bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tracking human genes along the translational continuum
Authors: Lee Kyubum , Clyne Mindy , Yu Wei , Lu Zhiyong , Khoury Muin J. 
Published: October 2019

AbstractUnderstanding the drivers of research on human genes is a critical component to success of translation efforts of genomics into medicine and public health. Using publicly available curated online databases we sought to identify specific genes that are featured in translational genetic research in comparison to all genomics research publications. Articles in the CDC’s Public Health Genomics and Precision Health Knowledge Base were stratified into studies that have moved beyond basic research to population and clinical epidemiologic studies (T1: clinical and population human genome epidemiology research), and studies that evaluate, implement, and assess impact of genes in clinical and public health areas (T2+: beyond bench to bedside). We examined gene counts and numbers of publications within these phases of translation in comparison to all genes from Medline. We are able to highlight those genes that are moving from basic research to clinical and public health translational research, namely in cancer and a few genetic diseases with high penetrance and clinical actionability. Identifying human genes of translational value is an important step towards determining an evidence-based trajectory of the human genome in clinical and public health practice over time.
High-precision microbeam radiotherapy reveals testicular tissue-sparing effects for male fertility preservation
Authors: Fukunaga Hisanori , Kaminaga Kiichi , Sato Takuya , Butterworth Karl T. , Watanabe Ritsuko , Usami Noriko , Ogawa Takehiko , Yokoya Akinari , Prise Kevin M. 
Published: October 2019

AbstractMicrobeam radiotherapy (MRT) is based on a spatial fractionation of synchrotron X-ray microbeams at the microscale level. Although the tissue-sparing effect (TSE) in response to non-uniform radiation fields was recognized more than one century ago, the TSE of MRT in the testes and its clinical importance for preventing male fertility remain to be determined. In this study, using the combination of MRT techniques and a unique ex vivo testes organ culture, we show, for the first time, the MRT-mediated TSE for the preservation of spermatogenesis. Furthermore, our high-precision microbeam analysis revealed that the survival and potential migration steps of the non-irradiated germ stem cells in the irradiated testes tissue would be needed for the effective TSE for spermatogenesis. Our findings indicated the distribution of dose irradiated in the testes at the microscale level is of clinical importance for delivering high doses of radiation to the tumor, while still preserving male fertility.
The Intrinsic Enzyme Activities of the Classic Polyoxometalates
Authors: Zhang Boyu , Zhao Mingming , Qi Yanfei , Tian Rui , Carter Boye B. , Zou Hangjin , Zhang Chuhan , Wang Chunyan 
Published: October 2019

AbstractThe mimicking enzyme activities of eighteen classic POMs with different structures, Keggin (H3PW12O40, H4SiW12O40, H4GeW12O40, K4GeW12O40, H3PMo12O40, H4SiMo12O40and Eu3PMo12O40), Wells-Dawson (H6P2Mo18O62, α-(NH4)6P2W18O62and α-K6P2W18O62·14H2O), lacunary-Keggin (Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34] and K8[γ-SiW10O36]), the transition-metal substituted-type (α-1,2,3-K6H[SiW9V3O34] and H5PMo10V2O40), sandwich-type (K10P2W18Fe4(H2O)2O68) and an isopolyoxotungstate (Na10H2W12O42) were screened and compared. The mechanisms and reaction conditions of POMs with mimicking enzyme-like activities were also analyzed. The results shown that the structures, the hybrid atoms, the coordination atoms, the substituted metal atoms, pH and substrate are the effect factors for the enzyme mimic activities of POM. Among the eighteen POMs, H3PW12O40, H4SiW12O40, H4GeW12O40, α-(NH4)6P2W18O62, α-K6P2W18O62·14H2O, Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34], K8[γ-SiW10O36], K10P2W18Fe4(H2O)2O68and Na10H2W12O42had the peroxidase activities. Eu3PMo12O40, H3PMo12O40, H4SiMo12O40, α-1,2,3-K6H [SiW9V3O34], H6P2Mo18O62and H5PMo10V2O40showed the oxidase-like activities. K4GeW12O40did not show the peroxidase and oxidase activities. The Na8H[α-PW9O34], Na10[α-SiW9O34] and Na10[α-GeW9O34] showed intrinsic enzyme activities at alkaline conditions, which were different from other type of POMs. The sandwich-type K10P2W18Fe4(H2O)2O68displayed the strongest peroxidase activity, which is similar to natural horseradish peroxidase.
Synthesis of Magnesium- and Silicon-modified Hydroxyapatites by Microwave-Assisted Method
Authors: Rasskazova Liudmila A. , Zhuk Ilya V. , Korotchenko Natalia M. , Brichkov Anton S. , Chen Yu-Wen , Paukshtis Evgeniy A. , Ivanov Vladimir K. , Kurzina Irina A. , Kozik Vladimir V. 
Published: October 2019

