bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TIP60-ATM axis regulates replication fork stability in BRCA-deficient cells
Authors: Schleicher Emily M. , Dhoonmoon Ashna , Jackson Lindsey M. , Khatib Jude B. , Nicolae Claudia M. , Moldovan George-Lucian 
Published: June 2022

AbstractMaintenance of replication fork stability is essential for genome preservation. Stalled replication forks can be reversed by translocases such as SMARCAL1, and unless protected through the activity of the BRCA pathway, are subsequently subjected to nucleolytic degradation. The ATM and ATR kinases are master regulators of the DNA damage response. ATM activation upon DNA damage is mediated by the acetyltransferase TIP60. Here, we show that the TIP60-ATM pathway promotes replication fork reversal by recruiting SMARCAL1 to stalled forks. This enables fork degradation in BRCA-deficient cells. We also show that this ATM activity is not shared by ATR. Moreover, we performed a series of genome-wide CRISPR knockout genetic screens to identify genetic determinants of the cellular sensitivity to ATM inhibition in wildtype and BRCA2-knockout cells, and validated the top hits from multiple screens. We provide a valuable list of common genes which regulate the response to multiple ATM inhibitors. Importantly, we identify a differential response of wildtype and BRCA2-deficient cells to these inhibitors. In BRCA2-knockout cells, DNA repair genes (including RAD17, MDC1, and USP28) were essential for survival upon ATM inhibitor treatment, which was not the case in wild-type cells. These findings may eventually help guide the way for rational deployment of ATM inhibitors in the clinic.
Dynamic metabolic interactions and trophic roles of human gut microbes identified using a minimal microbiome exhibiting ecological properties
Authors: Shetty Sudarshan A , Kostopoulos Ioannis , Geerlings Sharon Y , Smidt Hauke , de Vos Willem M , Belzer Clara 
Published: June 2022

AbstractMicrobe–microbe interactions in the human gut are influenced by host-derived glycans and diet. The high complexity of the gut microbiome poses a major challenge for unraveling the metabolic interactions and trophic roles of key microbes. Synthetic minimal microbiomes provide a pragmatic approach to investigate their ecology including metabolic interactions. Here, we rationally designed a synthetic microbiome termed Mucin and Diet based Minimal Microbiome (MDb-MM) by taking into account known physiological features of 16 key bacteria. We combined 16S rRNA gene-based composition analysis, metabolite measurements and metatranscriptomics to investigate community dynamics, stability, inter-species metabolic interactions and their trophic roles. The 16 species co-existed in the in vitro gut ecosystems containing a mixture of complex substrates representing dietary fibers and mucin. The triplicate MDb-MM’s followed the Taylor’s power law and exhibited strikingly similar ecological and metabolic patterns. The MDb-MM exhibited resistance and resilience to temporal perturbations as evidenced by the abundance and metabolic end products. Microbe-specific temporal dynamics in transcriptional niche overlap and trophic interaction network explained the observed co-existence in a competitive minimal microbiome. Overall, the present study provides crucial insights into the co-existence, metabolic niches and trophic roles of key intestinal microbes in a highly dynamic and competitive in vitro ecosystem.
Early-life stress exposure and large-scale covariance brain networks in extremely preterm-born infants
Authors: Lammertink Femke , van den Heuvel Martijn P. , Hermans Erno J. , Dudink Jeroen , Tataranno Maria L. , Benders Manon J. N. L. , Vinkers Christiaan H. 
Published: June 2022

AbstractThe stressful extrauterine environment following premature birth likely has far-reaching and persistent adverse consequences. The effects of early “third-trimester” ex utero stress on large-scale brain networks’ covariance patterns may provide a potential avenue to understand how early-life stress following premature birth increases risk or resilience. We evaluated the impact of early-life stress exposure (e.g., quantification of invasive procedures) on maturational covariance networks (MCNs) between 30 and 40 weeks of gestational age in 180 extremely preterm-born infants (<28 weeks of gestation; 43.3% female). We constructed MCNs using covariance of gray matter volumes between key nodes of three large-scale brain networks: the default mode network (DMN), executive control network (ECN), and salience network (SN). Maturational coupling was quantified by summating the number of within- and between-network connections. Infants exposed to high stress showed significantly higher SN but lower DMN maturational coupling, accompanied by DMN-SN decoupling. Within the SN, the insula, amygdala, and subthalamic nucleus all showed higher maturational covariance at the nodal level. In contrast, within the DMN, the hippocampus, parahippocampal gyrus, and fusiform showed lower coupling following stress. The decoupling between DMN-SN was observed between the insula/anterior cingulate cortex and posterior parahippocampal gyrus. Early-life stress showed longitudinal network-specific maturational covariance patterns, leading to a reprioritization of developmental trajectories of the SN at the cost of the DMN. These alterations may enhance the ability to cope with adverse stimuli in the short term but simultaneously render preterm-born individuals at a higher risk for stress-related psychopathology later in life.
Designed Ankyrin Repeat Proteins as a tool box for analyzing p63
Authors: Strubel Alexander , Münick Philipp , Chaikuad Apirat , Dreier Birgit , Schaefer Jonas , Gebel Jakob , Osterburg Christian , Tuppi Marcel , Schäfer Birgit , Knapp Stefan , Plückthun Andreas , Dötsch Volker 
Published: June 2022

