bluuebunny/crossref_metadata_2025 huggingface dataset:
A metallic anti-biofouling surface with a hierarchical topography containing nanostructures on curved micro-riblets
Authors: Kim Taekyung , Kwon Sunmok , Lee Jeehyeon , Lee Joon Sang , Kang Shinill
Published: January 2022

Metallic surface finishes have been used in the anti-biofouling, but it is very difficult to produce surfaces with hierarchically ordered structures. In the present study, anti-biofouling metallic surfaces with nanostructures superimposed on curved micro-riblets were produced via top-down fabrication. According to the attachment theory, these surfaces feature few attachment points for organisms, the nanostructures prevent the attachment of bacteria and algal zoospores, while the micro-riblets prohibit the settlement of macrofoulers. Anodic oxidation was performed to induce superhydrophilicity. It forms a hydration layer on the surface, which physically blocks foulant adsorption along with the anti-biofouling topography. We characterized the surfaces via scanning electron and atomic force microscopy, contact-angle measurement, and wear-resistance testing. The contact angle of the hierarchical structures was less than 1°. Laboratory settlement assays verified that bacterial attachment was dramatically reduced by the nanostructures and/or the hydration layer, attributable to superhydrophilicity. The micro-riblets prohibited the settlement of macrofoulers. Over 77 days of static immersion in the sea during summer, the metallic surface showed significantly less biofouling compared to a surface painted with an anticorrosive coating.
Supportive treatment of vascular dysfunction in pediatric subjects with obesity: the OBELIX study
Authors: Pecoraro Luca , Zoller Thomas , Atkinson Richard L. , Nisi Fulvio , Antoniazzi Franco , Cavarzere Paolo , Piacentini Giorgio , Pietrobelli Angelo
Published: January 2022

Introduction

Overweight or obese children develop abnormal endothelial cell dysfunction and arterial intima–media thickening with increased vasomotor tone and inflammation. Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D have shown beneficial effects on endothelial function. We test, among overweight and obese pediatric subjects, the effects on the endothelium of a combination of curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D.

Methods

Forty-eight subjects (6–17 years) were randomized into two groups (placebo vs treatment) attended three visits at 0, 3, and 6 months (±15 days). Endothelial function was assessed by means of a post-occlusive release hyperemic (PORH) test for estimation of delta flow (DF) and hyperemic AUC index, and a heat provocation test (HPT) to measure DF HPT (DFHPT).

Results

Significant DF difference was noted at 6 months in both groups (p < 0.001). Overall time trend was significantly different between baseline, 3 months, and 6 months both in placebo (p < 0.05) and treatment (p < 0.001) groups and their comparison (p < 0.001). No differences were noted in hyperemic AUC index (3 and 6 months), whilst there were significant differences in time trends of rreatment (p < 0.001) and placebo (p < 0.05) groups and their comparison (p < 0.001). DFHPT difference between groups was significant at 3 and 6 months (p < 0.05). The overall time trend was significant exclusively in Treatment group between 3 and 6 months (p < 0.05). Correlation with anthropometrics was found for DF and body mass index (r = 0.677 6 months, p < 0.05), as well as for hyperemic AUC index and males (r = 0.348, p < 0.05), while DFHPT showed no correlation.

Conclusion

Curcumin, resveratrol, zinc, magnesium, selenium, and vitamin D appear to be promising in enhancing endothelial function by improvement of both DF in the PORH test and DF in the HPT, lowering the risk of developing cardiovascular diseases in overweight and obese pediatric subjects.
Graph theory analysis of whole brain functional connectivity to assess disturbances associated with suicide attempts in bipolar disorder
Authors: Sankar Anjali , Scheinost Dustin , Goldman Danielle A. , Drachman Rebecca , Colic Lejla , Villa Luca M. , Kim Jihoon A. , Gonzalez Yarani , Marcelo Imani , Shinomiya Mei , Pittman Brian , Lacadie Cheryl M. , Oquendo Maria A. , Constable R. Todd , Blumberg Hilary P.
Published: January 2022

