bluuebunny/crossref_metadata_2025_split huggingface dataset:
Covariation of Slab Tracers, Volatiles, and Oxidation During Subduction Initiation
Authors: Brounce Maryjo , Reagan Mark K. , Kelley Katherine A. , Cottrell Elizabeth , Shimizu Kenji , Almeev Renat 
Published: May 2021

AbstractSubduction‐related lavas have higher Fe3+/∑Fe than midocean ridge basalts (MORB). Hypotheses for this offset include imprint from subducting slabs and differentiation in thickened crust. These ideas are readily tested through examination of the time‐dependent evolution of slab‐derived signatures, thickening crust of the overriding plate, and evolving redox during subduction initiation. Here, we present Fe3+/ΣFe and volatile element abundances of volcanic glasses recovered from International Ocean Discovery Program (IODP) Expedition 352 to the Izu‐Bonin‐Mariana (IBM) forearc. The samples include forearc basalts (FAB) that are stratigraphically overlain by low‐ and high‐silica boninite lavas. The FAB glasses have 0.18–0.85 wt% H2O, 75–233 ppm CO2, S contents controlled by saturation with a sulfide phase (602–1,386 ppm), Ba/La from 3.9‐10, and Fe3+/ΣFe ratios from 0.136 to 0.177. These compositions are similar to MORB and suggest that decompression melting of dry and reduced mantle dominates the earliest stages of subduction initiation. Low‐ and high‐silica boninite glasses have 1.51–3.19 wt% H2O, CO2 below detection, S contents below those required for sulfide saturation (5–235 ppm), Ba/La from 11 to 29, and Fe3+/∑Fe from 0.181 to 0.225. The compositions are broadly similar to modern arc lavas in the IBM arc. These data demonstrate that the establishment of fluid‐fluxed melting of the mantle, which occurs in just 0.6–1.2 my after subduction initiation, is synchronous with the production of oxidized, mantle‐derived magmas. The coherence of high Fe3+/∑Fe and Ba/La ratios with high H2O contents in Expedition 352 glasses and the modern IBM arc rocks strongly links the production of oxidized arc magmas to signatures of slab dehydration.
Do genetic risk scores for childhood adiposity operate independent of BMI of their mothers?
Authors: Huang Lam O. , Morgen Camilla S. , Ängquist Lars , Nohr Ellen A. , Kilpeläinen Tuomas O. , Hansen Torben , Sørensen Thorkild I. A. , Schnurr Theresia M. 
Published: May 2021

Abstract
Objectives
Genetic predisposition and maternal body mass index (BMI) are risk factors for childhood adiposity, defined by either BMI or overweight. We aimed to investigate whether childhood-specific genetic risk scores (GRSs) for adiposity-related traits are associated with childhood adiposity independent of maternal BMI, or whether the associations are modified by maternal BMI.

Methods
We constructed a weighted 26-SNP child BMI-GRS and a weighted 17-SNP child obesity-GRS in overall 1674 genotyped children within the Danish National Birth Cohort. We applied a case-cohort (N = 1261) and exposure-based cohort (N = 912) sampling design. Using logistic regression models we estimated associations of the GRSs and child overweight at age 7 years and examined if the GRSs influence child adiposity independent of maternal BMI (per standard deviation units).

Results
In the case-cohort design analysis, maternal BMI and the child GRSs were associated with increased odds for childhood overweight [OR for maternal BMI: 2.01 (95% CI: 1.86; 2.17), OR for child BMI-GRS: 1.56 (95% CI: 1.47; 1.66), and OR for child obesity-GRS 1.46 (95% CI: 1.37; 1.54)]. Adjustment for maternal BMI did not change the results, and there were no significant interactions between the GRSs and maternal BMI. However, in the exposure-based cohort design analysis, significant interactions between the child GRSs and maternal BMI on child overweight were observed, suggesting 0.85–0.87-fold attenuation on ORs of child overweight at higher values of maternal BMI and child GRS.

Conclusion
GRSs for childhood adiposity are strongly associated with childhood adiposity even when adjusted for maternal BMI, suggesting that the child-specific GRSs and maternal BMI contribute to childhood overweight independent of each other. However, high maternal BMI may attenuate the effects of child GRSs in children.
Final results of a phase 1b study of isatuximab short-duration fixed-volume infusion combination therapy for relapsed/refractory multiple myeloma
Authors: Usmani Saad Z. , Karanes Chatchada , Bensinger William I. , D’Souza Anita , Raje Noopur , Tuchman Sascha A. , Sborov Douglas , Laubach Jacob P. , Bianchi Giada , Kanagavel Dheepak , Saleem Rao , Dubin Franck , Campana Frank , Richardson Paul G. 
Published: May 2021