AbstractThe function of the p53 transcription factor family is dependent on several folded domains. In addition to a DNA-binding domain, members of this family contain an oligomerization domain. p63 and p73 also contain a C-terminal Sterile α-motif domain. Inhibition of most transcription factors is difficult as most of them lack deep pockets that can be targeted by small organic molecules. Genetic knock-out procedures are powerful in identifying the overall function of a protein, but they do not easily allow one to investigate roles of individual domains. Here we describe the characterization of Designed Ankyrin Repeat Proteins (DARPins) that were selected as tight binders against all folded domains of p63. We determine binding affinities as well as specificities within the p53 protein family and show that DARPins can be used as intracellular inhibitors for the modulation of transcriptional activity. By selectively inhibiting DNA binding of the ΔNp63α isoform that competes with p53 for the same promoter sites, we show that p53 can be reactivated. We further show that inhibiting the DNA binding activity stabilizes p63, thus providing evidence for a transcriptionally regulated negative feedback loop. Furthermore, the ability of DARPins to bind to the DNA-binding domain and the Sterile α-motif domain within the dimeric-only and DNA-binding incompetent conformation of TAp63α suggests a high structural plasticity within this special conformation. In addition, the developed DARPins can also be used to specifically detect p63 in cell culture and in primary tissue and thus constitute a very versatile research tool for studying the function of p63.
Implementation of a combined CDK inhibition and arginine-deprivation approach to target arginine-auxotrophic glioblastoma multiforme cells
Authors: Riess Christin , del Moral Katharina , Fiebig Adina , Kaps Philipp , Linke Charlotte , Hinz Burkhard , Rupprecht Anne , Frank Marcus , Fiedler Tomas , Koczan Dirk , Troschke-Meurer Sascha , Lode Holger N. , Engel Nadja , Freitag Thomas , Classen Carl Friedrich , Maletzki Claudia 
Published: June 2022

AbstractConstitutive activation of cyclin-dependent kinases (CDKs) or arginine auxotrophy are hallmarks of Glioblastoma multiforme (GBM). The latter metabolic defect renders tumor cells vulnerable to arginine-depleting substances, such as arginine deiminase from Streptococcus pyogenes (SpyADI). Previously, we confirmed the susceptibility of patient-derived GBM cells towards SpyADI as well as CDK inhibitors (CDKis). To improve therapeutic effects, we here applied a combined approach based on SpyADI and CDKis (dinaciclib, abemaciclib). Three arginine-auxotrophic patient-derived GBM lines with different molecular characteristics were cultured in 2D and 3D and effects of this combined SpyADI/CDKi approach were analyzed in-depth. All CDKi/SpyADI combinations yielded synergistic antitumoral effects, especially when given sequentially (SEQ), i.e., CDKi in first-line and most pronounced in the 3D models. SEQ application demonstrated impaired cell proliferation, invasiveness, and viability. Mitochondrial impairment was demonstrated by increasing mitochondrial membrane potential and decreasing oxygen consumption rate and extracellular acidification rate after SpyADI/abemaciclib monotherapy or its combination regimens. The combined treatment even induced autophagy in target cells (abemaciclib/SpyADI > dinaciclib/SpyADI). By contrast, the unfolded protein response and p53/p21 induced senescence played a minor role. Transmission electron microscopy confirmed damaged mitochondria and endoplasmic reticulum together with increased vacuolization under CDKi mono- and combination therapy. SEQ-abemaciclib/SpyADI treatment suppressed the DSB repair system via NHEJ and HR, whereas SEQ-dinaciclib/SpyADI treatment increased γ-H2AX accumulation and induced Rad51/Ku80. The latter combination also activated the stress sensor GADD45 and β-catenin antagonist AXIN2 and induced expression changes of genes involved in cellular/cytoskeletal integrity. This study highlights the strong antitumoral potential of a combined arginine deprivation and CDK inhibition approach via complex effects on mitochondrial dysfunction, invasiveness as well as DNA-damage response. This provides a good starting point for further in vitro and in vivo proof-of-concept studies to move forward with this strategy.
Ct-OATP1B3 promotes high-grade serous ovarian cancer metastasis by regulation of fatty acid beta-oxidation and oxidative phosphorylation
Authors: Huang Yutang , Du Yan , Zheng Yujie , Wen Chunjie , Zou Hecun , Huang Jiafeng , Zhou Honghao , Zhao Hongbo , Wu Lanxiang 
Published: June 2022

