bluuebunny/crossref_metadata_2025_split huggingface dataset:
JAK2 unmutated erythrocytosis: current diagnostic approach and therapeutic views
Authors: Gangat Naseema , Szuber Natasha , Pardanani Animesh , Tefferi Ayalew 
Published: May 2021

AbstractJAK2unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g.,PHD2, HIF2A, VHL) or EPO signaling (e.g.,EPORmutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). “Idiopathic erythrocytosis” loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
Mitochondrial proteome of mouse oocytes and cisplatin-induced shifts in protein profile
Authors: Zhang Na , Sun An-di , Sun Si-man , Yang Rui , Shi Yan-yan , Wang Qi-long , Li Xin-yu , Ma Ji-hong , Yue Wei , Xie Bing-teng , Qiao Jie , Li Mo 
Published: May 2021

AbstractMitochondria are essential organelles that provide energy for mammalian cells and participate in multiple functions, such as signal transduction, cellular differentiation, and regulation of apoptosis. Compared with the mitochondria in somatic cells, oocyte mitochondria have an additional level of importance since they are required for germ cell maturation, dysfunction in which can lead to severe inherited disorders. Thus, a systematic proteomic profile of oocyte mitochondria is urgently needed to support the basic and clinical research, but the acquisition of such a profile has been hindered by the rarity of oocyte samples and technical challenges associated with capturing mitochondrial proteins from live oocytes. Here, in this work, using proximity labeling proteomics, we established a mitochondria-specific ascorbate peroxidase (APEX2) reaction in live GV-stage mouse oocytes and identified a total of 158 proteins in oocyte mitochondria. This proteome includes intrinsic mitochondrial structural and functional components involved in processes associated with “cellular respiration”, “ATP metabolism”, “mitochondrial transport”, etc. In addition, mitochondrial proteome capture after oocyte exposure to the antitumor chemotherapeutic cisplatin revealed differential changes in the abundance of several oocyte-specific mitochondrial proteins. Our study provides the first description of a mammalian oocyte mitochondrial proteome of which we are aware, and further illustrates the dynamic shifts in protein abundance associated with chemotherapeutic agents.
Qki activates Srebp2-mediated cholesterol biosynthesis for maintenance of eye lens transparency
Authors: Shin Seula , Zhou Hao , He Chenxi , Wei Yanjun , Wang Yunfei , Shingu Takashi , Zeng Ailiang , Wang Shaobo , Zhou Xin , Li Hongtao , Zhang Qiang , Mo Qinling , Long Jiafu , Lan Fei , Chen Yiwen , Hu Jian 
Published: May 2021

AbstractDefective cholesterol biosynthesis in eye lens cells is often associated with cataracts; however, how genes involved in cholesterol biosynthesis are regulated in lens cells remains unclear. Here, we show that Quaking (Qki) is required for the transcriptional activation of genes involved in cholesterol biosynthesis in the eye lens. At the transcriptome level, lens-specific Qki-deficient mice present downregulation of genes associated with the cholesterol biosynthesis pathway, resulting in a significant reduction of total cholesterol level in the eye lens. Mice with Qki depletion in lens epithelium display progressive accumulation of protein aggregates, eventually leading to cataracts. Notably, these defects are attenuated by topical sterol administration. Mechanistically, we demonstrate that Qki enhances cholesterol biosynthesis by recruiting Srebp2 and Pol II in the promoter regions of cholesterol biosynthesis genes. Supporting its function as a transcription co-activator, we show that Qki directly interacts with single-stranded DNA. In conclusion, we propose that Qki-Srebp2–mediated cholesterol biosynthesis is essential for maintaining the cholesterol level that protects lens from cataract development.
Sedimentary ancient DNA reveals a threat of warming-induced alpine habitat loss to Tibetan Plateau plant diversity
Authors: Liu Sisi , Kruse Stefan , Scherler Dirk , Ree Richard H. , Zimmermann Heike H. , Stoof-Leichsenring Kathleen R. , Epp Laura S. , Mischke Steffen , Herzschuh Ulrike 
Published: May 2021