AbstractNanopowders of hydroxyapatite (HA), modified by magnesium (MgHA) and by silicon (SiHA) were obtained by liquid-phase microwave synthesis method. X-ray diffraction and IR spectroscopy results showed that Mg2+ and SiO44− ions were present in the synthesized products both as secondary phases and as part of the HA phase. Whitlockite was found in the magnesium-modified HA (MgHA) and larnite was found in the silicon-modified HA (SiHA); ion substitution for both materials resulted in solid solutions. In the synthesized samples of modified HA, the increase of particle size of powders was in the order HA < SiHA < MgHA, which was calculated through data specific surface area and measured pycnometric density of the powders. The Lewis acid sites (Ca2+, Mg2+, Si4+) were present using spectral probes on the surface of the samples of HA, MgHA, and SiHA, and the acidity of these sites decreased in the order SiHA > MgHA > HA. The rates of calcium phosphate layer deposition on the surface of these materials at 37 °C in the model simulated body fluid solution showed similar dependence.
Imbalance in the response of pre- and post-synaptic components to amyloidopathy
Authors: Stephen Terri-Leigh , Tamagnini Francesco , Piegsa Judith , Sung Katherine , Harvey Joshua , Oliver-Evans Alice , Murray Tracey K. , Ahmed Zeshan , Hutton Michael L. , Randall Andrew , O’Neill Michael J. , Jackson Johanna S. 
Published: October 2019

AbstractAlzheimer’s disease (AD)-associated synaptic dysfunction drives the progression of pathology from its earliest stages. Amyloid β (Aβ) species, both soluble and in plaque deposits, have been causally related to the progressive, structural and functional impairments observed in AD. It is, however, still unclear how Aβ plaques develop over time and how they progressively affect local synapse density and turnover. Here we observed, in a mouse model of AD, that Aβ plaques grow faster in the earlier stages of the disease and if their initial area is >500 µm2; this may be due to deposition occurring in the outer regions of the plaque, the plaque cloud. In addition, synaptic turnover is higher in the presence of amyloid pathology and this is paralleled by a reduction in pre- but not post-synaptic densities. Plaque proximity does not appear to have an impact on synaptic dynamics. These observations indicate an imbalance in the response of the pre- and post-synaptic terminals and that therapeutics, alongside targeting the underlying pathology, need to address changes in synapse dynamics.
A CD146 FACS Protocol Enriches for Luminal Keratin 14/19 Double Positive Human Breast Progenitors
Authors: Ísberg Ólöf Gerdur , Kim Jiyoung , Fridriksdottir Agla J. , Morsing Mikkel , Timmermans-Wielenga Vera , Rønnov-Jessen Lone , Petersen Ole W. , Villadsen René 
Published: October 2019

AbstractHuman breast cancer is believed to arise in luminal progenitors within the normal breast. A subset of these are double positive (DP) for basal and luminal keratins and localizes to a putative stem cell zone within ducts. We here present a new protocol based on a combination of CD146 with CD117 and CD326 which provides an up to thirty fold enrichment of the DP cells. We show by expression profiling, colony formation, and morphogenesis that CD146high/CD117high/CD326high DP cells belong to a luminal progenitor compartment. While these DP cells are located quite uniformly in ducts, with age a variant type of DP (vDP) cells, which is mainly CD146-negative, accumulates in lobules. Intriguingly, in specimens with BRCA1 mutations known to predispose for cancer, higher frequencies of lobular vDP cells are observed. We propose that vDP cells are strong candidates for tracing the cellular origin of breast cancer.
CD44/CD133-Positive Colorectal Cancer Stem Cells are Sensitive to Trifluridine Exposure
Authors: Tsunekuni Kenta , Konno Masamitsu , Haraguchi Naotsugu , Koseki Jun , Asai Ayumu , Matsuoka Kazuaki , Kobunai Takashi , Takechi Teiji , Doki Yuichiro , Mori Masaki , Ishii Hideshi 
Published: October 2019

