bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased vitamin D levels in obsessive-compulsive disorder patients
Authors: Marazziti Donatella , Barberi Filippo M. , Fontenelle Leonardo , Buccianelli Beatrice , Carbone Manuel G. , Parra Elisabetta , Palermo Stefania , Massa Lucia , Tagliarini Claudia , Della Vecchia Alessandra , Mucci Federico , Arone Alessandro , Dell’Osso Liliana
Published: September 2021

Objective

The present paper compared vitamin D levels in adult patients with obsessive-compulsive disorder (OCD) and explored possible correlations with patients’ characteristics.

Methods

Fifty outpatients with OCD, according to DSM-5 criteria, were included and assessed with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Hamilton Rating Scale for Depression (HRDS).

Results

All the patients except one showed lower vitamin D levels than normative values (>30 nm/L). Vitamin D values of the whole sample were negatively correlated with Y-BOCS total, compulsion subscale, and some items’ scores, specifically “interference from obsessions,” “distress associated with obsessions,” and “time spent on compulsions”. The same relationships were detected in men, while women showed negative correlations between vitamin D levels and Y-BOCS compulsion subscale and “resistance to compulsions,” “degree of control of compulsions,” “insight” item scores.

Conclusions

Our findings would indicate that vitamin D might be involved in the pathophysiology of OCD, and that it is possibly related to the severity of the disorder and to typical symptoms, with some sex-related peculiarities. Further studies are necessary to support or not our findings and to ascertain the effectiveness of vitamin D supplementation in patients with OCD.
INTERACTION OF A SINGULAR SURFACE WITH A STRONG SHOCK IN THE INTERSTELLAR GAS CLOUDS
Authors: JENA J. , MITTAL S.
Published: September 2021

We investigate the interaction between a singular surface and a strong shock in the self-gravitating interstellar gas clouds with the assumption of spherical symmetry. Using the method of the Lie group of transformations, a particular solution of the flow variables and the cooling–heating function for an infinitely strong shock is obtained. This paper explores an application of the singular surface theory in the evolution of an acceleration wave front propagating through an unperturbed medium. We discuss the formation of an acceleration, considering the cases of compression and expansion waves. The influence of the cooling–heating function on a shock formation is explained. The results of a collision between a strong shock and an acceleration wave are discussed using the Lax evolutionary conditions.
Massive GNSS Network Analysis Without Baselines: Undifferenced Ambiguity Resolution
Authors: Geng Jianghui , Mao Shuyin
Published: September 2021

Integer ambiguity resolution (IAR) plays a key role in high‐precision Global Navigation Satellite System (GNSS). While GNSS network analysis is usually achieved through double‐difference (DD) IAR, undifferenced (UD) IAR has also been developed in recent years to achieve network analysis station by station. It is normally acquiesced in that DD‐IAR and UD‐IAR should achieve equivalent results, which is however not the case in a number of studies. We investigated four representatives DD‐IAR and UD‐IAR strategies using 1 year of GPS data from 192 globally distributed stations, where the position repeatability and the root mean squares error (RMSE) against the International GNSS Service weekly solutions were both quantified. We found that the position repeatability and the RMSE of DD‐IAR were both worse than those of UD‐IAR at over 90% of stations for the east component, though the largest deteriorations were only 0.6 and 0.7 mm, respectively. We demonstrate that it is the incorrectly resolved DD ambiguities, though accounting for far less than 1%, that degrade DD‐IAR. Identifying such problematic ambiguities requires sophisticated quality control for DD‐IAR, because the integer offset of an incorrect DD ambiguity might have been absorbed evenly by the cross‐connected mass of DD ambiguities throughout the network, and consequently does not manifest as an outlier in the ambiguity‐fixed solution. We, therefore, recommend UD‐IAR for GNSS network analysis since it is immune to the error propagation resulting from incorrect integer ambiguities at other stations and thus more efficient to achieve ambiguity‐fixed solutions.
The NPF Effect on CCN Number Concentrations: A Review and Re‐Evaluation of Observations From 35 Sites Worldwide
Authors: Ren Jingye , Chen Lu , Fan Tianyi , Liu Jieyao , Jiang Sihui , Zhang Fang
Published: September 2021