AbstractPart B of this phase 1b study (ClinicalTrials.gov number, NCT02283775) evaluated safety and efficacy of a fixed-volume infusion of isatuximab, an anti-CD38 monoclonal antibody, in combination with pomalidomide and dexamethasone (Pd) in relapsed/refractory multiple myeloma patients. Isatuximab (10 mg/kg weekly for 4 weeks, then every other week) was administered as a fixed-volume infusion of 250 mL (mL/h infusion rate) with standard doses of Pd on 28-day cycles. Patients (N = 47) had a median of three prior treatment lines (range, 1–8). Median duration of exposure was 36.9 weeks and median duration of first, second, and 3+ infusions were 3.7, 1.8, and 1.2 h, respectively. The most common non-hematologic treatment-emergent adverse events were fatigue (63.8%), infusion reactions (IRs), cough, and upper respiratory tract infection (40.4% each). IRs were all grade 2 and occurred only during the first infusion. The overall response rate was 53.2% in all patients (55.5% in response-evaluable population, 60.0% in daratumumab-naïve patients). Efficacy and safety findings were consistent with data from the isatuximab plus Pd infusion schedule in Part A of this study and also from the phase 3 ICARIA-MM study, and these new data confirm the safety, efficacy, and feasibility of fixed-volume infusion of isatuximab.
Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity
Authors: Wang Xiao-Lan , Kooijman Sander , Gao Yuanqing , Tzeplaeff Laura , Cosquer Brigitte , Milanova Irina , Wolff Samantha E. C. , Korpel Nikita , Champy Marie-France , Petit-Demoulière Benoit , Goncalves Da Cruz Isabelle , Sorg-Guss Tania , Rensen Patrick C. N. , Cassel Jean-Christophe , Kalsbeek Andries , Boutillier Anne-Laurence , Yi Chun-Xia 
Published: May 2021

AbstractMicroglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia–ischemia
Authors: Martinello Kathryn A. , Meehan Christopher , Avdic-Belltheus Adnan , Lingam Ingran , Mutshiya Tatenda , Yang Qin , Akin Mustafa Ali , Price David , Sokolska Magdalena , Bainbridge Alan , Hristova Mariya , Tachtsidis Ilias , Tann Cally J. , Peebles Donald , Hagberg Henrik , Wolfs Tim G. A. M. , Klein Nigel , Kramer Boris W. , Fleiss Bobbi , Gressens Pierre , Golay Xavier , Robertson Nicola J. 
Published: May 2021

Abstract
Background
Perinatal inflammation combined with hypoxia–ischemia (HI) exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown.

Methods
Twelve newborn piglets received a 2 µg/kg bolus and 1 µg/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 °C 1–25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured.

Results
Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT.

Conclusions
We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. Immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.

Impact

Acute infection/inflammation is known to exacerbate perinatal brain injury and can worsen the outcomes in neonatal encephalopathy.

Therapeutic HT is the current standard of care for all infants with NE, but the benefit in infants with coinfection/inflammation is unknown.

In a piglet model of inflammation (LPS)-sensitized HI, we observed no evidence of neuroprotection with cooling for 24 h, based on our primary outcome measures: aEEG, MRS Lac/NAA, and histological brain cell death.

Additional neuroprotective agents, with beneficial immunomodulatory effects, require exploration in IS-HI models.
PNO1 regulates autophagy and apoptosis of hepatocellular carcinoma via the MAPK signaling pathway
Authors: Han Zhiqiang , Liu Dongming , Chen Lu , He Yuchao , Tian Xiangdong , Qi Lisha , Chen Liwei , Luo Yi , Chen Ziye , Hu Xiaomeng , Li Guangtao , Zhan Linlin , Wang Yu , Li Qiang , Chen Peng , Liu Zhiyong , Guo Hua 
Published: May 2021

AbstractSome studies have reported that activated ribosomes are positively associated with malignant tumors, especially in hepatocellular carcinoma (HCC). The RNA-binding protein PNO1 is a critical ribosome rarely reported in human tumors. This study aimed to explore the molecular mechanisms of PNO1 in HCC. Using 150 formalin-fixed and paraffin-embedded samples and 8 fresh samples, we found high PNO1 expression in HCC tumor tissues through Western blotting and RT-PCR. Moreover, the higher PNO1 expression was associated with poor HCC prognosis patients. In vitro and in vivo experiments indicated that PNO1 overexpression promoted the proliferation and depressed the apoptosis of HCC cells. High PNO1 expression also increased the autophagy of HCC cells. The molecular mechanisms underlying PNO1 were examined by RNA-seq analysis and a series of functional experiments. Results showed that PNO1 promoted HCC progression through the MAPK signaling pathway. Therefore, PNO1 was overexpressed in HCC, promoted autophagy, and inhibited the apoptosis of HCC cells through the MAPK signaling pathway.
Nuclear exosome HMGB3 secreted by nasopharyngeal carcinoma cells promotes tumour metastasis by inducing angiogenesis
Authors: Zhang Kaiwen , Liu Dong , Zhao Jianmei , Shi Si , He Xin , Da Peng , You Yiwen , You Bo 
Published: May 2021

