cells and therefore a potentially problematic feature for an anticancer drug. In this study, we show that GB and a structurally related compound, called gambogenic acid (GBA), induce a robust HSR, in a thiol-dependent manner. Using heat shock factor 1 (HSF1) orHSF2knockout cells, we show that the GB or GBA-induced HSR is HSF1-dependent. Intriguingly, using closed form ATP-bound HSP90-mutants that can be co-precipitated with HSF1, a known facilitator of cancer, we show that also endogenous HSF2 binds to the HSP90-HSF1 complex. GB and GBA treatment disrupt the interaction between HSP90 and HSF1 and HSF2. Our study implies that these compounds should be used cautiously if developed for cancer therapies, since GB and its derivative GBA are strong inducers of the HSR, in multiple cell types, by involving the dissociation of a HSP90-HSF1-HSF2 complex.
Genetic characteristics of human papillomavirus type 16, 18, 52 and 58 in southern China
Authors: Zu Yuee , Ou Zhihua , Wu Dan , Liu Wei , Liu Liwen , Wu Di , Zhao Yanping , Ren Peidi , Zhang Yanqing , Li Wangsheng , Fu Shujin , Wen Yongchun , Cai Xianchu , Liao Wenbo , Geng Chunyu , Zhou Hongcheng , Wang Xiaman , Lu Haorong , Peng Huanhuan , Liu Na , Zhu Shida , Liu Jiyang , Wang Dongbo , Li Junhua 
Published: April 2021

AbstractPersistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 358 viral genomes of four major HPV types, including HPV 16 (n=82), 18 (n=35), 52 (n=121) and 58 (n=100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 strains associated with potentially high oncogenicity. These findings expanded our knowledge on the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.
Phospholipid exchange shows insulin receptor activity is supported by both the propensity to form wide bilayers and ordered domains (rafts)
Authors: Suresh Pavana , Miller W. Todd , London Erwin 
Published: April 2021

ABSTRACTUsing efficient methyl-alpha-cyclodextrin mediated lipid exchange, we studied the effect of altering plasma membrane outer leaflet phospholipid composition upon the activity of insulin receptor (IR) in mammalian cells. After substitution of endogenous lipids with lipids having an ability to form liquid ordered (Lo) domains (sphingomyelins) or liquid disordered (Ld) domains (unsaturated phosphatidylcholines (PCs)), we found that the propensity of lipids to form ordered domains is required for high IR activity. Additional substitution experiments using a series of saturated PCs showed that IR activity increased substantially with increasing acyl chain length. Increasing acyl chain length increases both bilayer width and the propensity to form ordered domains. To distinguish the effects of membrane width and domain formation, we incorporated purified IR into alkyl maltoside micelles with increasing hydrocarbon lengths. IR activity increases with increased chain length, but more modestly than by increasing lipid acyl chain length in cells. This suggests that the ability to form Lo domains as well as wide bilayer width contributes to increased IR activity. Inhibition of phosphatases with sodium orthovanadate showed that some of the lipid dependence of IR activity upon lipid structure reflected protection from phosphatases by lipids that support Lo domain formation. The results are consistent with a model in which a combination of bilayer width and ordered domain formation modulate IR activity via effects upon IR conformation and accessibility to phosphatases.SignificanceThis study shows how methyl-α-cyclodextrin mediated lipid exchange can be used to probe the influence of lipid structure upon the functioning of a transmembrane receptor. Plasma membranes having a propensity to form Lo domains are required to support a high level of IR activity. The studies indicate this may reflect an effect of lipid environment upon IR domain localization, which in turn alters its conformation and vulnerability to phosphatases. Alterations in lipid composition could conceivably regulate IR activityin vivo.
Circulating miRNA diversity, origin and response to changing metabolic and reproductive states, new insights from the rainbow trout
Authors: Emilie Cardona E , Cervin Guyomar C , Desvignes Thomas , Jérôme Montfort J , Guendouz Samia , Postlethwait John H. , Sandrine Skiba-Cassy S , Bobe Julien 
Published: April 2021