Brain targets to lower the high risk of suicide in Bipolar Disorder (BD) are needed. Neuroimaging studies employing analyses dependent on regional assumptions could miss hubs of dysfunction critical to the pathophysiology of suicide behaviors and their prevention. This study applied intrinsic connectivity distribution (ICD), a whole brain graph‐theoretical approach, to identify hubs of functional connectivity (FC) disturbances associated with suicide attempts in BD. ICD, from functional magnetic resonance imaging data acquired while performing a task involving implicit emotion regulation processes important in BD and suicide behaviors, was compared across 40 adults with BD with prior suicide attempts (SAs), 49 with BD with no prior attempts (NSAs) and 51 healthy volunteers (HVs). Areas of significant group differences were used as seeds to identify regional FC differences and explore associations with suicide risk-related measures. ICD was significantly lower in SAs than in NSAs and HVs in bilateral ventromedial prefrontal cortex (vmPFC) and right anterior insula (RaIns). Seed connectivity revealed altered FC from vmPFC to bilateral anteromedial orbitofrontal cortex, left ventrolateral PFC (vlPFC) and cerebellum, and from RaIns to right vlPFC and temporopolar cortices. VmPFC and RaIns ICD were negatively associated with suicidal ideation severity, and vmPFC ICD with hopelessness and attempt lethality severity. The findings suggest that SAs with BD have vmPFC and RaIns hubs of dysfunction associated with altered FC to other ventral frontal, temporopolar and cerebellar cortices, and with suicidal ideation, hopelessness, and attempt lethality. These hubs may be targets for novel therapeutics to reduce suicide risk in BD.
Sex-specific neural responses to acute psychosocial stress in depression
Authors: Dong Daifeng , Ironside Maria , Belleau Emily L. , Sun Xiaoqiang , Cheng Chang , Xiong Ge , Nickerson Lisa D. , Wang Xiang , Yao Shuqiao , Pizzagalli Diego A.
Published: January 2022

Major Depressive Disorder (MDD) is characterized by increased stress sensitivity. Emerging findings in healthy adults suggest that stress responses within limbic/striatal-prefrontal regions are moderated by sex and unfold over time. Thus, we hypothesized that stress response abnormalities in MDD might be affected by sex and stress exposure time. The Montreal Imaging Stress Task was administered to 124 unmedicated patients with first-episode MDD (76 females) and 243 healthy controls (HC; 137 females) during functional magnetic resonance imaging (fMRI). Based on prior studies, amygdala, hippocampus, medial orbitofrontal cortex (mOFC), nucleus accumbens (NAc) and dorsolateral prefrontal cortex (dlPFC) were selected as a priori regions of interest. In a complementary approach, we probed the effects of stress on the frontoparietal network (FPN) and a network including the amygdala, NAc and anterior cingulate cortex (ACC). Across groups, males exhibited higher dlPFC activity and right FPN amplitude than females. Relative to female HCs, the female MDD group had less deactivation in limbic/striatal regions (amygdala, NAc, hippocampus, Amygdala-NAc-ACC network). Furthermore, unlike female HCs, the female MDD group failed to show a significant increase of deactivation over stress exposure time in the amygdala, mOFC and NAc. Our findings confirm the importance of considering sex differences when investigating neural stress responses. Case-control differences in neural stress responses observed in females (but not males) provide insights into sex differences in the etiology and pathophysiology of depression. The failure to deactivate limbic/NAc regions in depressed females point to dysfunction of adaptive stress responses over stress exposure time.
Comprehensive exploration of the genetic contribution of the dopaminergic and serotonergic pathways to psychiatric disorders
Authors: Cabana-Domínguez Judit , Torrico Bàrbara , Reif Andreas , Fernàndez-Castillo Noèlia , Cormand Bru
Published: January 2022

Psychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to play an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (attention-deficit hyperactivity disorder (ADHD), anorexia nervosa (ANO), autism spectrum disorder (ASD), bipolar disorder (BIP), major depression (MD), obsessive-compulsive disorder (OCD), schizophrenia (SCZ) and Tourette’s syndrome (TS)) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium that include more than 160,000 cases and 275,000 controls. To do so, we elaborated four different gene sets: two ‘wide’ selections for dopamine (DA) and for serotonin (SERT) using the Gene Ontology and KEGG pathways tools, and two’core’ selections for the same systems, manually curated. At the gene level, we found 67 genes from the DA and/or SERT gene sets significantly associated with one of the studied disorders, and 12 of them were associated with two different disorders. Gene-set analysis revealed significant associations for ADHD and ASD with the wide DA gene set, for BIP with the wide SERT gene set, and for MD with the core SERT set. Interestingly, interrogation of a cross-disorder GWAS meta-analysis of the eight psychiatric conditions displayed association with the wide DA gene set. To our knowledge, this is the first systematic examination of genes encoding proteins essential to the function of these two neurotransmitter systems in these disorders. Our results support a pleiotropic contribution of the dopaminergic and serotonergic systems in several psychiatric conditions.
Microglial replacement in the aged brain restricts neuroinflammation following intracerebral hemorrhage
Authors: Li Xiuping , Gao Xiaolin , Zhang Wenyan , Liu Mingming , Han Zhaoli , Li Minshu , Lei Ping , Liu Qiang
Published: January 2022