AbstractStudies along elevational gradients worldwide usually find the highest plant taxa richness in mid-elevation forest belts. Hence, an increase in upper elevation diversity is expected in the course of warming-related treeline rise. Here, we use a time-series approach to infer past taxa richness from sedimentary ancient DNA from the south-eastern Tibetan Plateau over the last ~18,000 years. We find the highest total plant taxa richness during the cool phase after glacier retreat when the area contained extensive and diverse alpine habitats (14–10 ka); followed by a decline when forests expanded during the warm early- to mid-Holocene (10–3.6 ka). Livestock grazing since 3.6 ka promoted plant taxa richness only weakly. Based on these inferred dependencies, our simulation yields a substantive decrease in plant taxa richness in response to warming-related alpine habitat loss over the next centuries. Accordingly, efforts of Tibetan biodiversity conservation should include conclusions from palaeoecological evidence.
Diversity-oriented functionalization of 2-pyridones and uracils
Authors: Shang Yong , Wu Chenggui , Gao Qianwen , Liu Chang , Li Lisha , Zhang Xinping , Cheng Hong-Gang , Liu Shanshan , Zhou Qianghui 
Published: May 2021

AbstractHeterocycles 2-pyridone and uracil are privileged pharmacophores. Diversity-oriented synthesis of their derivatives is in urgent need in medicinal chemistry. Herein, we report a palladium/norbornene cooperative catalysis enabled dual-functionalization of iodinated 2-pyridones and uracils. The success of this research depends on the use of two unique norbornene derivatives as the mediator. Readily available alkyl halides/tosylates and aryl bromides are utilized as ortho-alkylating and -arylating reagents, respectively. Widely accessible ipso-terminating reagents, including H/DCO2Na, boronic acid/ester, terminal alkene and alkyne are compatible with this protocol. Thus, a large number of valuable 2-pyridone derivatives, including deuterium/CD3-labeled 2-pyridones, bicyclic 2-pyridones, 2-pyridone-fenofibrate conjugate, axially chiral 2-pyridone (97% ee), as well as uracil and thymine derivatives, can be quickly prepared in a predictable manner (79 examples reported), which will be very useful in new drug discovery.
Transcriptional signature in microglia associated with Aβ plaque phagocytosis
Authors: Grubman Alexandra , Choo Xin Yi , Chew Gabriel , Ouyang John F. , Sun Guizhi , Croft Nathan P. , Rossello Fernando J. , Simmons Rebecca , Buckberry Sam , Landin Dulce Vargas , Pflueger Jahnvi , Vandekolk Teresa H. , Abay Zehra , Zhou Yichen , Liu Xiaodong , Chen Joseph , Larcombe Michael , Haynes John M. , McLean Catriona , Williams Sarah , Chai Siew Yeen , Wilson Trevor , Lister Ryan , Pouton Colin W. , Purcell Anthony W. , Rackham Owen J. L. , Petretto Enrico , Polo Jose M. 
Published: May 2021

AbstractThe role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4+) and non-containing (XO4−) microglia from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories in ageing and AD mice. XO4+microglial transcriptomes demonstrated dysregulated expression of genes associated with late onset AD. We further showed that the transcriptional program associated with XO4+microglia from mice is present in a subset of human microglia isolated from brains of individuals with AD. XO4−microglia displayed transcriptional signatures associated with accelerated ageing and contained more intracellular post-synaptic material than XO4+microglia, despite reduced active synaptosome phagocytosis. We identified HIF1α as potentially regulating synaptosome phagocytosis in vitro using primary human microglia, and BV2 mouse microglial cells. Together, these findings provide insight into molecular mechanisms underpinning the functional diversity of microglia in AD.
Allostery through DNA drives phenotype switching
Authors: Rosenblum Gabriel , Elad Nadav , Rozenberg Haim , Wiggers Felix , Jungwirth Jakub , Hofmann Hagen 
Published: May 2021

AbstractAllostery is a pervasive principle to regulate protein function. Growing evidence suggests that also DNA is capable of transmitting allosteric signals. Yet, whether and how DNA-mediated allostery plays a regulatory role in gene expression remained unclear. Here, we show that DNA indeed transmits allosteric signals over long distances to boost the binding cooperativity of transcription factors. Phenotype switching in Bacillus subtilis requires an all-or-none promoter binding of multiple ComK proteins. We use single-molecule FRET to demonstrate that ComK-binding at one promoter site increases affinity at a distant site. Cryo-EM structures of the complex between ComK and its promoter demonstrate that this coupling is due to mechanical forces that alter DNA curvature. Modifications of the spacer between sites tune cooperativity and show how to control allostery, which allows a fine-tuning of the dynamic properties of genetic circuits.
High-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer
Authors: Pierce Sarah E. , Granja Jeffrey M. , Greenleaf William J. 
Published: May 2021