AbstractCancer stem cells (CSCs) are involved in metastatic colorectal cancer recurrence, but no effective therapy targeting these cells is currently available. Because trifluridine (FTD)/tipiracil therapy is used for refractory colorectal cancer, we sought to determine whether FTD is effective against CSC-like cells. CD44+CD133+high-expressing and other populations of human DLD-1 colon cancer cells were separately isolated through fluorescence-activated cell sorting. The sphere-forming activity of each population and the anti-sphere-forming effects of FTD and fluorouracil (5-FU) on CD44+CD133+cells were then measured. CD44+CD133+DLD-1 cells formed substantially more spheres than other cells. Moreover, treating CD44+CD133+DLD-1 cells with subtoxic concentrations of FTD (1 µM) inhibited sphere formation, and this was superior to the effect of subtoxic concentrations (1 µM) of 5-FU. The associated inhibition rates for FTD and 5-FU were 58.2% and 26.1%, respectively. Further, CD44+CD133+DLD-1 cells expressed higher levels of thymidine kinase 1, which is responsible for FTD phosphorylation, than DLD-1 cells, and FTD was incorporated into the DNA of CD44+CD133+DLD-1 cells. Thus, our data show that FTD treatment is effective against CSC-like cells and might be applied as CSC-targeting chemotherapy for tumor subtypes with high CD44 and CD133 expression.
High-resolution transcriptional profiling of Anopheles gambiae spermatogenesis reveals mechanisms of sex chromosome regulation
Authors: Taxiarchi Chrysanthi , Kranjc Nace , Kriezis Antonios , Kyrou Kyros , Bernardini Federica , Russell Steven , Nolan Tony , Crisanti Andrea , Galizi Roberto 
Published: October 2019

AbstractAlthough of high priority for the development of genetic tools to control malaria-transmitting mosquitoes, only a few germline-specific regulatory regions have been characterised to date and the presence of global regulatory mechanisms, such as dosage compensation and meiotic sex chromosome inactivation (MSCI), are mostly assumed from transcriptomic analyses of reproductive tissues or whole gonads. In such studies, samples include a significant portion of somatic tissues inevitably complicating the reconstruction of a defined transcriptional map of gametogenesis. By exploiting recent advances in transgenic technologies and gene editing tools, combined with fluorescence-activated cell sorting and RNA sequencing, we have separated four distinct cell lineages from the Anopheles gambiae male gonads: premeiotic, meiotic (primary and secondary spermatocytes) and postmeiotic. By comparing the overall expression levels of X-linked and autosomal genes across the four populations, we revealed a striking transcriptional repression of the X chromosome coincident with the meiotic phase, classifiable as MSCI, and highlighted genes that may evade silencing. In addition, chromosome-wide median expression ratios of the premeiotic population confirmed the absence of dosage compensation in the male germline. Applying differential expression analysis, we highlighted genes and transcript isoforms enriched at specific timepoints and reconstructed the expression dynamics of the main biological processes regulating the key stages of sperm development and maturation. We generated the first transcriptomic atlas of A. gambiae spermatogenesis that will expand the available toolbox for the genetic engineering of vector control technologies. We also describe an innovative and multidimensional approach to isolate specific cell lineages that can be used for the targeted analysis of other A. gambiae organs or transferred to other medically relevant species and model organisms.
Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model
Authors: Kim Tae Yun , Jeng Paul , Hwang JungMin , Pfeiffer Zachary , Patel Divyang , Cooper Leroy L , Kossidas Konstantinos , Centracchio Jason , Peng Xuwen , Koren Gideon , Qu Zhilin , Choi Bum-Rak 
Published: October 2019