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony–stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.
Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia
Authors: Gianni’ Maurizio , Goracci Laura , Schlaefli Anna , Di Veroli Alessandra , Kurosaki Mami , Guarrera Luca , Bolis Marco , Foglia Marika , Lupi Monica , Tschan Mario P. , Cruciani Gabriele , Terao Mineko , Garattini Enrico
Published: January 2022

The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.
RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis
Authors: Huang Yongsheng , Liu Sijia , Shan Mengjie , Hagenaars Sophie C. , Mesker Wilma E. , Cohen Danielle , Wang Lin , Zheng Zhi , Devilee Peter , Tollenaar Rob A. E. M. , Li Zhangfu , Song Yongmei , Zhang Long , Li Dan , ten Dijke Peter
Published: January 2022

Transforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.
Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition
Authors: Rimbach Rebecca , Yamada Yosuke , Sagayama Hiroyuki , Ainslie Philip N. , Anderson Lene F. , Anderson Liam J. , Arab Lenore , Baddou Issaad , Bedu-Addo Kweku , Blaak Ellen E. , Blanc Stephane , Bonomi Alberto G. , Bouten Carlijn V. C. , Bovet Pascal , Buchowski Maciej S. , Butte Nancy F. , Camps Stefan G. J. A. , Close Graeme L. , Cooper Jamie A. , Das Sai Krupa , Dugas Lara R. , Ekelund Ulf , Entringer Sonja , Forrester Terrence , Fudge Barry W. , Goris Annelies H. , Gurven Michael , Hambly Catherine , El Hamdouchi Asmaa , Hoos Marije B. , Hu Sumei , Joonas Noorjehan , Joosen Annemiek M. , Katzmarzyk Peter , Kempen Kitty P. , Kimura Misaka , Kraus William E. , Kushner Robert F. , Lambert Estelle V. , Leonard William R. , Lessan Nader , Martin Corby K. , Medin Anine C. , Meijer Erwin P. , Morehen James C. , Morton James P. , Neuhouser Marian L. , Nicklas Theresa A. , Ojiambo Robert M. , Pietiläinen Kirsi H. , Pitsiladis Yannis P. , Plange-Rhule Jacob , Plasqui Guy , Prentice Ross L. , Rabinovich Roberto A. , Racette Susan B. , Raichlen David A. , Ravussin Eric , Reynolds Rebecca M. , Roberts Susan B. , Schuit Albertine J. , Sjödin Anders M. , Stice Eric , Urlacher Samuel S. , Valenti Giulio , Van Etten Ludo M. , Van Mil Edgar A. , Wells Jonathan C. K. , Wilson George , Wood Brian M. , Yanovski Jack , Yoshida Tsukasa , Zhang Xueying , Murphy-Alford Alexia J. , Loechl Cornelia U. , Luke Amy H. , Rood Jennifer , Schoeller Dale A. , Westerterp Klaas R. , Wong William W. , Speakman John R. , Pontzer Herman ,   The IAEA DLW Database Consortium, Speakman John R.
Published: January 2022

Low total energy expenditure (TEE, MJ/d) has been a hypothesized risk factor for weight gain, but repeatability of TEE, a critical variable in longitudinal studies of energy balance, is understudied. We examine repeated doubly labeled water (DLW) measurements of TEE in 348 adults and 47 children from the IAEA DLW Database (mean ± SD time interval: 1.9 ± 2.9 y) to assess repeatability of TEE, and to examine if TEE adjusted for age, sex, fat-free mass, and fat mass is associated with changes in weight or body composition. Here, we report that repeatability of TEE is high for adults, but not children. Bivariate Bayesian mixed models show no among or within-individual correlation between body composition (fat mass or percentage) and unadjusted TEE in adults. For adults aged 20–60 y (N = 267; time interval: 7.4 ± 12.2 weeks), increases in adjusted TEE are associated with weight gain but not with changes in body composition; results are similar for subjects with intervals >4 weeks (N = 53; 29.1 ± 12.8 weeks). This suggests low TEE is not a risk factor for, and high TEE is not protective against, weight or body fat gain over the time intervals tested.
A method to construct the dynamic landscape of a bio-membrane with experiment and simulation
Authors: Smith Albert A. , Vogel Alexander , Engberg Oskar , Hildebrand Peter W. , Huster Daniel
Published: January 2022