AbstractHigh-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy mainly due to its extensive metastasis. Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a newly discovered splice variant of solute carrier organic anion transporter family member 1B3 (SLCO1B3), has been reported to be overexpressed in several types of cancer. However, the biological function of Ct-OATP1B3 remains largely unknown. Here, we reveal that Ct-OATP1B3 is overexpressed in HGSOC and promotes the metastasis of HGSOC in vivo and in vitro. Mechanically, Ct-OATP1B3 directly interacts with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), an RNA-binding protein, which results in enhancement of the mRNA stability and expression of carnitine palmitoyltransferase 1A (CPT1A) and NADH:Ubiquinone Oxidoreductase Subunit A2 (NDUFA2), leading to increased mitochondrial fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) activities. The increased FAO and OXPHOS activities further facilitate adenosine triphosphate (ATP) production and cellular lamellipodia formation, which is the initial step in the processes of tumor cell migration and invasion. Taken together, our study provides an insight into the function and underlying mechanism of Ct-OATP1B3 in HGSOC metastasis, and highlights Ct-OATP1B3 as a novel prognostic marker as well as therapeutic target in HGSOC.
Bioorthogonally activatable cyanine dye with torsion-induced disaggregation for in vivo tumor imaging
Authors: Zhang Xianghan , Gao Jingkai , Tang Yingdi , Yu Jie , Liew Si Si , Qiao Chaoqiang , Cao Yutian , Liu Guohuan , Fan Hongyu , Xia Yuqiong , Tian Jie , Pu Kanyi , Wang Zhongliang 
Published: June 2022

AbstractAdvancement of bioorthogonal chemistry in molecular optical imaging lies in expanding the repertoire of fluorophores that can undergo fluorescence signal changes upon bioorthogonal ligation. However, most available bioorthogonally activatable fluorophores only emit shallow tissue-penetrating visible light via an intramolecular charge transfer mechanism. Herein, we report a serendipitous “torsion-induced disaggregation (TIDA)” phenomenon in the design of near-infrared (NIR) tetrazine (Tz)-based cyanine probe. The TIDA of the cyanine is triggered upon Tz-transcyclooctene ligation, converting its heptamethine chain from S-trans to S-cis conformation. Thus, after bioorthogonal reaction, the tendency of the resulting cyanine towards aggregation is reduced, leading to TIDA-induced fluorescence enhancement response. This Tz-cyanine probe sensitively delineates the tumor in living mice as early as 5 min post intravenous injection. As such, this work discovers a design mechanism for the construction of bioorthogonally activatable NIR fluorophores and opens up opportunities to further exploit bioorthogonal chemistry in in vivo imaging.
Neuromorphic object localization using resistive memories and ultrasonic transducers
Authors: Moro Filippo , Hardy Emmanuel , Fain Bruno , Dalgaty Thomas , Clémençon Paul , De Prà Alessio , Esmanhotto Eduardo , Castellani Niccolò , Blard François , Gardien François , Mesquida Thomas , Rummens François , Esseni David , Casas Jérôme , Indiveri Giacomo , Payvand Melika , Vianello Elisa 
Published: June 2022