AbstractThe initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.
Uncovering low-level mosaicism in human embryonic stem cells using high throughput single cell shallow sequencing
Authors: Keller Alexander , Tilleman Laurentijn , Dziedzicka Dominika , Zambelli Filippo , Sermon Karen , Van Nieuwerburgh Filip , Spits Claudia , Geens Mieke 
Published: October 2019

AbstractHuman pluripotent stem cells (hPSCs) have significant levels of low-grade genetic mosaicism, which commonly used techniques fail to detect in bulk DNA. These copy number variations remain a hurdle for the clinical translation of hPSC, as their effect in vivo ranges from unknown to dangerous, and the ability to detect them will be necessary as the field advances. As such there is need for techniques which can efficiently analyse genetic content in single cells with higher throughput and lower costs. We report here on the use of the Fluidigm C1 single cell WGA platform in combination with shallow whole genome sequencing to analyse the genetic content of single hPSCs. From a hPSC line carrying an isochromosome 20, 56 single cells were analysed and found to carry a total of 50 aberrations, across 23% of cells, which could not be detected by bulk analysis. Aberrations were predominantly segmental gains, with a fewer number of segmental losses and aneuploidies. Interestingly, 40% of the breakpoints seen here correspond to known DNA fragile sites. Our results therefore demonstrate the feasibility of single cell shallow sequencing of hPSC and further expand upon the biological importance and frequency of single cell mosaicism in hPSC.
A Predictor of Pathological Complete Response to Neoadjuvant Chemotherapy Stratifies Triple Negative Breast Cancer Patients with High Risk of Recurrence
Authors: Fournier Marcia V. , Goodwin Edward C. , Chen Joan , Obenauer John C. , Tannenbaum Susan H. , Brufsky Adam M. 
Published: October 2019

AbstractWe developed a test to predict which patients will achieve pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and which will have residual disease (RD). Gene expression data from pretreatment biopsies of patients with all breast cancer subtypes were combined into a 519-patient cohort containing 177 TNBC patients. Two RNA classifiers of 16 genes each were sequentially applied to the total cohort, classifying patients into 3 distinct classes. The test performance was further validated in an independent 304-patient cohort. The test accurately identified 70.5% (79/112) of pCR and 83.5% (340/407) of RD patients in the total population, and 75.0% (45/60) of pCR and 75.2% (88/117) of RD patients in the TNBC subset. For the independent cohort, the test identified 91.5% RD patients in the total population and 86.2% RD patients in the TNBC subset. However, the identification of pCR in both total and TNBC population are as low as 21.1% and 30%, respectively. The TNBC RD patients were subdivided by our classifiers, with one class showing significantly higher levels of Ki67 expression and having significantly poorer survival rates than the other classes. This stratification of patients may allow predicted residual disease classes to be assigned an alternative therapy.
A Super-Learner Model for Tumor Motion Prediction and Management in Radiation Therapy: Development and Feasibility Evaluation
Authors: Lin Hui , Zou Wei , Li Taoran , Feigenberg Steven J. , Teo Boon-Keng K. , Dong Lei 
Published: October 2019