Biomolecular function is based on a complex hierarchy of molecular motions. While biophysical methods can reveal details of specific motions, a concept for the comprehensive description of molecular dynamics over a wide range of correlation times has been unattainable. Here, we report an approach to construct the dynamic landscape of biomolecules, which describes the aggregate influence of multiple motions acting on various timescales and on multiple positions in the molecule. To this end, we use 13C NMR relaxation and molecular dynamics simulation data for the characterization of fully hydrated palmitoyl-oleoyl-phosphatidylcholine bilayers. We combine dynamics detector methodology with a new frame analysis of motion that yields site-specific amplitudes of motion, separated both by type and timescale of motion. In this study, we show that this separation allows the detailed description of the dynamic landscape, which yields vast differences in motional amplitudes and correlation times depending on molecular position.
Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease
Authors: Yang Yun , Tapias Victor , Acosta Diana , Xu Hui , Chen Huanlian , Bhawal Ruchika , Anderson Elizabeth T. , Ivanova Elena , Lin Hening , Sagdullaev Botir T. , Chen Jianer , Klein William L. , Viola Kirsten L. , Gandy Sam , Haroutunian Vahram , Beal M. Flint , Eliezer David , Zhang Sheng , Gibson Gary E.
Published: January 2022

Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer’s disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.
The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1
Authors: Singh Jai Prakash , Li Yang , Chen Yi-Yun , Hsu Shang-Te Danny , Page Rebecca , Peti Wolfgang , Meng Tzu-Ching
Published: January 2022

T-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells. TCPTP is a critical component of a variety of key signaling pathways that are directly associated with the formation of cancer and inflammation. Thus, understanding the molecular mechanism of TCPTP activation and regulation is essential for the development of TCPTP therapeutics. Under basal conditions, TCPTP is largely inactive, although how this is achieved is poorly understood. By combining biomolecular nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and chemical cross-linking coupled with mass spectrometry, we show that the C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that controls the TCPTP catalytic activity. Activation of TCPTP is achieved by cellular competition, i.e., the intrinsically disordered cytosolic tail of Integrin-α1 displaces the TCPTP autoinhibitory tail, allowing for the full activation of TCPTP. This work not only defines the mechanism by which TCPTP is regulated but also reveals that the intrinsically disordered tails of two of the most closely related PTPs (PTP1B and TCPTP) autoregulate the activity of their cognate PTPs via completely different mechanisms.
Molecular insights into the unusually promiscuous and catalytically versatile Fe(II)/α-ketoglutarate-dependent oxygenase SptF
Authors: Tao Hui , Mori Takahiro , Chen Heping , Lyu Shuang , Nonoyama Akihito , Lee Shoukou , Abe Ikuro
Published: January 2022

Non-heme iron and α-ketoglutarate-dependent (Fe/αKG) oxygenases catalyze various oxidative biotransformations. Due to their catalytic flexibility and high efficiency, Fe/αKG oxygenases have attracted keen attention for their application as biocatalysts. Here, we report the biochemical and structural characterizations of the unusually promiscuous and catalytically versatile Fe/αKG oxygenase SptF, involved in the biosynthesis of fungal meroterpenoid emervaridones. The in vitro analysis revealed that SptF catalyzes several continuous oxidation reactions, including hydroxylation, desaturation, epoxidation, and skeletal rearrangement. SptF exhibits extremely broad substrate specificity toward various meroterpenoids, and efficiently produced unique cyclopropane-ring-fused 5/3/5/5/6/6 and 5/3/6/6/6 scaffolds from terretonins. Moreover, SptF also hydroxylates steroids, including androsterone, testosterone, and progesterone, with different regiospecificities. Crystallographic and structure-based mutagenesis studies of SptF revealed the molecular basis of the enzyme reactions, and suggested that the malleability of the loop region contributes to the remarkable substrate promiscuity. SptF exhibits great potential as a promising biocatalyst for oxidation reactions.
Imaging moiré deformation and dynamics in twisted bilayer graphene
Authors: de Jong Tobias A. , Benschop Tjerk , Chen Xingchen , Krasovskii Eugene E. , de Dood Michiel J. A. , Tromp Rudolf M. , Allan Milan P. , van der Molen Sense Jan
Published: January 2022