The new particle formation (NPF) effect on cloud condensation nuclei (CCN) differs from region to region and remains highly uncertain. Here, we re‐evaluate the NPF‐initiated enhancements in CCN number concentrations (E_NCCN) by compiling results from 35 field sites worldwide and five global models. We show the E_NCCN at sites close to the anthropogenic sources are more than 2‐fold as large as that at remote sites with supersaturations of 0.1%–1.0%. The enhancements anti‐correlate with the time scales for the new particles to grow to CCN size, which are 5–10 and 20–30 hr at polluted and remote sites, respectively. We further reveal that under polluted environments the condensational growth of new particles may be accelerated, leading to larger E_NCCN. The models fail to simulate the E_NCCN in polluted regions. Our study highlights the importance of parameterizing the time scale of NPF to affect CCN differently for remote and polluted regions in models.
Electromagnetic Response of the Mid‐Latitude Ionosphere to Power Transmission Lines
Authors: Fedorov E. N. , Mazur N. G. , Pilipenko V. A.
Published: September 2021

To foresee a plausible electromagnetic contamination of the near‐Earth space by anthropogenic activity, a magnitude of electromagnetic response in the upper ionosphere to 50/60 Hz power line emission (PLE) is to be modeled. For that we have calculated the spatial structure of electromagnetic disturbance in the mid‐latitude atmosphere and ionosphere immersed into an inclined geomagnetic field . The electromagnetic field is excited by a large‐scale 50/150 Hz oscillating linear current suspended above the ground. The elaborated model is based on numerical solution of full‐wave equations in a realistic ionosphere whose parameters have been reconstructed with the use of the International Reference Ionosphere (IRI) model. The PLE wave beam in the ionosphere is not guided by , but still is shifted equatorward from the vertical. The response of the nightside upper ionosphere is slowly decreasing with diminishing of latitude. The amplitude of PLE electric component in the upper ionosphere generated by the unbalanced power line current with intensity of 10 Amperes can reach 1 V/m which is sufficient to be detected by a low‐Earth‐orbit satellite. For a better insight into PLE transmission through the ionosphere a basic information about ELF waves in the multi‐ion plasma is provided.
Growth factor signaling predicts therapy resistance mechanisms and defines neuroblastoma subtypes
Authors: Lebedev Timofey , Vagapova Elmira , Spirin Pavel , Rubtsov Petr , Astashkova Olga , Mikheeva Alesya , Sorokin Maxim , Vladimirova Uliana , Suntsova Maria , Konovalov Dmitry , Roumiantsev Alexander , Stocking Carol , Buzdin Anton , Prassolov Vladimir
Published: September 2021

Neuroblastoma (NB) has a low frequency of recurrent mutations compared to other cancers, which hinders the development of targeted therapies and novel risk stratification strategies. Multikinase inhibitors have shown potential in treating high-risk NB, but their efficacy is likely impaired by the cancer cells’ ability to adapt to these drugs through the employment of alternative signaling pathways. Based on the expression of 48 growth factor-related genes in 1189 NB tumors, we have developed a model for NB patient survival prediction. This model discriminates between stage 4 NB tumors with favorable outcomes (>80% overall survival) and very poor outcomes (<10%) independently from MYCN-amplification status. Using signaling pathway analysis and gene set enrichment methods in 60 NB patients with known therapy response, we identified signaling pathways, including EPO, NGF, and HGF, upregulated in patients with no or partial response. In a therapeutic setting, we showed that among six selected growth factors, EPO, and NGF showed the most pronounced protective effects in vitro against several promising anti-NB multikinase inhibitors: imatinib, dasatinib, crizotinib, cabozantinib, and axitinib. Mechanistically kinase inhibitors potentiated NB cells to stronger ERK activation by EPO and NGF. The protective action of these growth factors strongly correlated with ERK activation and was ERK-dependent. ERK inhibitors combined with anticancer drugs, especially with dasatinib, showed a synergistic effect on NB cell death. Consideration of growth factor signaling activity benefits NB outcome prediction and tailoring therapy regimens to treat NB.
Incomplete tricarboxylic acid cycle and proton gradient in Pandoravirus massiliensis: is it still a virus?
Authors: Aherfi Sarah , Brahim Belhaouari Djamal , Pinault Lucile , Baudoin Jean-Pierre , Decloquement Philippe , Abrahao Jonatas , Colson Philippe , Levasseur Anthony , Lamb David C , Chabriere Eric , Raoult Didier , La Scola Bernard
Published: September 2021

