bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional annotation of breast cancer risk loci: current progress and future directions
Authors: Romualdo Cardoso Shirleny , Gillespie Andrea , Haider Syed , Fletcher Olivia 
Published: November 2021

AbstractGenome-wide association studies coupled with large-scale replication and fine-scale mapping studies have identified more than 150 genomic regions that are associated with breast cancer risk. Here, we review efforts to translate these findings into a greater understanding of disease mechanism. Our review comes in the context of a recently published fine-scale mapping analysis of these regions, which reported 352 independent signals and a total of 13,367 credible causal variants. The vast majority of credible causal variants map to noncoding DNA, implicating regulation of gene expression as the mechanism by which functional variants influence risk. Accordingly, we review methods for defining candidate-regulatory sequences, methods for identifying putative target genes and methods for linking candidate-regulatory sequences to putative target genes. We provide a summary of available data resources and identify gaps in these resources. We conclude that while much work has been done, there is still much to do. There are, however, grounds for optimism; combining statistical data from fine-scale mapping with functional data that are more representative of the normal “at risk” breast, generated using new technologies, should lead to a greater understanding of the mechanisms that influence an individual woman’s risk of breast cancer.
Dihydroartemisinin is potential therapeutics for treating late-stage CRC by targeting the elevated c-Myc level
Authors: Hu Xianjing , Fatima Sarwat , Chen Minting , Huang Tao , Chen Yuen Wa , Gong Ruihong , Wong Hoi Leong Xavier , Yu Rongmin , Song Liyan , Kwan Hiu Yee , Bian Zhaoxiang 
Published: November 2021

AbstractCurrently, no frontline treatment is effective for the late-stage colorectal cancer (CRC). Understanding the molecular differences in different stages of CRC can help us to identify the critical therapeutic targets for designing therapeutic strategy. Our data show that c-Myc protein is highly expressed in late-stage CRC when compared with early-stage CRC in both clinical samples and in cell lines representing different cancer stages. Given that c-Myc is a well-known oncogenic driver in CRC, its high expression in the late-stage CRC may represent a critical therapeutic target for treating the cancer. Dihydroartemisinin treatment significantly increases c-Myc protein degradation and hence reduces its expression in CRC. The treatment also reduces CRC cell viability. Interestingly, dihydroartemisinin exhibits a more potent growth-inhibitory effect in late-stage CRC than the early-stage CRC. The treatment also possesses potent growth-inhibitory effects in mouse models bearing c-Myc-overexpressed CRC. The reduced c-Myc level and its reduced transcriptional activity reduce the expressions of acetyl-CoA carboxylase, fatty acid synthase, carnitine–palmitoyltransferase-1, and medium-chain acyl-CoA dehydrogenase in the cancer cells. Lipidomics study also shows that dihydroartemisinin treatment changes the metabolic phenotypes in CRC, reduces oxygen consumption, respiration, and ATP production, hence reduces the cell proliferation and induces apoptosis. Our study provides strong pharmacological evidence to support the translation of dihydroartemisinin for the treatment of late-stage CRC by targeting c-Myc.
Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma
Authors: Zeng Huishan , Yang Huiru , Song Yifan , Fang Dong , Chen Liang , Zhao Zhijun , Wang Chaojie , Xie Songqiang 
Published: November 2021

AbstractMetastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.
Mitigation potential of global ammonia emissions and related health impacts in the trade network
Authors: Ma Rong , Li Ke , Guo Yixin , Zhang Bo , Zhao Xueli , Linder Soeren , Guan ChengHe , Chen Guoqian , Gan Yujie , Meng Jing 
Published: November 2021

AbstractAmmonia (NH3) emissions, mainly from agricultural sources, generate substantial health damage due to the adverse effects on air quality. NH3 emission reduction strategies are still far from being effective. In particular, a growing trade network in this era of globalization offers untapped emission mitigation potential that has been overlooked. Here we show that about one-fourth of global agricultural NH3 emissions in 2012 are trade-related. Globally they induce 61 thousand PM2.5-related premature mortalities, with 25 thousand deaths associated with crop cultivation and 36 thousand deaths with livestock production. The trade-related health damage network is regionally integrated and can be characterized by three trading communities. Thus, effective cooperation within trade-dependent communities will achieve considerable NH3 emission reductions allowed by technological advancements and trade structure adjustments. Identification of regional communities from network analysis offers a new perspective on addressing NH3 emissions and is also applicable to agricultural greenhouse gas emissions mitigation.
BEAR reveals that increased fidelity variants can successfully reduce the mismatch tolerance of adenine but not cytosine base editors
Authors: Tálas András , Simon Dorottya A. , Kulcsár Péter I. , Varga Éva , Krausz Sarah L. , Welker Ervin 
Published: November 2021