In ‘magic angle’ twisted bilayer graphene (TBG) a flat band forms, yielding correlated insulator behavior and superconductivity. In general, the moiré structure in TBG varies spatially, influencing the overall conductance properties of devices. Hence, to understand the wide variety of phase diagrams observed, a detailed understanding of local variations is needed. Here, we study spatial and temporal variations of the moiré pattern in TBG using aberration-corrected Low Energy Electron Microscopy (AC-LEEM). We find a smaller spatial variation than reported previously. Furthermore, we observe thermal fluctuations corresponding to collective atomic displacements over 70 pm on a timescale of seconds. Remarkably, no untwisting is found up to 600 ∘C. We conclude that thermal annealing can be used to decrease local disorder. Finally, we observe edge dislocations in the underlying atomic lattice, the moiré structure acting as a magnifying glass. These topological defects are anticipated to exhibit unique local electronic properties.
A mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their disease-associated regulation
Authors: Morioka Shin , Nakanishi Hiroki , Yamamoto Toshiyoshi , Hasegawa Junya , Tokuda Emi , Hikita Tomoya , Sakihara Tomoko , Kugii Yuuki , Oneyama Chitose , Yamazaki Masakazu , Suzuki Akira , Sasaki Junko , Sasaki Takehiko
Published: January 2022

Phosphoinositides are a family of membrane lipids essential for many biological and pathological processes. Due to the existence of multiple phosphoinositide regioisomers and their low intracellular concentrations, profiling these lipids and linking a specific acyl variant to a change in biological state have been difficult. To enable the comprehensive analysis of phosphoinositide phosphorylation status and acyl chain identity, we develop PRMC-MS (Phosphoinositide Regioisomer Measurement by Chiral column chromatography and Mass Spectrometry). Using this method, we reveal a severe skewing in acyl chains in phosphoinositides in Pten-deficient prostate cancer tissues, extracellular mobilization of phosphoinositides upon expression of oncogenic PIK3CA, and a unique profile for exosomal phosphoinositides. Thus, our approach allows characterizing the dynamics of phosphoinositide acyl variants in intracellular and extracellular milieus.
Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association
Authors: Wu Chia-Chin , Wang Y. Alan , Livingston J. Andrew , Zhang Jianhua , Futreal P. Andrew
Published: January 2022

Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.
Assessing the energy transition in China towards carbon neutrality with a probabilistic framework
Authors: Zhang Shu , Chen Wenying
Published: January 2022

A profound transformation of China’s energy system is required to achieve carbon neutrality. Here, we couple Monte Carlo analysis with a bottom-up energy-environment-economy model to generate 3,000 cases with different carbon peak times, technological evolution pathways and cumulative carbon budgets. The results show that if emissions peak in 2025, the carbon neutrality goal calls for a 45–62% electrification rate, 47–78% renewable energy in primary energy supply, 5.2–7.9 TW of solar and wind power, 1.5–2.7 PWh of energy storage usage and 64–1,649 MtCO2 of negative emissions, and synergistically reducing approximately 80% of local air pollutants compared to the present level in 2050. The emission peak time and cumulative carbon budget have significant impacts on the decarbonization pathways, technology choices, and transition costs. Early peaking reduces welfare losses and prevents overreliance on carbon removal technologies. Technology breakthroughs, production and consumption pattern changes, and policy enhancement are urgently required to achieve carbon neutrality.
Vacuum laser acceleration of super-ponderomotive electrons using relativistic transparency injection
Authors: Singh P. K. , Li F.-Y. , Huang C.-K. , Moreau A. , Hollinger R. , Junghans A. , Favalli A. , Calvi C. , Wang S. , Wang Y. , Song H. , Rocca J. J. , Reinovsky R. E. , Palaniyappan S.
Published: January 2022