AbstractDistant metastasis accompanied by angiogenesis is the main cause of nasopharyngeal carcinoma (NPC)-related death. Nuclear exosomes (nEXOs) are potential tumour biomarkers. High mobility group box 3 (HMGB3), a nuclear protein, is known to be overexpressed in cancers. However, its role in NPC has not been elucidated. Here, we explore for the first time the function of nEXO HMGB3 in tumour angiogenesis involved in NPC metastasis using a series of in vitro experiments with NPC cell lines and clinical specimens and in vivo experiments with tumour xenograft zebrafish angiogenesis model. We found a high expression of HMGB3 in NPC, accompanied by the formation of micronuclei, to be associated with metastasis. Furthermore, the NPC-secreted HMGB3 expression was associated with tumour angiogenesis. Moreover, HMGB3-containing nEXOs, derived from the micronuclei of NPC cells, were ingested by the human umbilical vein endothelial cells (HUVECs), and accelerated angiogenesis in vitro and in vivo. Importantly, western blotting and flow cytometry analysis showed that circulating nEXO HMGB3 positively correlated with NPC metastasis. In summary, nEXO HMGB3 can be a significant biomarker of NPC metastasis and provide a novel basis for anti-angiogenesis therapy in clinical metastasis.
Ruler elements in chromatin remodelers set nucleosome array spacing and phasing
Authors: Oberbeckmann Elisa , Niebauer Vanessa , Watanabe Shinya , Farnung Lucas , Moldt Manuela , Schmid Andrea , Cramer Patrick , Peterson Craig L. , Eustermann Sebastian , Hopfner Karl-Peter , Korber Philipp 
Published: May 2021

AbstractArrays of regularly spaced nucleosomes dominate chromatin and are often phased by alignment to reference sites like active promoters. How the distances between nucleosomes (spacing), and between phasing sites and nucleosomes are determined remains unclear, and specifically, how ATP-dependent chromatin remodelers impact these features. Here, we used genome-wide reconstitution to probe how Saccharomyces cerevisiae ATP-dependent remodelers generate phased arrays of regularly spaced nucleosomes. We find that remodelers bear a functional element named the ‘ruler’ that determines spacing and phasing in a remodeler-specific way. We use structure-based mutagenesis to identify and tune the ruler element residing in the Nhp10 and Arp8 modules of the INO80 remodeler complex. Generally, we propose that a remodeler ruler regulates nucleosome sliding direction bias in response to (epi)genetic information. This finally conceptualizes how remodeler-mediated nucleosome dynamics determine stable steady-state nucleosome positioning relative to other nucleosomes, DNA bound factors, DNA ends and DNA sequence elements.
Impact of DNA methylation on 3D genome structure
Authors: Buitrago Diana , Labrador Mireia , Arcon Juan Pablo , Lema Rafael , Flores Oscar , Esteve-Codina Anna , Blanc Julie , Villegas Nuria , Bellido David , Gut Marta , Dans Pablo D. , Heath Simon C. , Gut Ivo G. , Brun Heath Isabelle , Orozco Modesto 
Published: May 2021

AbstractDetermining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases inSaccharomyces cerevisiaeand analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.
High proliferation and delamination during skin epidermal stratification
Authors: Damen Mareike , Wirtz Lisa , Soroka Ekaterina , Khatif Houda , Kukat Christian , Simons Benjamin D. , Bazzi Hisham 
Published: May 2021

AbstractThe development of complex stratified epithelial barriers in mammals is initiated from single-layered epithelia. How stratification is initiated and fueled are still open questions. Previous studies on skin epidermal stratification suggested a central role for perpendicular/asymmetric cell division orientation of the basal keratinocyte progenitors. Here, we use centrosomes, that organize the mitotic spindle, to test whether cell division orientation and stratification are linked. Genetically ablating centrosomes from the developing epidermis leads to the activation of the p53-, 53BP1- and USP28-dependent mitotic surveillance pathway causing a thinner epidermis and hair follicle arrest. The centrosome/p53-double mutant keratinocyte progenitors significantly alter their division orientation in the later stages without majorly affecting epidermal differentiation. Together with time-lapse imaging and tissue growth dynamics measurements, the data suggest that the first and major phase of epidermal development is boosted by high proliferation rates in both basal and suprabasally-committed keratinocytes as well as cell delamination, whereas the second phase maybe uncoupled from the division orientation of the basal progenitors. The data provide insights for tissue homeostasis and hyperproliferative diseases that may recapitulate developmental programs.
Retention time prediction using neural networks increases identifications in crosslinking mass spectrometry
Authors: Giese Sven H. , Sinn Ludwig R. , Wegner Fritz , Rappsilber Juri 
Published: May 2021