AbstractAdenine and cytosine base editors (ABE, CBE) allow for precision genome engineering. Here, Base Editor Activity Reporter (BEAR), a plasmid-based fluorescent tool is introduced, which can be applied to report on ABE and CBE editing in a virtually unrestricted sequence context or to label base edited cells for enrichment. Using BEAR-enrichment, we increase the yield of base editing performed by nuclease inactive base editors to the level of the nickase versions while maintaining significantly lower indel background. Furthermore, by exploiting the semi-high-throughput potential of BEAR, we examine whether increased fidelity SpCas9 variants can be used to decrease SpCas9-dependent off-target effects of ABE and CBE. Comparing them on the same target sets reveals that CBE remains active on sequences, where increased fidelity mutations and/or mismatches decrease the activity of ABE. Our results suggest that the deaminase domain of ABE is less effective to act on rather transiently separated target DNA strands, than that of CBE explaining its lower mismatch tolerance.
Role of mutations and post-translational modifications in systemic AL amyloidosis studied by cryo-EM
Authors: Radamaker Lynn , Karimi-Farsijani Sara , Andreotti Giada , Baur Julian , Neumann Matthias , Schreiner Sarah , Berghaus Natalie , Motika Raoul , Haupt Christian , Walther Paul , Schmidt Volker , Huhn Stefanie , Hegenbart Ute , Schönland Stefan O. , Wiese Sebastian , Read Clarissa , Schmidt Matthias , Fändrich Marcus 
Published: November 2021

AbstractSystemic AL amyloidosis is a rare disease that is caused by the misfolding of immunoglobulin light chains (LCs). Potential drivers of amyloid formation in this disease are post-translational modifications (PTMs) and the mutational changes that are inserted into the LCs by somatic hypermutation. Here we present the cryo electron microscopy (cryo-EM) structure of an ex vivo λ1-AL amyloid fibril whose deposits disrupt the ordered cardiomyocyte structure in the heart. The fibril protein contains six mutational changes compared to the germ line and three PTMs (disulfide bond, N-glycosylation and pyroglutamylation). Our data imply that the disulfide bond, glycosylation and mutational changes contribute to determining the fibril protein fold and help to generate a fibril morphology that is able to withstand proteolytic degradation inside the body.
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Authors: Kumar Manish , Molkentine David , Molkentine Jessica , Bridges Kathleen , Xie Tongxin , Yang Liangpeng , Hefner Andrew , Gao Meng , Bahri Reshub , Dhawan Annika , Frederick Mitchell J. , Seth Sahil , Abdelhakiem Mohamed , Beadle Beth M. , Johnson Faye , Wang Jing , Shen Li , Heffernan Timothy , Sheth Aakash , Ferris Robert L. , Myers Jeffrey N. , Pickering Curtis R. , Skinner Heath D. 
Published: November 2021

AbstractDespite radiation forming the curative backbone of over 50% of malignancies, there are no genomically-driven radiosensitizers for clinical use. Herein we perform in vivo shRNA screening to identify targets generally associated with radiation response as well as those exhibiting a genomic dependency. This identifies the histone acetyltransferases CREBBP/EP300 as a target for radiosensitization in combination with radiation in cognate mutant tumors. Further in vitro and in vivo studies confirm this phenomenon to be due to repression of homologous recombination following DNA damage and reproducible using chemical inhibition of histone acetyltransferase (HAT), but not bromodomain function. Selected mutations in CREBBP lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain of function targeted by HAT inhibition. Additionally, mutations in CREBBP/EP300 are associated with recurrence following radiation in squamous cell carcinoma cohorts. These findings provide both a mechanism of resistance and the potential for genomically-driven treatment.
Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit
Authors: Choi Jung-Hwan , Horowitz Lauren Bayer , Ringstad Niels 
Published: November 2021

AbstractAt chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.
Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation
Authors: Liu Yuxuan , Gu Zhimin , Cao Hui , Kaphle Pranita , Lyu Junhua , Zhang Yuannyu , Hu Wenhuo , Chung Stephen S. , Dickerson Kathryn E. , Xu Jian 
Published: November 2021

AbstractCancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid lineage-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid neoplasms with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically deregulate gene expression. We integrate results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooperation at single-cell and single-gene levels, and identify GEM as a regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution at single-cell resolution in vivo.
Engineered osteoclasts as living treatment materials for heterotopic ossification therapy
Authors: Jin Wenjing , Lin Xianfeng , Pan Haihua , Zhao Chenchen , Qiu Pengcheng , Zhao Ruibo , Hu Zihe , Zhou Yanyan , Wu Haiyan , Chen Xiao , Ouyang Hongwei , Xie Zhijian , Tang Ruikang 
Published: November 2021

AbstractOsteoclasts (OCs), the only cells capable of remodeling bone, can demineralize calcium minerals biologically. Naive OCs have limitations for the removal of ectopic calcification, such as in heterotopic ossification (HO), due to their restricted activity, migration and poor adhesion to sites of ectopic calcification. HO is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these unexpected calcified plaques. In the present study, we develop a chemical approach to modify OCs with tetracycline (TC) to produce engineered OCs (TC-OCs) with an enhanced capacity for targeting and adhering to ectopic calcified tissue due to a broad affinity for calcium minerals. Unlike naive OCs, TC-OCs are able to effectively remove HO both in vitro and in vivo. This achievement indicates that HO can be reversed using modified OCs and holds promise for engineering cells as “living treatment agents” for cell therapy.
Ultrafast high-harmonic nanoscopy of magnetization dynamics
Authors: Zayko Sergey , Kfir Ofer , Heigl Michael , Lohmann Michael , Sivis Murat , Albrecht Manfred , Ropers Claus 
Published: November 2021

AbstractLight-induced magnetization changes, such as all-optical switching, skyrmion nucleation, and intersite spin transfer, unfold on temporal and spatial scales down to femtoseconds and nanometers, respectively. Pump-probe spectroscopy and diffraction studies indicate that spatio-temporal dynamics may drastically affect the non-equilibrium magnetic evolution. Yet, direct real-space magnetic imaging on the relevant timescales has remained challenging. Here, we demonstrate ultrafast high-harmonic nanoscopy employing circularly polarized high-harmonic radiation for real-space imaging of femtosecond magnetization dynamics. We map quenched magnetic domains and localized spin structures in Co/Pd multilayers with a sub-wavelength spatial resolution down to 16 nm, and strobosocopically trace the local magnetization dynamics with 40 fs temporal resolution. Our compact experimental setup demonstrates the highest spatio-temporal resolution of magneto-optical imaging to date. Facilitating ultrafast imaging with high sensitivity to chiral and linear dichroism, we envisage a wide range of applications spanning magnetism, phase transitions, and carrier dynamics.
Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression
Authors: Croucher Danielle C. , Richards Laura M. , Tsofack Serges P. , Waller Daniel , Li Zhihua , Wei Ellen Nong , Huang Xian Fang , Chesi Marta , Bergsagel P. Leif , Sebag Michael , Pugh Trevor J. , Trudel Suzanne 
Published: November 2021

AbstractMolecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*MYC myeloma mouse model. Using samples obtained from mice with serologically undetectable disease, we identify malignant cells as early as 30 weeks of age and show that these tumours contain subclonal copy number variations that persist throughout progression. We detect intratumoural heterogeneity driven by transcriptional variability during active disease and show that subclonal expression programs are enriched at different times throughout early disease. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. These findings therefore present a model of precursor progression in Vκ*MYC mice, nominate an adaptive mechanism important for myeloma survival, and highlight the need for single-cell analyses to understand the biological underpinnings of disease progression.
Pseudoknot length modulates the folding, conformational dynamics, and robustness of Xrn1 resistance of flaviviral xrRNAs
Authors: Niu Xiaolin , Sun Ruirui , Chen Zhifeng , Yao Yirong , Zuo Xiaobing , Chen Chunlai , Fang Xianyang 
Published: November 2021

AbstractTo understand how RNA dynamics is regulated and connected to its function, we investigate the folding, conformational dynamics and robustness of Xrn1 resistance of a set of flaviviral xrRNAs using SAXS, smFRET and in vitro enzymatic assays. Flaviviral xrRNAs form discrete ring-like 3D structures, in which the length of a conserved long-range pseudoknot (PK2) ranges from 2 bp to 7 bp. We find that xrRNAs’ folding, conformational dynamics and Xrn1 resistance are strongly correlated and highly Mg2+-dependent, furthermore, the Mg2+-dependence is modulated by PK2 length variations. xrRNAs with long PK2 require less Mg2+to stabilize their folding, exhibit reduced conformational dynamics and strong Xrn1 resistance even at low Mg2+, and tolerate mutations at key tertiary motifs at high Mg2+, which generally are destructive to xrRNAs with short PK2. These results demonstrate an unusual regulatory mechanism of RNA dynamics providing insights into the functions and future biomedical applications of xrRNAs.
Striping of orbital-order with charge-disorder in optimally doped manganites
Authors: Chen Wei-Tin , Wang Chin-Wei , Cheng Ching-Chia , Chuang Yu-Chun , Simonov Arkadiy , Bristowe Nicholas C. , Senn Mark S. 
Published: November 2021