Intense lasers can accelerate electrons to very high energy over a short distance. Such compact accelerators have several potential applications including fast ignition, high energy physics, and radiography. Among the various schemes of laser-based electron acceleration, vacuum laser acceleration has the merits of super-high acceleration gradient and great simplicity. Yet its realization has been difficult because injecting free electrons into the fast-oscillating laser field is not trivial. Here we demonstrate free-electron injection and subsequent vacuum laser acceleration of electrons up to 20 MeV using the relativistic transparency effect. When a high-contrast intense laser drives a thin solid foil, electrons from the dense opaque plasma are first accelerated to near-light speed by the standing laser wave in front of the solid foil and subsequently injected into the transmitted laser field as the opaque plasma becomes relativistically transparent. It is possible to further optimize the electron injection/acceleration by manipulating the laser polarization, incident angle, and temporal pulse shaping. Our result also sheds light on the fundamental relativistic transparency process, crucial for producing secondary particle and light sources.
Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Authors: Jiwaji Zoeb , Tiwari Sachin S. , Avilés-Reyes Rolando X. , Hooley Monique , Hampton David , Torvell Megan , Johnson Delinda A. , McQueen Jamie , Baxter Paul , Sabari-Sankar Kayalvizhi , Qiu Jing , He Xin , Fowler Jill , Febery James , Gregory Jenna , Rose Jamie , Tulloch Jane , Loan Jamie , Story David , McDade Karina , Smith Amy M. , Greer Peta , Ball Matthew , Kind Peter C. , Matthews Paul M. , Smith Colin , Dando Owen , Spires-Jones Tara L. , Johnson Jeffrey A. , Chandran Siddharthan , Hardingham Giles E.
Published: January 2022

Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
Resonator nanophotonic standing-wave array trap for single-molecule manipulation and measurement
Authors: Ye Fan , Inman James T. , Hong Yifeng , Hall Porter M. , Wang Michelle D.
Published: January 2022

Nanophotonic tweezers represent emerging platforms with significant potential for parallel manipulation and measurements of single biological molecules on-chip. However, trapping force generation represents a substantial obstacle for their broader utility. Here, we present a resonator nanophotonic standing-wave array trap (resonator-nSWAT) that demonstrates significant force enhancement. This platform integrates a critically-coupled resonator design to the nSWAT and incorporates a novel trap reset scheme. The nSWAT can now perform standard single-molecule experiments, including stretching DNA molecules to measure their force-extension relations, unzipping DNA molecules, and disrupting and mapping protein-DNA interactions. These experiments have realized trapping forces on the order of 20 pN while demonstrating base-pair resolution with measurements performed on multiple molecules in parallel. Thus, the resonator-nSWAT platform now meets the benchmarks of a table-top precision optical trapping instrument in terms of force generation and resolution. This represents the first demonstration of a nanophotonic platform for such single-molecule experiments.
Cortical state dynamics and selective attention define the spatial pattern of correlated variability in neocortex
Authors: Shi Yan-Liang , Steinmetz Nicholas A. , Moore Tirin , Boahen Kwabena , Engel Tatiana A.
Published: January 2022

Correlated activity fluctuations in the neocortex influence sensory responses and behavior. Neural correlations reflect anatomical connectivity but also change dynamically with cognitive states such as attention. Yet, the network mechanisms defining the population structure of correlations remain unknown. We measured correlations within columns in the visual cortex. We show that the magnitude of correlations, their attentional modulation, and dependence on lateral distance are explained by columnar On-Off dynamics, which are synchronous activity fluctuations reflecting cortical state. We developed a network model in which the On-Off dynamics propagate across nearby columns generating spatial correlations with the extent controlled by attentional inputs. This mechanism, unlike previous proposals, predicts spatially non-uniform changes in correlations during attention. We confirm this prediction in our columnar recordings by showing that in superficial layers the largest changes in correlations occur at intermediate lateral distances. Our results reveal how spatially structured patterns of correlated variability emerge through interactions of cortical state dynamics, anatomical connectivity, and attention.
Imagined speech can be decoded from low- and cross-frequency intracranial EEG features
Authors: Proix Timothée , Delgado Saa Jaime , Christen Andy , Martin Stephanie , Pasley Brian N. , Knight Robert T. , Tian Xing , Poeppel David , Doyle Werner K. , Devinsky Orrin , Arnal Luc H. , Mégevand Pierre , Giraud Anne-Lise
Published: January 2022