AbstractCirculating miRNAs (c-miRNAs) are found in most, if not all, biological fluids and are becoming well established biomarkers of many human pathologies. The aim of the present study was to investigate the potential of c-miRNAs as biomarkers of reproductive and metabolic states in fish, a question that has received little attention. Plasma was collected throughout the reproductive cycle from rainbow trout females subjected to two different feeding levels to trigger contrasting metabolic states; ovarian fluid was sample at ovulation. Fluid samples were subjected to small RNA-seq analysis followed by quantitative PCR validation for a subset of promising c-miRNA biomarkers. A comprehensive miRNA repertoire, which was lacking in trout, was first established to allow subsequent analysis. We first showed that biological fluids miRNAomes are complex and encompass a high proportion of the overall species miRNAome. While sharing a high proportion of common miRNAs, plasma and ovarian fluid miRNAomes exhibited strong fluid-specific signatures. We further showed that the plasma miRNAome exhibited major significant changes depending on metabolic and reproductive state. We subsequently identified three (miR-1-1/2-3p, miR-133-a-1/2-3p and miR-206-3p) evolutionarily conserved muscle-specific miRNA that accumulate in the plasma in response to high feeding rates, making these myomiRs strong candidate biomarkers of active myogenesis. We also identified miR-202-5p as a candidate biomarker for reproductive success that could be used to predict ovulation and/or egg quality. These highly promising results reveal the high potential of c-miRNAs as physiologically relevant biomarkers and pave the way for the use of c-miRNAs for non-invasive phenotyping in various fish species.
Proteomic signature of the Dravet syndrome in the geneticScn1a-A1783V mouse model
Authors: Miljanovic Nina , Hauck Stefanie M. , van Dijk R. Maarten , Liberto Valentina Di , Rezaei Ali , Potschka Heidrun 
Published: April 2021

AbstractBackgroundDravet syndrome is a rare, severe pediatric epileptic encephalopathy associated with intellectual and motor disabilities. Proteomic profiling in a mouse model of Dravet syndrome can provide information about the molecular consequences of the genetic deficiency and about pathophysiological mechanisms developing during the disease course.MethodsA knock-in mouse model of Dravet syndrome withScn1ahaploinsufficiency was used for whole proteome, seizure and behavioral analysis. Hippocampal tissue was dissected from two-(prior to epilepsy manifestation) and four-(following epilepsy manifestation) week-old male mice and analyzed using LC-MS/MS with label-free quantification. Proteomic data sets were subjected to bioinformatic analysis including pathway enrichment analysis. The differential expression of selected proteins was confirmed by immunohistochemical staining.ResultsThe findings confirmed an increased susceptibility to hyperthermia-associated seizures, the development of spontaneous seizures, and behavioral alterations in the novelScn1a-A1873V mouse model of Dravet syndrome. As expected, proteomic analysis demonstrated more pronounced alterations following epilepsy manifestation. In particular, proteins involved in neurotransmitter dynamics, receptor and ion channel function, synaptic plasticity, astrogliosis, neoangiogenesis, and nitric oxide signaling showed a pronounced regulation in Dravet mice. Pathway enrichment analysis identified several significantly regulated pathways at the later time point, with pathways linked to synaptic transmission and glutamatergic signaling dominating the list.ConclusionIn conclusion, the whole proteome analysis in a mouse model of Dravet syndrome demonstrated complex molecular alterations in the hippocampus. Some of these alterations may have an impact on excitability or may serve a compensatory function, which, however, needs to be further confirmed by future investigations. The proteomic data indicate that, due to the molecular consequences of the genetic deficiency, the pathophysiological mechanisms may become more complex during the course of the disease. Resultantly, the management of Dravet syndrome may need to consider further molecular and cellular alterations. Ensuing functional follow-up studies, this data set may provide valuable guidance for the future development of novel therapeutic approaches.
Inositol Polyphosphate-5-phosphatase K (Inpp5k) enhances sprouting of corticospinal tract axons after CNS trauma
Authors: Kauer Sierra D. , Fink Kathren L. , Li Elizabeth H.F. , Evans Brian P. , Golan Noa , Cafferty William BJ 
Published: April 2021