AbstractCrosslinking mass spectrometry has developed into a robust technique that is increasingly used to investigate the interactomes of organelles and cells. However, the incomplete and noisy information in the mass spectra of crosslinked peptides limits the numbers of protein–protein interactions that can be confidently identified. Here, we leverage chromatographic retention time information to aid the identification of crosslinked peptides from mass spectra. Our Siamese machine learning model xiRT achieves highly accurate retention time predictions of crosslinked peptides in a multi-dimensional separation of crosslinked E. coli lysate. Importantly, supplementing the search engine score with retention time features leads to a substantial increase in protein–protein interactions without affecting confidence. This approach is not limited to cell lysates and multi-dimensional separation but also improves considerably the analysis of crosslinked multiprotein complexes with a single chromatographic dimension. Retention times are a powerful complement to mass spectrometric information to increase the sensitivity of crosslinking mass spectrometry analyses.
Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy
Authors: Bian Zhen , Shi Lei , Kidder Koby , Zen Ke , Garnett-Benson Charlie , Liu Yuan 
Published: May 2021

AbstractRadiotherapy (RT)-induced tumoricidal immunity is severely limited when tumors are well-established. Here, we report that depleting SIRPα on intratumoral macrophages augments efficacy of RT to eliminate otherwise large, treatment-resistant colorectal (MC38) and pancreatic (Pan02 and KPC) tumors, inducing complete abscopal remission and long-lasting humoral and cellular immunity that prevent recurrence. SIRPα-deficient macrophages activated by irradiated tumor-released DAMPs exhibit robust efficacy and orchestrate an anti-tumor response that controls late-stage tumors. Upon RT-mediated activation, intratumoral SIRPα-deficient macrophages acquire potent proinflammatory features and conduct immunogenic antigen presentation that confer a tumoricidal microenvironment highly infiltrated by tumor-specific cytotoxic T cells, NK cells and inflammatory neutrophils, but with limited immunosuppressive regulatory T cells, myeloid derived suppressor cells and post-radiation wound-healing. The results demonstrate that SIRPα is a master regulator underlying tumor resistance to RT and provide proof-of-principle for SIRPα-deficient macrophage-based therapies to treat a broad spectrum of cancers, including those at advanced stages with low immunogenicity and metastases.
A deep learning system for detecting diabetic retinopathy across the disease spectrum
Authors: Dai Ling , Wu Liang , Li Huating , Cai Chun , Wu Qiang , Kong Hongyu , Liu Ruhan , Wang Xiangning , Hou Xuhong , Liu Yuexing , Long Xiaoxue , Wen Yang , Lu Lina , Shen Yaxin , Chen Yan , Shen Dinggang , Yang Xiaokang , Zou Haidong , Sheng Bin , Jia Weiping 
Published: May 2021

AbstractRetinal screening contributes to early detection of diabetic retinopathy and timely treatment. To facilitate the screening process, we develop a deep learning system, named DeepDR, that can detect early-to-late stages of diabetic retinopathy. DeepDR is trained for real-time image quality assessment, lesion detection and grading using 466,247 fundus images from 121,342 patients with diabetes. Evaluation is performed on a local dataset with 200,136 fundus images from 52,004 patients and three external datasets with a total of 209,322 images. The area under the receiver operating characteristic curves for detecting microaneurysms, cotton-wool spots, hard exudates and hemorrhages are 0.901, 0.941, 0.954 and 0.967, respectively. The grading of diabetic retinopathy as mild, moderate, severe and proliferative achieves area under the curves of 0.943, 0.955, 0.960 and 0.972, respectively. In external validations, the area under the curves for grading range from 0.916 to 0.970, which further supports the system is efficient for diabetic retinopathy grading.
Robust learning from noisy, incomplete, high-dimensional experimental data via physically constrained symbolic regression
Authors: Reinbold Patrick A. K. , Kageorge Logan M. , Schatz Michael F. , Grigoriev Roman O. 
Published: May 2021

AbstractMachine learning offers an intriguing alternative to first-principle analysis for discovering new physics from experimental data. However, to date, purely data-driven methods have only proven successful in uncovering physical laws describing simple, low-dimensional systems with low levels of noise. Here we demonstrate that combining a data-driven methodology with some general physical principles enables discovery of a quantitatively accurate model of a non-equilibrium spatially extended system from high-dimensional data that is both noisy and incomplete. We illustrate this using an experimental weakly turbulent fluid flow where only the velocity field is accessible. We also show that this hybrid approach allows reconstruction of the inaccessible variables – the pressure and forcing field driving the flow.