Reconstructing intended speech from neural activity using brain-computer interfaces holds great promises for people with severe speech production deficits. While decoding overt speech has progressed, decoding imagined speech has met limited success, mainly because the associated neural signals are weak and variable compared to overt speech, hence difficult to decode by learning algorithms. We obtained three electrocorticography datasets from 13 patients, with electrodes implanted for epilepsy evaluation, who performed overt and imagined speech production tasks. Based on recent theories of speech neural processing, we extracted consistent and specific neural features usable for future brain computer interfaces, and assessed their performance to discriminate speech items in articulatory, phonetic, and vocalic representation spaces. While high-frequency activity provided the best signal for overt speech, both low- and higher-frequency power and local cross-frequency contributed to imagined speech decoding, in particular in phonetic and vocalic, i.e. perceptual, spaces. These findings show that low-frequency power and cross-frequency dynamics contain key information for imagined speech decoding.
C/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer
Authors: Liu Xiao-Zheng , Rulina Anastasiia , Choi Man Hung , Pedersen Line , Lepland Johanna , Takle Sina T. , Madeleine Noelly , Peters Stacey D’mello , Wogsland Cara Ellen , Grøndal Sturla Magnus , Lorens James B. , Goodarzi Hani , Lønning Per E. , Knappskog Stian , Molven Anders , Halberg Nils
Published: January 2022

Epidemiological studies have established a positive association between obesity and the incidence of postmenopausal breast cancer. Moreover, it is known that obesity promotes stem cell-like properties of breast cancer cells. However, the cancer cell-autonomous mechanisms underlying this correlation are not well defined. Here we demonstrate that obesity-associated tumor formation is driven by cellular adaptation rather than expansion of pre-existing clones within the cancer cell population. While there is no correlation with specific mutations, cellular adaptation to obesity is governed by palmitic acid (PA) and leads to enhanced tumor formation capacity of breast cancer cells. This process is governed epigenetically through increased chromatin occupancy of the transcription factor CCAAT/enhancer-binding protein beta (C/EBPB). Obesity-induced epigenetic activation of C/EBPB regulates cancer stem-like properties by modulating the expression of key downstream regulators including CLDN1 and LCN2. Collectively, our findings demonstrate that obesity drives cellular adaptation to PA drives tumor initiation in the obese setting through activation of a C/EBPB dependent transcriptional network.
Identifying the impact of the covalent-bonded carbon matrix to FeN4 sites for acidic oxygen reduction
Authors: Li Xueli , Xiang Zhonghua
Published: January 2022

The atomic configurations of FeNx moieties are the key to affect the activity of oxygen rection reaction (ORR). However, the traditional synthesis relying on high-temperature pyrolysis towards combining sources of Fe, N, and C often results in the plurality of local environments for the FeNx sites. Unveiling the effect of carbon matrix adjacent to FeNx sites towards ORR activity is important but still is a great challenge due to inevitable connection of diverse N as well as random defects. Here, we report a proof-of-concept study on the evaluation of covalent-bonded carbon environment connected to FeN4 sites on their catalytic activity via pyrolysis-free approach. Basing on the closed π conjugated phthalocyanine-based intrinsic covalent organic polymers (COPs) with well-designed structures, we directly synthesized a series of atomically dispersed Fe-N-C catalysts with various pure carbon environments connected to the same FeN4 sites. Experiments combined with density functional theory demonstrates that the catalytic activities of these COPs materials appear a volcano plot with the increasement of delocalized π electrons in their carbon matrix. The delocalized π electrons changed anti-bonding d-state energy level of the single FeN4 moieties, hence tailored the adsorption between active centers and oxygen intermediates and altered the rate-determining step.
Percolation in networks with local homeostatic plasticity
Authors: Rapisardi Giacomo , Kryven Ivan , Arenas Alex
Published: January 2022

Percolation is a process that impairs network connectedness by deactivating links or nodes. This process features a phase transition that resembles paradigmatic critical transitions in epidemic spreading, biological networks, traffic and transportation systems. Some biological systems, such as networks of neural cells, actively respond to percolation-like damage, which enables these structures to maintain their function after degradation and aging. Here we study percolation in networks that actively respond to link damage by adopting a mechanism resembling synaptic scaling in neurons. We explain critical transitions in such active networks and show that these structures are more resilient to damage as they are able to maintain a stronger connectedness and ability to spread information. Moreover, we uncover the role of local rescaling strategies in biological networks and indicate a possibility of designing smart infrastructures with improved robustness to perturbations.
Folded network and structural transition in molten tin
Authors: Xu Liang , Wang Zhigang , Chen Jian , Chen Songyi , Yang Wenge , Ren Yang , Zuo Xiaobing , Zeng Jianrong , Wu Qiang , Sheng Howard
Published: January 2022

