bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss-induced nonreciprocity
Authors: Huang Xinyao , Lu Cuicui , Liang Chao , Tao Honggeng , Liu Yong-Chun 
Published: February 2021

AbstractNonreciprocity is important in both optical information processing and topological photonics studies. Conventional principles for realizing nonreciprocity rely on magnetic fields, spatiotemporal modulation, or nonlinearity. Here we propose a generic principle for generating nonreciprocity by taking advantage of energy loss, which is usually regarded as harmful. The loss in a resonance mode induces a phase lag, which is independent of the energy transmission direction. When multichannel lossy resonance modes are combined, the resulting interference gives rise to nonreciprocity, with different coupling strengths for the forward and backward directions, and unidirectional energy transmission. This study opens a new avenue for the design of nonreciprocal devices without stringent requirements.
How machine-learning recommendations influence clinician treatment selections: the example of antidepressant selection
Authors: Jacobs Maia , Pradier Melanie F. , McCoy Thomas H. , Perlis Roy H. , Doshi-Velez Finale , Gajos Krzysztof Z. 
Published: February 2021

AbstractDecision support systems embodying machine learning models offer the promise of an improved standard of care for major depressive disorder, but little is known about how clinicians’ treatment decisions will be influenced by machine learning recommendations and explanations. We used a within-subject factorial experiment to present 220 clinicians with patient vignettes, each with or without a machine-learning (ML) recommendation and one of the multiple forms of explanation. We found that interacting with ML recommendations did not significantly improve clinicians’ treatment selection accuracy, assessed as concordance with expert psychopharmacologist consensus, compared to baseline scenarios in which clinicians made treatment decisions independently. Interacting with incorrect recommendations paired with explanations that included limited but easily interpretable information did lead to a significant reduction in treatment selection accuracy compared to baseline questions. These results suggest that incorrect ML recommendations may adversely impact clinician treatment selections and that explanations are insufficient for addressing overreliance on imperfect ML algorithms. More generally, our findings challenge the common assumption that clinicians interacting with ML tools will perform better than either clinicians or ML algorithms individually.
Metabolomics reveals biomarkers of opioid use disorder
Authors: Ghanbari Reza , Li Yuanyuan , Pathmasiri Wimal , McRitchie Susan , Etemadi Arash , Pollock Jonathan D. , Poustchi Hossein , Rahimi-Movaghar Afarin , Amin-Esmaeili Masoumeh , Roshandel Gholamreza , Shayanrad Amaneh , Abaei Behrouz , Malekzadeh Reza , Sumner Susan C. J. 
Published: February 2021

AbstractOpioid use disorder (OUD) is diagnosed using the qualitative criteria defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Diagnostic biomarkers for OUD do not currently exist. Our study focused on developing objective biological markers to differentiate chronic opiate users with OUD from chronic opiate users without OUD. Using biospecimens from the Golestan Cohort Study, we compared the metabolomics profiles of high opium users who were diagnosed as OUD positive with high opium users who were diagnosed as OUD negative. High opium use was defined as maximum weekly opium usage greater than or equal to the median usage (2.4 g per week), and OUD was defined as having 2 or more DSM-5 criteria in any 12-month period. Among the 218 high opium users in this study, 80 were diagnosed as OUD negative, while 138 were diagnosed as OUD positive. Seven hundred and twelve peaks differentiated high opium users diagnosed as OUD positive from high opium users diagnosed as OUD negative. Stepwise logistic regression modeling of subject characteristics data together with the 712 differentiating peaks revealed a signature that is 95% predictive of an OUD positive diagnosis, a significant (p < 0.0001) improvement over a 63% accurate prediction based on subject characteristic data for these samples. These results suggest that a metabolic profile can be used to predict an OUD positive diagnosis.
Functional network alterations differently associated with suicidal ideas and acts in depressed patients: an indirect support to the transition model
Authors: Wagner Gerd , Li Meng , Sacchet Matthew D. , Richard-Devantoy Stéphane , Turecki Gustavo , Bär Karl-Jürgen , Gotlib Ian H. , Walter Martin , Jollant Fabrice 
Published: February 2021