AbstractChromatin accessibility profiling can identify putative regulatory regions genome wide; however, pooled single-cell methods for assessing the effects of regulatory perturbations on accessibility are limited. Here, we report a modified droplet-based single-cell ATAC-seq protocol for perturbing and evaluating dynamic single-cell epigenetic states. This method (Spear-ATAC) enables simultaneous read-out of chromatin accessibility profiles and integrated sgRNA spacer sequences from thousands of individual cells at once. Spear-ATAC profiling of 104,592 cells representing 414 sgRNA knock-down populations reveals the temporal dynamics of epigenetic responses to regulatory perturbations in cancer cells and the associations between transcription factor binding profiles.
Sex as an important factor in nanomedicine
Authors: Hajipour Mohammah Javad , Aghaverdi Haniyeh , Serpooshan Vahid , Vali Hojatollah , Sheibani Sara , Mahmoudi Morteza 
Published: May 2021

AbstractNanomedicine has demonstrated substantial potential to improve the quality and efficacy of healthcare systems. Although the promise of nanomedicine to transform conventional medicine is evident, significant numbers of therapeutic nanomedicine products have failed in clinical trials. Most studies in nanomedicine have overlooked several important factors, including the significance of sex differences at various physiological levels. This report attempts to highlight the importance of sex in nanomedicine at cellular and molecular level. A more thorough consideration of sex physiology, among other critical variations (e.g., health status of individuals), would enable researchers to design and develop safer and more-efficient sex-specific diagnostic and therapeutic nanomedicine products.
Deep learning predicts cardiovascular disease risks from lung cancer screening low dose computed tomography
Authors: Chao Hanqing , Shan Hongming , Homayounieh Fatemeh , Singh Ramandeep , Khera Ruhani Doda , Guo Hengtao , Su Timothy , Wang Ge , Kalra Mannudeep K. , Yan Pingkun 
Published: May 2021

AbstractCancer patients have a higher risk of cardiovascular disease (CVD) mortality than the general population. Low dose computed tomography (LDCT) for lung cancer screening offers an opportunity for simultaneous CVD risk estimation in at-risk patients. Our deep learning CVD risk prediction model, trained with 30,286 LDCTs from the National Lung Cancer Screening Trial, achieves an area under the curve (AUC) of 0.871 on a separate test set of 2,085 subjects and identifies patients with high CVD mortality risks (AUC of 0.768). We validate our model against ECG-gated cardiac CT based markers, including coronary artery calcification (CAC) score, CAD-RADS score, and MESA 10-year risk score from an independent dataset of 335 subjects. Our work shows that, in high-risk patients, deep learning can convert LDCT for lung cancer screening into a dual-screening quantitative tool for CVD risk estimation.
Optimized CRISPR tools and site-directed transgenesis towards gene drive development in Culex quinquefasciatus mosquitoes
Authors: Feng Xuechun , López Del Amo Víctor , Mameli Enzo , Lee Megan , Bishop Alena L. , Perrimon Norbert , Gantz Valentino M. 
Published: May 2021

AbstractCulex mosquitoes are a global vector for multiple human and animal diseases, including West Nile virus, lymphatic filariasis, and avian malaria, posing a constant threat to public health, livestock, companion animals, and endangered birds. While rising insecticide resistance has threatened the control of Culex mosquitoes, advances in CRISPR genome-editing tools have fostered the development of alternative genetic strategies such as gene drive systems to fight disease vectors. However, though gene-drive technology has quickly progressed in other mosquitoes, advances have been lacking in Culex. Here, we develop a Culex-specific Cas9/gRNA expression toolkit and use site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We show that gRNA scaffold variants improve transgenesis efficiency in both Culex quinquefasciatus and Drosophila melanogaster and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.
Deep learning the structural determinants of protein biochemical properties by comparing structural ensembles with DiffNets
Authors: Ward Michael D. , Zimmerman Maxwell I. , Meller Artur , Chung Moses , Swamidass S. J. , Bowman Gregory R. 
Published: May 2021