The fundamental relationships between the structure and properties of liquids are far from being well understood. For instance, the structural origins of many liquid anomalies still remain unclear, but liquid-liquid transitions (LLT) are believed to hold a key. However, experimental demonstrations of LLTs have been rather challenging. Here, we report experimental and theoretical evidence of a second-order-like LLT in molten tin, one which favors a percolating covalent bond network at high temperatures. The observed structural transition originates from the fluctuating metallic/covalent behavior of atomic bonding, and consequently a new paradigm of liquid structure emerges. The liquid structure, described in the form of a folded network, bridges two well-established structural models for disordered systems, i.e., the random packing of hard-spheres and a continuous random network, offering a large structural midground for liquids and glasses. Our findings provide an unparalleled physical picture of the atomic arrangement for a plethora of liquids, shedding light on the thermodynamic and dynamic anomalies of liquids but also entailing far-reaching implications for studying liquid polyamorphism and dynamical transitions in liquids.
Context-independent encoding of passive and active self-motion in vestibular afferent fibers during locomotion in primates
Authors: Mackrous Isabelle , Carriot Jérome , Cullen Kathleen E.
Published: January 2022

The vestibular system detects head motion to coordinate vital reflexes and provide our sense of balance and spatial orientation. A long-standing hypothesis has been that projections from the central vestibular system back to the vestibular sensory organs (i.e., the efferent vestibular system) mediate adaptive sensory coding during voluntary locomotion. However, direct proof for this idea has been lacking. Here we recorded from individual semicircular canal and otolith afferents during walking and running in monkeys. Using a combination of mathematical modeling and nonlinear analysis, we show that afferent encoding is actually identical across passive and active conditions, irrespective of context. Thus, taken together our results are instead consistent with the view that the vestibular periphery relays robust information to the brain during primate locomotion, suggesting that context-dependent modulation instead occurs centrally to ensure that coding is consistent with behavioral goals during locomotion.
Zinc ion thermal charging cell for low-grade heat conversion and energy storage
Authors: Li Zhiwei , Xu Yinghong , Wu Langyuan , An Yufeng , Sun Yao , Meng Tingting , Dou Hui , Xuan Yimin , Zhang Xiaogang
Published: January 2022

Converting low-grade heat from environment into electricity shows great sustainability for mitigating the energy crisis and adjusting energy configurations. However, thermally rechargeable devices typically suffer from poor conversion efficiency when a semiconductor is employed. Breaking the convention of thermoelectric systems, we propose and demonstrate a new zinc ion thermal charging cell to generate electricity from low-grade heat via the thermo-extraction/insertion and thermodiffusion processes of insertion-type cathode (VO2-PC) and stripping/plating behaviour of Zn anode. Based on this strategy, an impressively high thermopower of ~12.5 mV K−1 and an excellent output power of 1.2 mW can be obtained. In addition, a high heat-to-current conversion efficiency of 0.95% (7.25% of Carnot efficiency) is achieved with a temperature difference of 45 K. This work, which demonstrates extraordinary energy conversion efficiency and adequate energy storage, will pave the way towards the construction of thermoelectric setups with attractive properties for high value-added utilization of low-grade heat.
CD4 and CD8 co-receptors modulate functional avidity of CD1b-restricted T cells
Authors: James Charlotte A. , Xu Yuexin , Aguilar Melissa S. , Jing Lichen , Layton Erik D. , Gilleron Martine , Minnaard Adriaan J. , Scriba Thomas J. , Day Cheryl L. , Warren Edus H. , Koelle David M. , Seshadri Chetan
Published: January 2022

T cells recognize mycobacterial glycolipid (mycolipid) antigens presented by CD1b molecules, but the role of CD4 and CD8 co-receptors in mycolipid recognition is unknown. Here we show CD1b-mycolipid tetramers reveal a hierarchy in which circulating T cells expressing CD4 or CD8 co-receptor stain with a higher tetramer mean fluorescence intensity than CD4-CD8- T cells. CD4+ primary T cells transduced with mycolipid-specific T cell receptors bind CD1b-mycolipid tetramer with a higher fluorescence intensity than CD8+ primary T cells. The presence of either CD4 or CD8 also decreases the threshold for interferon-γ secretion. Co-receptor expression increases surface expression of CD3ε, suggesting a mechanism for increased tetramer binding and activation. Targeted transcriptional profiling of mycolipid-specific T cells from individuals with active tuberculosis reveals canonical markers associated with cytotoxicity among CD8+ compared to CD4+ T cells. Thus, expression of co-receptors modulates T cell receptor avidity for mycobacterial lipids, leading to in vivo functional diversity during tuberculosis disease.