AbstractThe transition from suicidal ideas to a suicide act is an important topic of research for the identification of those patients at risk of acting out. We investigated here whether specific brain activity and connectivity measures at rest may be differently associated with suicidal thoughts and behaviors. A large sample of acutely depressed patients with major depressive disorder was recruited in three different centers (Montreal/Canada, Stanford/USA, and Jena/Germany), covering four different phenotypes: patients with a past history of suicide attempt (n = 53), patients with current suicidal ideas but no past history of suicide attempt (n = 40), patients without current suicidal ideation nor past suicide attempts (n = 42), and healthy comparison subjects (n = 107). 3-T resting-state functional magnetic resonance imaging (fMRI) measures of the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were obtained and examined in a whole-brain data-driven analysis. Past suicide attempt was associated with a double cortico-subcortical dissociation in ALFF values. Decreased ALFF and DC values mainly in a frontoparietal network and increased ALFF values in some subcortical regions (hippocampus and thalamus) distinguished suicide attempters from suicide ideators, patient controls, and healthy controls. No clear neural differences were identified in relation to suicidal ideas. Suicide attempters appear to be a distinct subgroup of patients with widespread brain alterations in functional activity and connectivity that could represent factors of vulnerability. Our results also indirectly support at the neurobiological level the relevance of the transition model described at the psychological and clinical levels. The brain bases of suicidal ideas occurrence in depressed individuals needs further investigations.
Cortical thinning and associated connectivity changes in patients with anorexia nervosa
Authors: de la Cruz Feliberto , Schumann Andy , Suttkus Stefanie , Helbing Nadin , Zopf Regine , Bär Karl-Jürgen 
Published: February 2021

AbstractStructural brain abnormalities are a consistent finding in anorexia nervosa (AN) and proposed as a state biomarker of the disorder. Yet little is known about how regional structural changes affect intrinsic resting-state functional brain connectivity (rsFC). Using a cross-sectional, multimodal imaging approach, we investigated the association between regional cortical thickness abnormalities and rsFC in AN. Twenty-two acute AN patients and twenty-six age- and gender-matched healthy controls underwent a resting-state functional magnetic resonance imaging scan and cognitive tests. We performed group comparisons of whole-brain cortical thickness, seed-based rsFC, and network-based statistical (NBS) analyses. AN patients showed cortical thinning in the precuneus and inferior parietal lobules, regions involved in visuospatial memory and imagery. Cortical thickness in the precuneus correlated with nutritional state and cognitive functions in AN, strengthening the evidence for a critical role of this region in the disorder. Cortical thinning was accompanied by functional connectivity reductions in major brain networks, namely default mode, sensorimotor and visual networks. Similar to the seed-based approach, the NBS analysis revealed a single network of reduced functional connectivity in patients, comprising mainly sensorimotor- occipital regions. Our findings provide evidence that structural and functional brain abnormalities in AN are confined to specific regions and networks involved in visuospatial and somatosensory processing. We show that structural changes of the precuneus are linked to nutritional and functional states in AN, and future longitudinal research should assess how precuneus changes might be related to the evolution of the disorder.
Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression
Authors: Rappl Peter , Rösser Silvia , Maul Patrick , Bauer Rebekka , Huard Arnaud , Schreiber Yannick , Thomas Dominique , Geisslinger Gerd , Jakobsson Per-Johan , Weigert Andreas , Brüne Bernhard , Schmid Tobias 
Published: February 2021