AbstractReal-world sensory-processing applications require compact, low-latency, and low-power computing systems. Enabled by their in-memory event-driven computing abilities, hybrid memristive-Complementary Metal-Oxide Semiconductor neuromorphic architectures provide an ideal hardware substrate for such tasks. To demonstrate the full potential of such systems, we propose and experimentally demonstrate an end-to-end sensory processing solution for a real-world object localization application. Drawing inspiration from the barn owl’s neuroanatomy, we developed a bio-inspired, event-driven object localization system that couples state-of-the-art piezoelectric micromachined ultrasound transducer sensors to a neuromorphic resistive memories-based computational map. We present measurement results from the fabricated system comprising resistive memories-based coincidence detectors, delay line circuits, and a full-custom ultrasound sensor. We use these experimental results to calibrate our system-level simulations. These simulations are then used to estimate the angular resolution and energy efficiency of the object localization model. The results reveal the potential of our approach, evaluated in orders of magnitude greater energy efficiency than a microcontroller performing the same task.
Simulated co-optimization of renewable energy and desalination systems in Neom, Saudi Arabia
Authors: Riera Jefferson A. , Lima Ricardo M. , Hoteit Ibrahim , Knio Omar 
Published: June 2022

AbstractThe interdependence between the water and power sectors is a growing concern as the need for desalination increases globally. Therefore, co-optimizing interdependent systems is necessary to understand the impact of one sector on another. We propose a framework to identify the optimal investment mix for a co-optimized water-power system and apply it to Neom, Saudi Arabia. Our results show that investment strategies that consider the co-optimization of both systems result in total cost savings for the power sector compared to independent approaches. Analysis results suggest that systems with higher shares of non-dispatchable renewables experience the most significant cost reductions.
A practical fluorosulfonylating platform via photocatalytic imidazolium-based SO2F radical reagent
Authors: Zhang Weigang , Li Heyin , Li Xiaojuan , Zou Zhenlei , Huang Mengjun , Liu Jiyang , Wang Xiaochen , Ni Shengyang , Pan Yi , Wang Yi 
Published: June 2022

AbstractSulfonyl fluorides are key components in the fields of chemical biology, materials science and drug discovery. In this line, the highly active SO2F radical has been employed for the construction of sulfonyl fluorides, but the utilization of gaseous ClSO2F as radical precursor is limited due to the tedious and hazardous preparation. Meanwhile, the synthesis of sulfonyl fluorides from inert SO2F2 gas through a fluorosulfonyl radical (·SO2F) process has met with inevitable difficulties due to the high homolytic bond dissociation energy of the S(VI)-F bond. Here we report a radical fluorosulfonylation strategy for the stereoselective synthesis of alkenyl sulfonyl fluorides and functional alkyl sulfonyl fluorides with an air-stable crystalline benzimidazolium fluorosulfonate cationic salt reagent. This bench-stable redox-active reagent offers a useful and operational protocol for the radical fluorosulfonylation of unsaturated hydrocarbons with good yield and high stereoselectivity, which can be further transformed into valuable functional SO2F moieties.
Daily precipitation dataset at 0.1° for the Yarlung Zangbo River basin from 2001 to 2015
Authors: Zhao Keke , Peng Dingzhi , Gu Yu , Pang Bo , Zhu Zhongfan 
Published: June 2022

AbstractIn order to obtain higher precision regional precipitation dataset in the Yarlung Zangbo River basin, two different schemes were proposed on the basis of the two most application potential satellite-based precipitation products, IMERG and CMORPH_BLD. The first method aimed to correct the positive error of IMERG based on high correlation (CC > 0.9) between IMERG and gauges. The second algorithm was developed to merge IMERG with CMORPH_BLD by the stepwise linear regression. As the reference, IMERG played a key role in correction of precipitation ratio determination and precipitation event detection. Two daily datasets with 0.1° resolution (BRD_IMERG and IGREA_IMERG-CMORPH) performed better than IMERG in CC, RMSE, ME, FAR and CSI, and streamflow simulation in the whole basin (NS: 0.86 and 0.87; RBIAS: −19% and −11%) and sub-basins. The two proposed methods were relatively simple and efficient for reconstructing higher precision regional precipitation, and the datasets provided a good application demonstration in the alpine region.
Possible role of insulin resistance in activation of plasma xanthine oxidoreductase in health check-up examinees
Authors: Kurajoh Masafumi , Fukumoto Shinya , Akari Seigo , Murase Takayo , Nakamura Takashi , Takahashi Kanae , Yoshida Hisako , Nakatani Shinya , Tsuda Akihiro , Morioka Tomoaki , Mori Katsuhito , Imanishi Yasuo , Hirata Kazuto , Emoto Masanori 
Published: June 2022