ABSTRACTFailure of CNS neurons to mount a significant intrinsic growth response after trauma results in chronic functional deficits after spinal cord injury. Approaches to identify novel axon growth activators include transcriptional and repressor screening of embryonic cortical and retinal ganglion neuronsin vitro. These high throughput approaches have identified several candidates; however, their inability to comprehensively model the adult CNS has resulted in their exploitationin vivofailing to stimulate significant anatomical and functional gains. To identify novel cell autonomous axon growth activators while maintaining CNS complexity, we screened intact adult corticospinal neurons (CSNs) undergoing functional plasticity after unilateral pyramidotomy. RNA-seq of intact sprouting corticospinal tract (CST) axons showed an enrichment of genes in the 3-phosphoinositide degradation pathways, including six 5-phosphatases. We explored whether Inositol Polyphosphate-5-phosphatase K (Inpp5k) could enhance CST axon growth in clinical models of CNS trauma. Overexpression ofInpp5kin intact adult CSNs enhanced sprouting of intact CST terminals into the denervated cervical cord after pyramidotomy and cortical stroke lesion.Inpp5koverexpression also stimulated sprouting of CST axons in the cervical cord after acute and chronic severe thoracic spinal contusion. We show thatInpp5kstimulates axon growth by elevating the density of active cofilin in the cytosol of labile growth cones, thus stimulating actin polymerization and enhancing microtubule protrusion into distal filopodia. This study identifiesInpp5kas a novel CST growth activator and underscores the veracity of usingin vivotranscriptional screening to identify the next generation of cell autonomous factors capable of repairing the damaged CNS.SIGNIFICANCE STATEMENTNeurological recovery is limited after spinal cord injury as CNS neurons are incapable of self-repair post trauma.In vitroscreening strategies exploit the intrinsically high growth capacity of embryonic CNS neurons to identify novel axon growth activators. While promising candidates have been shown to stimulate axon growthin vivo, concomitant functional recovery remains incomplete. Using transcriptional profiling of intact adult corticospinal tract neurons undergoing functional plasticity, we identifiedInpp5kas a novel axon growth activator capable of stimulating CST axon growth after pyramidotomy, stroke and acute and chronic contusion injuries. These data support usingin vivoscreening approaches to identify novel axon growth activators.
Multiple generations of antibiotic exposure and isolation influence host fitness and the microbiome in a model zooplankton species
Authors: Cooper Reilly O. , Tjards Sarah , Rischling Jessica , Nguyen David T. , Cressler Clayton E. 
Published: April 2021

AbstractBackgroundChronic antibiotic exposure impacts host health through changes to the microbiome, increasing disease risk and reducing the functional repertoire of community members. The detrimental effects of antibiotic perturbation on microbiome structure and function after one host generation of exposure have been well-studied. However, much less is understood about the multigenerational effects of antibiotic exposure and how the microbiome may recover across host generations.ResultsIn this study, we examined microbiome composition and host fitness across five generations of exposure to a suite of three antibiotics in the model zooplankton hostDaphnia magna. By utilizing a split-brood design where half of the offspring from antibiotic-exposed parents were allowed to recover and half were maintained in antibiotics, we aimed to examine recovery and resilience of the microbiome. Unexpectedly, we discovered that experimental isolation of single host individuals across generations also exerted a strong effect on microbiome composition, with composition becoming less diverse over generations regardless of treatment. Simultaneously,Daphnia magnabody size and cumulative reproduction increased across generations while survival decreased. Though antibiotics did cause substantial changes to microbiome composition, the microbiome generally became similar to the no antibiotic control treatment within one generation of recovery no matter how many prior generations were spent in antibiotics.ConclusionsContrary to results found in vertebrate systems,Daphnia magnamicrobiome composition recovers quickly after antibiotic exposure. However, our results suggest that the isolation of individual hosts leads to the stochastic extinction of rare taxa in the microbiome, indicating that these taxa are likely maintained via transmission in host populations rather than intrinsic mechanisms. This may explain the intriguing result that microbiome diversity loss increased host fitness.
Real time observation of chaperone-modulated talin mechanics with single molecule resolution
Authors: Chakraborty Soham , Chaudhuri Deep , Banerjee Souradeep , Bhatt Madhu , Haldar Shubhasis 
Published: April 2021

AbstractRecent single-molecule studies have recognized talin as a mechanosensitive hub in focal adhesion, where its function is strongly regulated by mechanical force. For instance, at low force (below 5 pN), folded talin binds RIAM for integrin activation; whereas at high force (above 5 pN), it unfolds to activate vinculin binding for focal adhesion stabilization. Being a cytoplasmic protein, talin might interact with several cytosolic chaperones: however, the role of chaperones in talin mechanics is unknown.To address this question, we investigated the force response of a mechanically stable talin domain with a set of well-known holdase (DnaJ, DnaK, Hsp70, and Hsp40) and foldase (DnaKJE, DsbA) chaperones, using single-molecule magnetic tweezers. Our findings demonstrate that chaperone could affect adhesion proteins stability by changing their folding mechanics; while holdase chaperones reduce their unfolding force to ∼6 pN, foldase chaperones shift it up to ∼15 pN. Since talin is mechanically synced within 2 pN force ranges, these changes are significant in cellular condition. Furthermore, we determined the fundamental mechanism of this altered mechanical stability, where chaperones directly reshape their energy landscape: unfoldase chaperone (DnaK) decreases the unfolding barrier height from 26.8 to 21.7 kBT, while foldase chaperone (DsbA) increases it to 33.5 kBT. We reconciled our observations with eukaryotic Hsp70 and Hsp40 chaperones and observed their similar function of decreasing the talin unfolding barrier to 23.1 kBT. The quantitative mapping of this chaperone-induced talin folding landscape directly illustrates that chaperones perturb the adhesion protein stability under physiological force, thereby influencing their force-dependent interactions and adhesion dynamics.