AbstractDespite the progress to understand inflammatory reactions, mechanisms causing their resolution remain poorly understood. Prostanoids, especially prostaglandin E2(PGE2), are well-characterized mediators of inflammation. PGE2is produced in an inducible manner in macrophages (Mϕ) by microsomal PGE2-synthase-1 (mPGES-1), with the notion that it also conveys pro-resolving properties. We aimed to characterize the role of mPGES-1 during resolution of acute, zymosan-induced peritonitis. Experimentally, we applied the mPGES-1 inhibitor compound III (CIII) once the inflammatory response was established and confirmed its potent PGE2-blocking efficacy. mPGES-1 inhibition resulted in an incomplete removal of neutrophils and a concomitant increase in monocytes and Mϕ during the resolution process. The mRNA-seq analysis identified enhanced C-X3-C motif receptor 1 (CX3CR1) expression in resident and infiltrating Mϕ upon mPGES-1 inhibition. Besides elevatedCx3cr1expression, its ligand CX3CL1 was enriched in the peritoneal lavage of the mice, produced by epithelial cells upon mPGES-1 inhibition. CX3CL1 not only increased adhesion and survival of Mϕ but its neutralization also completely reversed elevated inflammatory cell numbers, thereby normalizing the cellular, peritoneal composition during resolution. Our data suggest that mPGES-1-derived PGE2contributes to the resolution of inflammation by preventing CX3CL1-mediated retention of activated myeloid cells at sites of injury.
Overexpressed P75CUX1 promotes EMT in glioma infiltration by activating β-catenin
Authors: Xu Anqi , Wang Xizhao , Luo Jie , Zhou Mingfeng , Yi Renhui , Huang Tengyue , Lin Jie , Wu Zhiyong , Xie Cheng , Ding Shengfeng , Zeng Yu , Song Ye 
Published: February 2021

AbstractThe homeobox protein cut-like 1 (CUX1) comprises three isoforms and has been shown to be involved in the development of various types of malignancies. However, the expression and role of the CUX1 isoforms in glioma remain unclear. Herein, we first identified that P75CUX1 isoform exhibited consistent expression among three isoforms in glioma with specifically designed antibodies to identify all CUX1 isoforms. Moreover, a significantly higher expression of P75CUX1 was found in glioma compared with non-tumor brain (NB) tissues, analyzed with western blot and immunohistochemistry, and the expression level of P75CUX1 was positively associated with tumor grade. In addition, Kaplan–Meier survival analysis indicated that P75CUX1 could serve as an independent prognostic indicator to identify glioma patients with poor overall survival. Furthermore, CUX1 knockdown suppressed migration and invasion of glioma cells both in vitro and in vivo. Mechanistically, this study found that P75CUX1 regulated epithelial–mesenchymal transition (EMT) process mediated via β-catenin, and CUX1/β-catenin/EMT is a novel signaling cascade mediating the infiltration of glioma. Besides, CUX1 was verified to promote the progression of glioma via multiple other signaling pathways, such as Hippo and PI3K/AKT. In conclusion, we suggested that P75CUX1 could serve as a potential prognostic indicator as well as a novel treatment target in malignant glioma.
ABIN-1 is a key regulator in RIPK1-dependent apoptosis (RDA) and necroptosis, and ABIN-1 deficiency potentiates necroptosis-based cancer therapy in colorectal cancer
Authors: Cai Jiali , Hu Die , Sakya Judy , Sun Tao , Wang Daoyong , Wang Lin , Mao Xiaohua , Su Zhenyi 
Published: February 2021

AbstractABIN-1, also called TNIP1, is an ubiquitin-binding protein that serves an important role in suppressing RIPK1-independent apoptosis, necroptosis, and NF-κB activation. However, the involvement of ABIN-1 in the regulation of RIPK1-dependent apoptosis (RDA) is unknown. In this study, we found that poly(I:C) + TAK1 inhibitor 5Z-7-oxozeaenol (P5) concurrently induces RDA and necroptosis in Abin-1−/−, but not in Abin-1+/+ mouse embryonic fibroblasts (MEFs). Upon P5 stimulation, cells initially die by necroptosis and subsequently by RDA. Furthermore, we explored the therapeutic effect of ABIN-1 deficiency in necroptosis-based cancer therapy in colorectal cancer (CRC). We found that poly(I:C) + 5Z-7-oxozeaenol + IDN-6556 (P5I) yields a robust pro-necroptosis response, and ABIN-1 deficiency additionally enhances this P5I-induced necroptosis. Moreover, phase I/II cIAP inhibitor birinapant with clinical caspase inhibitor IDN-6556 (BI) alone and 5-fluorouracil with IDN-6556 (FI) alone are sufficient to induce necroptotic cell death in CRC cells by promoting auto-secretion of tumor necrosis factor (TNF); ABIN-1 deficiency amplifies the BI- or FI-induced necroptosis. Two independent xenograft experiments using HT-29 or COLO205 cells show that both BI and P5I remarkably inhibit tumor growth via necroptosis activation. For poly(I:C)-induced cell death, the sensitizing effect of ABIN-1 deficiency on cell death may be attributed to increased expression of TLR3. In TNF-induced necroptosis, ABIN-1 deficiency increases TNF-induced RIPK1 polyubiquitination by reducing the recruitment of ubiquitin-editing enzyme A20 to the TNFR1 signaling complex and induces more TNF secretion in CRC cells upon pro-necroptosis stimulation. With this combined data, ABIN-1 deficiency promotes greater sensitization of CRC cells to necroptosis.
The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway
Authors: Xiang Tian , Yuan Chunhui , Guo Xia , Wang Honghao , Cai Qinzhen , Xiang Yun , Luo Wei , Liu Gao 
Published: February 2021