AbstractThe phase diagrams of LaMnO3 perovskites have been intensely studied due to the colossal magnetoresistance (CMR) exhibited by compositions around the $${\frac{3}{8}}^{th}$$

3

8

t
h

doping level. However, phase segregation between ferromagnetic (FM) metallic and antiferromagnetic (AFM) insulating states, which itself is believed to be responsible for the colossal change in resistance under applied magnetic field, has prevented an atomistic-level understanding of the orbital ordered (OO) state at this doping level. Here, through the detailed crystallographic analysis of the phase diagram of a prototype system (AMn$${}_{3}^{A^{\prime} }$$

3

A

′

Mn$${}_{4}^{B}$$

4

B

O12), we show that the superposition of two distinct lattice modes gives rise to a striping of OO Jahn-Teller active Mn3+ and charge disordered (CD) Mn3.5+ layers in a 1:3 ratio. This superposition only gives a cancellation of the Jahn-Teller-like displacements at the critical doping level. This striping of CD Mn3.5+ with Mn3+ provides a natural mechanism though which long range OO can melt, giving way to a conducting state.
Structural library and visualization of endogenously oxidized phosphatidylcholines using mass spectrometry-based techniques
Authors: Matsuoka Yuta , Takahashi Masatomo , Sugiura Yuki , Izumi Yoshihiro , Nishiyama Kazuhiro , Nishida Motohiro , Suematsu Makoto , Bamba Takeshi , Yamada Ken-ichi 
Published: November 2021

AbstractAlthough oxidized phosphatidylcholines (oxPCs) play critical roles in numerous pathological events, the type and production sites of endogenous oxPCs remain unknown because of the lack of structural information and dedicated analytical methods. Herein, a library of 465 oxPCs is constructed using high-resolution mass spectrometry-based non-targeted analytical methods and employed to detect 70 oxPCs in mice with acetaminophen-induced acute liver failure. We show that doubly oxygenated polyunsaturated fatty acid (PUFA)-PCs (PC PUFA;O2), containing epoxy and hydroxide groups, are generated in the early phase of liver injury. Hybridization with in-vivo 18O labeling and matrix-assisted laser desorption/ionization-tandem MS imaging reveals that PC PUFA;O2 are accumulated in cytochrome P450 2E1-expressing and glutathione-depleted hepatocytes, which are the major sites of liver injury. The developed library and visualization methodology should facilitate the characterization of specific lipid peroxidation events and enhance our understanding of their physiological and pathological significance in lipid peroxidation-related diseases.
Insecticide resistance by a host-symbiont reciprocal detoxification
Authors: Sato Yuya , Jang Seonghan , Takeshita Kazutaka , Itoh Hideomi , Koike Hideaki , Tago Kanako , Hayatsu Masahito , Hori Tomoyuki , Kikuchi Yoshitomo 
Published: November 2021

AbstractInsecticide resistance is one of the most serious problems in contemporary agriculture and public health. Although recent studies revealed that insect gut symbionts contribute to resistance, the symbiont-mediated detoxification process remains unclear. Here we report the in vivo detoxification process of an organophosphorus insecticide, fenitrothion, in the bean bug Riptortus pedestris. Using transcriptomics and reverse genetics, we reveal that gut symbiotic bacteria degrade this insecticide through a horizontally acquired insecticide-degrading enzyme into the non-insecticidal but bactericidal compound 3-methyl-4-nitrophenol, which is subsequently excreted by the host insect. This integrated “host-symbiont reciprocal detoxification relay” enables the simultaneous maintenance of symbiosis and efficient insecticide degradation. We also find that the symbiont-mediated detoxification process is analogous to the insect genome-encoded fenitrothion detoxification system present in other insects. Our findings highlight the capacity of symbiosis, combined with horizontal gene transfer in the environment, as a powerful strategy for an insect to instantly eliminate a toxic chemical compound, which could play a critical role in the human-pest arms race.