AbstractIn cancer radiation therapy, large tumor motion due to respiration can lead to uncertainties in tumor target delineation and treatment delivery, thus making active motion management an essential step in thoracic and abdominal tumor treatment. In current practice, patients with tumor motion may be required to receive two sets of CT scans – the initial free-breathing 4-dimensional CT (4DCT) scan for tumor motion estimation and a second CT scan under appropriate motion management such as breath-hold or abdominal compression. The aim of this study is to assess the feasibility of a predictive model for tumor motion estimation in three-dimensional space based on machine learning algorithms. The model was developed based on sixteen imaging features extracted from non-4D diagnostic CT images and eleven clinical features extracted from the Electronic Health Record (EHR) database of 150 patients to characterize the lung tumor motion. A super-learner model was trained to combine four base machine learning models including the Random Forest, Multi-Layer Perceptron, LightGBM and XGBoost, the hyper-parameters of which were also optimized to obtain the best performance. The outputs of the super-learner model consist of tumor motion predictions in the Superior-Inferior (SI), Anterior-Posterior (AP) and Left-Right (LR) directions, and were compared against tumor motions measured in the free-breathing 4DCT scans. The accuracy of predictions was evaluated using Mean Absolute Error (MAE) and Root Mean Square Error (RMSE) through ten rounds of independent tests. The MAE and RMSE of predictions in the SI direction were 1.23 mm and 1.70 mm; the MAE and RMSE of predictions in the AP direction were 0.81 mm and 1.19 mm, and the MAE and RMSE of predictions in the LR direction were 0.70 mm and 0.95 mm. In addition, the relative feature importance analysis demonstrated that the imaging features are of great importance in the tumor motion prediction compared to the clinical features. Our findings indicate that a super-learner model can accurately predict tumor motion ranges as measured in the 4DCT, and could provide a machine learning framework to assist radiation oncologists in determining the active motion management strategy for patients with large tumor motion.
De novo transcriptome of Gymnema sylvestre identified putative lncRNA and genes regulating terpenoid biosynthesis pathway
Authors: Ayachit Garima , Shaikh Inayatullah , Sharma Preeti , Jani Bhavika , Shukla Labdhi , Sharma Priyanka , Bhairappanavar Shivarudrappa B. , Joshi Chaitanya , Das Jayashankar 
Published: October 2019

AbstractGymnema sylvestre is a highly valuable medicinal plant in traditional Indian system of medicine and used in many polyherbal formulations especially in treating diabetes. However, the lack of genomic resources has impeded its research at molecular level. The present study investigated functional gene profile of G. sylvestre via RNA sequencing technology. The de novo assembly of 88.9 million high quality reads yielded 23,126 unigenes, of which 18116 were annotated against databases such as NCBI nr database, gene ontology (GO), KEGG, Pfam, CDD, PlantTFcat, UniProt & GreeNC. Total 808 unigenes mapped to 78 different Transcription Factor families, whereas 39 unigenes assigned to CYP450 and 111 unigenes coding for enzymes involved in the biosynthesis of terpenoids including transcripts for synthesis of important compounds like Vitamin E, beta-amyrin and squalene. Among them, presence of six important enzyme coding transcripts were validated using qRT-PCR, which showed high expression of enzymes involved in methyl-erythritol phosphate (MEP) pathway. This study also revealed 1428 simple sequence repeats (SSRs), which may aid in molecular breeding studies. Besides this, 8 putative long non-coding RNAs (lncRNAs) were predicted from un-annotated sequences, which may hold key role in regulation of essential biological processes in G. sylvestre. The study provides an opportunity for future functional genomic studies and to uncover functions of the lncRNAs in G. sylvestre.
Anatomical Pathology of Subtle Lisfranc Injury
Authors: Haraguchi Naoki , Ota Koki , Ozeki Takuma , Nishizaka Shingo 
Published: October 2019

AbstractThe extent and patterns of Lisfranc joint complex disruption in subtle Lisfranc injuries have not been well clarified. We reviewed the direct intraoperative findings for 87 patients, examined computed tomography images that had been obtained preoperatively for 73 of the patients, and classified the injuries according to the Kaar et al. criteria as the transverse type (instability between the first cuneiform [C1] and the second metatarsal [M2] and between the second cuneiform [C2] and M2) or longitudinal type (instability between C1 and M2 and between C1 and C2). Our patients’ injuries were classified as follows: longitudinal type (38%), transverse type (30%), transverse type and first tarsometatarsal (TMT) joint injury (20%), longitudinal type plus transverse type (7%), longitudinal type and first TMT joint injury (3%), and longitudinal type, transverse type, and first TMT joint injury (2%). In 11 patients, the longitudinal injury extended into the naviculo-first cuneiform joint. In 41 (56%) of the 73 patients for whom CT images were obtained, 1 or more fractures (not counting small avulsion fragments between C1 and M2) were found. Orthopedic surgeons should be aware of the various injury patterns possible in cases of subtle Lisfranc injury.