AbstractHelicobacter pylori (H. pylori) is listed as a class I carcinogen in human gastric cancer; however, the underlying mechanisms are poorly understood. In this study, we identified Protogenin (PRTG) was upregulated in both gastric cancer tissues and H. pylori-infected tissues by analyzing dysregulated genes in TCGA and GEO databases. Importantly, upregulated PRTG predicted poor prognosis of gastric cancer patients and integrative analysis revealed that PRTG served as an oncogenic protein in gastric cancer and was required for H. pylori-mediated tumorigenic activities in in vitro cellular and in vivo tumor-bearing mouse models. Mechanistically, H. pylori infection enhanced PRTG expression by promoting transcriptional factor ZEB1 stabilization and recruitment to the PRTG promoter, and which then activated the sub-following cGMP/PKG signaling pathway in bioinformatic and cellular studies. Cellular studies further confirmed that PRTG depended on activating cGMP/PKG axis to promote proliferation, metastasis, and chemoresistance of gastric cancer cells. The PKG inhibitor KT5823 played synergistic anti-tumor effects with cisplatin and paclitaxel to gastric cancer cells in in vitro cellular and in vivo tumor-bearing mouse models. Taken together, our findings suggested that H. pylori infection depends on ZEB1 to induce PRTG upregulation, and which leading to the development and progression of gastric cancer through activating cGMP/PKG signaling pathway. Blocking PRTG/cGMP/PKG axis, therefore, presents a promising novel therapeutic strategy for gastric cancer.
Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells
Authors: Wang Lingling , Sun Jiashen , Yin Yueyuan , Sun Yanan , Ma Jinyi , Zhou Ruimin , Chang Xinzhong , Li Ding , Yao Zhi , Tian Shanshan , Zhang Kai , Liu Zhe , Ma Zhenyi 
Published: February 2021

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
Bi-allelic loss of function variants in SLC30A5 as cause of perinatal lethal cardiomyopathy
Authors: Lieberwirth Johann Kaspar , Joset Pascal , Heinze Anja , Hentschel Julia , Stein Anja , Iannaccone Antonella , Steindl Katharina , Kuechler Alma , Abou Jamra Rami 
Published: February 2021

AbstractPerinatal mortality is a heavy burden for both affected parents and physicians. However, the underlying genetic causes have not been sufficiently investigated and most cases remain without diagnosis. This impedes appropriate counseling or therapy. We describe four affected children of two unrelated families with cardiomyopathy, hydrops fetalis, or cystic hygroma that all deceased perinatally. In the four patients, we found the following homozygous loss of function (LoF) variants in SLC30A5 NM_022902.4:c.832_836del p.(Ile278Phefs*33) and NM_022902.4:c.1981_1982del p.(His661Tyrfs*10). Knockout of SLC30A5 has previously been shown a cardiac phenotype in mouse models and no homozygous LoF variants in SLC30A5 are currently described in gnomAD. Taken together, we present SLC30A5 as a new gene for a severe and perinatally lethal form of cardiomyopathy.
LlWRKY39 is involved in thermotolerance by activating LlMBF1c and interacting with LlCaM3 in lily (Lilium longiflorum)
Authors: Ding Liping , Wu Ze , Teng Renda , Xu Sujuan , Cao Xing , Yuan Guozhen , Zhang Dehua , Teng Nianjun 
Published: February 2021