AbstractWe previously found an association of insulin resistance (IR) with plasma xanthine oxidoreductase (XOR) activity in a cross-sectional study. However, whether IR induces increased XOR activity has not been elucidated. This retrospective longitudinal observational study included 347 participants (173 males, 174 females) who underwent annual health examinations and were medication naïve. Homeostasis model assessment of IR (HOMA-IR) index, and physical and laboratory measurements were determined at the baseline. At baseline and 12-month follow-up examinations, plasma XOR activity was determined using our novel assay based on [13C2,15N2] xanthine and liquid chromatography/triple quadrupole mass spectrometry. Subjects with IR, defined as HOMA-IR index ≥ 1.7 (n = 92), exhibited significantly (p < 0.001) higher plasma XOR activity levels than those without IR (n = 255), with an increase in that activity seen in 180 (51.9%) after 12 months. Multivariable linear and logistic regression analyses showed that IR, but not BMI or waist circumference, at baseline was significantly associated with plasma XOR activity (β = 0.094,p = 0.033) and increased plasma XOR activity over the 12-month period (odds ratio, 1.986; 95% confidence interval, 1.048–3.761;p = 0.035), after adjustments for various clinical parameters, including plasma XOR activity at baseline. These results suggest that IR induces increased plasma XOR activity in a manner independent of adiposity.
Combining host and vector data informs emergence and potential impact of an Usutu virus outbreak in UK wild birds
Authors: Lawson Becki , Robinson Robert A. , Briscoe Andrew G. , Cunningham Andrew A. , Fooks Anthony R. , Heaver Joseph P. , Hernández-Triana Luis M. , John Shinto K. , Johnson Nicholas , Johnston Colin , Lean Fabian Z. X. , Macgregor Shaheed K. , Masters Nicholas J. , McCracken Fiona , McElhinney Lorraine M. , Medlock Jolyon M. , Pearce-Kelly Paul , Seilern-Moy Katharina , Spiro Simon , Vaux Alexander G. C. , Folly Arran J. 
Published: June 2022

AbstractFollowing the first detection in the United Kingdom of Usutu virus (USUV) in wild birds in 2020, we undertook a multidisciplinary investigation that combined screening host and vector populations with interrogation of national citizen science monitoring datasets to assess the potential for population impacts on avian hosts. Pathological findings from six USUV-positive wild passerines were non-specific, highlighting the need for molecular and immunohistochemical examinations to confirm infection. Mosquito surveillance at the index site identified USUV RNA in Culex pipiens s.l. following the outbreak. Although the Eurasian blackbird (Turdus merula) is most frequently impacted by USUV in Europe, national syndromic surveillance failed to detect any increase in occurrence of clinical signs consistent with USUV infection in this species. Furthermore, there was no increase in recoveries of dead blackbirds marked by the national ringing scheme. However, there was regional clustering of blackbird disease incident reports centred near the index site in 2020 and a contemporaneous marked reduction in the frequency with which blackbirds were recorded in gardens in this area, consistent with a hypothesis of disease-mediated population decline. Combining results from multidisciplinary schemes, as we have done, in real-time offers a model for the detection and impact assessment of future disease emergence events.
Rupture pressure values of cerebral arteries in the presence of unruptured intracranial aneurysm
Authors: Lombarski Leszek , Kunert Przemysław , Tarka Sylwia , Piechna Adam , Kujawski Sławomir , Marchel Andrzej 
Published: June 2022

AbstractCerebral arteries (CAs) are prone to the saccular aneurysm formation. Since aneurysms may be considered as balloon-like dilations of the locally weakened arterial wall, it should be determined whether the presence of intracranial aneurysm is related to the generalized weakening of CAs. Among 184 consecutive forensic autopsies, eight brains with a single unruptured saccular aneurysm were identified. Aneurysms with adjacent CAs and specific CA segments were excised, namely: the anterior communicating artery complex, and bifurcations of the basilar artery, internal carotid arteries, and middle cerebral arteries. Then, aneurysm and CA specimens were subjected to pressure-inflation tests until rupture occurred at the arterial bifurcation or at the wall of the CA or aneurysm. The same protocol was applied to the control group composed of CAs excised from eight brains without aneurysm. No significant differences were noted between the experimental and control groups, depending on the mean rupture pressure (1054 vs. 1048 mmHg) and rupture site (bifurcation vs. wall) of the analyzed specimens. These findings indicate that the presence of unruptured saccular aneurysm is not related to generalized weakening of CAs among autopsy subjects. Moreover, the CA bifurcations do not represent regions of decreased wall strength.