AbstractUnderstanding the structural determinants of a protein’s biochemical properties, such as activity and stability, is a major challenge in biology and medicine. Comparing computer simulations of protein variants with different biochemical properties is an increasingly powerful means to drive progress. However, success often hinges on dimensionality reduction algorithms for simplifying the complex ensemble of structures each variant adopts. Unfortunately, common algorithms rely on potentially misleading assumptions about what structural features are important, such as emphasizing larger geometric changes over smaller ones. Here we present DiffNets, self-supervised autoencoders that avoid such assumptions, and automatically identify the relevant features, by requiring that the low-dimensional representations they learn are sufficient to predict the biochemical differences between protein variants. For example, DiffNets automatically identify subtle structural signatures that predict the relative stabilities of β-lactamase variants and duty ratios of myosin isoforms. DiffNets should also be applicable to understanding other perturbations, such as ligand binding.
The poleward enhanced Arctic Ocean cooling machine in a warming climate
Authors: Shu Qi , Wang Qiang , Song Zhenya , Qiao Fangli 
Published: May 2021

AbstractAs a cooling machine of the Arctic Ocean, the Barents Sea releases most of the incoming ocean heat originating from the North Atlantic. The related air-sea heat exchange plays a crucial role in both regulating the climate and determining the deep circulation in the Arctic Ocean and beyond. It was reported that the cooling efficiency of this cooling machine has decreased significantly. In this study, we find that the overall cooling efficiency did not really drop: When the cooling efficiency decreased in the southern Barents Sea, it increased in the northern Barents and Kara Seas, indicating that the cooling machine has expanded poleward. According to climate model projections, it is very likely that the cooling machine will continue to expand to the Kara Sea and then to the Arctic Basin in a warming climate. As a result, the Arctic Atlantification will be enhanced and pushed poleward in the future.
Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
Authors: Scott Erika N. , Wright Galen E. B. , Drögemöller Britt I. , Hasbullah Jafar S. , Gunaretnam Erandika P. , Miao Fudan , Bhavsar Amit P. , Shen Fei , Schneider Bryan P. , Carleton Bruce C. , Ross Colin J. D. 
Published: May 2021

AbstractAnthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = −4.30, P = 1.70 × 10−5), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10−3). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.
Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment
Authors: Wang Zhongju , Zhu Yongchang , Ye Linyan , Li Qiyang , Guo Bo , Zhao Hao , Bao Xiuqin , Zhuo Qiqi , Yang Tengfei , Li Zhaoqiang , Li Shufen , Hao Bingtao , Zhao Cunyou 
Published: May 2021

AbstractGenome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia.
Antibody avidity, persistence, and response to antigen recall: comparison of vaccine adjuvants
Authors: Budroni Sonia , Buricchi Francesca , Cavallone Andrea , Bourguignon Patricia , Caubet Magalie , Dewar Vincent , D’Oro Ugo , Finco Oretta , Garçon Nathalie , El Idrissi Mohamed , Janssens Michel , Leroux-Roels Geert , Marchant Arnaud , Schwarz Tino , Van Damme Pierre , Volpini Gianfranco , van der Most Robbert , Didierlaurent Arnaud M. , Burny Wivine 
Published: May 2021

AbstractDifferences in innate immune ‘imprinting’ between vaccine adjuvants may mediate dissimilar effects on the quantity/quality of persisting adaptive responses. We compared antibody avidity maturation, antibody/memory B cell/CD4+ T cell response durability, and recall responses to non-adjuvanted fractional-dose antigen administered 1-year post-immunization (Day [D]360), between hepatitis B vaccines containing Adjuvant System (AS)01B, AS01E, AS03, AS04, or Alum (NCT00805389). Both the antibody and B cell levels ranked similarly (AS01B/E/AS03 > AS04 > Alum) at peak response, at D360, and following their increases post-antigen recall (D390). Proportions of high-avidity antibodies increased post-dose 2 across all groups and persisted at D360, but avidity maturation appeared to be more strongly promoted by AS vs. Alum. Post-antigen recall, frequencies of subjects with high-avidity antibodies increased only markedly in the AS groups. Among the AS, total antibody responses were lowest for AS04. However, proportions of high-avidity antibodies were similar between groups, suggesting that MPL in AS04 contributes to avidity maturation. Specific combinations of immunoenhancers in the AS, regardless of their individual nature, increase antibody persistence and avidity maturation.