AbstractWRKY transcription factors (TFs) are of great importance in plant responses to different abiotic stresses. However, research on their roles in the regulation of thermotolerance remains limited. Here, we investigated the function of LlWRKY39 in the thermotolerance of lily (Lilium longiflorum ‘white heaven’). According to multiple alignment analyses, LlWRKY39 is in the WRKY IId subclass and contains a potential calmodulin (CaM)-binding domain. Further analysis has shown that LlCaM3 interacts with LlWRKY39 by binding to its CaM-binding domain, and this interaction depends on Ca2+. LlWRKY39 was induced by heat stress (HS), and the LlWRKY39-GFP fusion protein was detected in the nucleus. The thermotolerance of lily and Arabidopsis was increased with the ectopic overexpression of LlWRKY39. The expression of heat-related genes AtHSFA1, AtHSFA2, AtMBF1c, AtGolS1, AtDREB2A, AtWRKY39, and AtHSP101 was significantly elevated in transgenic Arabidopsis lines, which might have promoted an increase in thermotolerance. Then, the promoter of LlMBF1c was isolated from lily, and LlWRKY39 was found to bind to the conserved W-box element in its promoter to activate its activity, suggesting that LlWRKY39 is an upstream regulator of LlMBF1c. In addition, a dual-luciferase reporter assay showed that via protein interaction, LlCaM3 negatively affected LlWRKY39 in the transcriptional activation of LlMBF1c, which might be an important feedback regulation pathway to balance the LlWRKY39-mediated heat stress response (HSR). Collectively, these results imply that LlWRKY39 might participate in the HSR as an important regulator through Ca2+-CaM and multiprotein bridging factor pathways.
Novel ARG1 variants identified in a patient with arginase 1 deficiency
Authors: Yokoi Katsuyuki , Nakajima Yoko , Yasui Toshihiro , Yoshino Makoto , Yoshikawa Tetsushi , Kurahashi Hiroki , Ito Tetsuya 
Published: February 2021

AbstractWe report a case of a 13-year-old boy with arginase 1 deficiency carrying a new variant in ARG1. Sanger sequencing identified the compound heterozygous variants: NM_000045.4: c.365G>A (p.Trp122*)/c.820G>A (p.Asp274Asn). Although not previously reported, the p.Asp274Asn variant is predicted to have strong pathogenicity because it is located in a highly conserved domain in the protein core and arginase activity in the patient was below measurement sensitivity.
Gating the pore of the calcium-activated chloride channel TMEM16A
Authors: Lam Andy K. M. , Rheinberger Jan , Paulino Cristina , Dutzler Raimund 
Published: February 2021

AbstractThe binding of cytoplasmic Ca2+ to the anion-selective channel TMEM16A triggers a conformational change around its binding site that is coupled to the release of a gate at the constricted neck of an hourglass-shaped pore. By combining mutagenesis, electrophysiology, and cryo-electron microscopy, we identified three hydrophobic residues at the intracellular entrance of the neck as constituents of this gate. Mutation of each of these residues increases the potency of Ca2+ and results in pronounced basal activity. The structure of an activating mutant shows a conformational change of an α-helix that contributes to Ca2+ binding as a likely cause for the basal activity. Although not in physical contact, the three residues are functionally coupled to collectively contribute to the stabilization of the gate in the closed conformation of the pore, thus explaining the low open probability of the channel in the absence of Ca2+.
Responses of intended and unintended receivers to a novel sexual signal suggest clandestine communication
Authors: Tinghitella Robin M. , Broder E. Dale , Gallagher James H. , Wikle Aaron W. , Zonana David M. 
Published: February 2021

AbstractInadvertent cues can be refined into signals through coevolution between signalers and receivers, yet the earliest steps in this process remain elusive. In Hawaiian populations of the Pacific field cricket, a new morph producing a novel and incredibly variable song (purring) has spread across islands. Here we characterize the current sexual and natural selection landscape acting on the novel signal by (1) determining fitness advantages of purring through attraction to mates and protection from a prominent deadly natural enemy, and (2) testing alternative hypotheses about the strength and form of selection acting on the novel signal. In field studies, female crickets respond positively to purrs, but eavesdropping parasitoid flies do not, suggesting purring may allow private communication among crickets. Contrary to the sensory bias and preference for novelty hypotheses, preference functions (selective pressure) are nearly flat, driven by extreme inter-individual variation in function shape. Our study offers a rare empirical test of the roles of natural and sexual selection in the earliest stages of signal evolution.