The discovery of Acanthamoeba polyphaga Mimivirus, the first isolated giant virus of amoeba, challenged the historical hallmarks defining a virus. Giant virion sizes are known to reach up to 2.3 µm, making them visible by optical microscopy. Their large genome sizes of up to 2.5 Mb can encode proteins involved in the translation apparatus. We have investigated possible energy production in Pandoravirus massiliensis. Mitochondrial membrane markers allowed for the detection of a membrane potential in purified virions and this was enhanced by a regulator of the tricarboxylic acid cycle but abolished by the use of a depolarizing agent. Bioinformatics was employed to identify enzymes involved in virion proton gradient generation and this approach revealed that eight putative P. massiliensis proteins exhibited low sequence identities with known cellular enzymes involved in the universal tricarboxylic acid cycle. Further, all eight viral genes were transcribed during replication. The product of one of these genes, ORF132, was cloned and expressed in Escherichia coli, and shown to function as an isocitrate dehydrogenase, a key enzyme of the tricarboxylic acid cycle. Our findings show for the first time that a membrane potential can exist in Pandoraviruses, and this may be related to tricarboxylic acid cycle. The presence of a proton gradient in P. massiliensis makes this virus a form of life for which it is legitimate to ask the question “what is a virus?”.
TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells
Authors: Woznicki Jerzy A. , Saini Nisha , Flood Peter , Rajaram Subhasree , Lee Ciaran M. , Stamou Panagiota , Skowyra Agnieszka , Bustamante-Garrido Milan , Regazzoni Karine , Crawford Nyree , McDade Simon S. , Longley Daniel B. , Aza-Blanc Pedro , Shanahan Fergus , Zulquernain Syed A. , McCarthy Jane , Melgar Silvia , McRae Bradford L. , Nally Ken
Published: September 2021

Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). Th1-type cytokines—IFN-γ and TNF-α—occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs.
Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway
Authors: Lu Hongwei , Jia Chao , Wu Dengying , Jin Haidong , Lin Zeng , Pan Jun , Li Xiucui , Wang Wei
Published: September 2021

Osteoarthritis (OA) is a complex condition that involves both apoptosis and senescence and currently cannot be cured. Fibroblast growth factor 21 (FGF21), known for its role as a potent regulator of glucose and energy metabolism, protects from various diseases, possibly by mediating autophagy. In the present study, the role of FGF21 in the progression of OA was investigated in both in vitro and in vivo experiments. In vitro, the results revealed that FGF21 administration alleviated apoptosis, senescence, and extracellular matrix (ECM) catabolism of the chondrocytes induced by tert-butyl hydroperoxide (TBHP) by mediating autophagy flux. Furthermore, CQ, an autophagy flux inhibitor, could reverse the protective effect of FGF21. It was observed that the FGF21-induced autophagy flux enhancement was mediated by the nuclear translocation of TFEB, which occurs due to the activation of the SIRT1-mTOR signaling pathway. The in vivo experiments demonstrated that FGF21 treatment could reduce OA in the DMM model. Taken together, these findings suggest that FGF21 protects chondrocytes from apoptosis, senescence, and ECM catabolism via autophagy flux upregulation and also reduces OA development in vivo, demonstrating its potential as a therapeutic agent in OA.
Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone
Authors: He Yunfei , Cheng Dongdong , Lian Cheng , Liu Yingjie , Luo Wenqian , Wang Yuan , Ma Chengxin , Wu Qiuyao , Tian Pu , He Dasa , Jia Zhenchang , Lv Xianzhe , Zhang Xue , Pan Zhen , Lu Jinxi , Xiao Yansen , Zhang Peiyuan , Liang Yajun , Yang Qingcheng , Hu Guohong
Published: September 2021

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.
Physical basis for the determination of lumen shape in a simple epithelium
Authors: Vasquez Claudia G. , Vachharajani Vipul T. , Garzon-Coral Carlos , Dunn Alexander R.
Published: September 2021

The formation of a hollow lumen in a formerly solid mass of cells is a key developmental process whose dysregulation leads to diseases of the kidney and other organs. Hydrostatic pressure has been proposed to drive lumen expansion, a view that is supported by experiments in the mouse blastocyst. However, lumens formed in other tissues adopt irregular shapes with cell apical faces that are bowed inward, suggesting that pressure may not be the dominant contributor to lumen shape in all cases. Here we use live-cell imaging to study the physical mechanism of lumen formation in Madin-Darby Canine Kidney cell spheroids, a canonical cell-culture model for lumenogenesis. We find that in this system, lumen shape reflects basic geometrical considerations tied to the establishment of apico-basal polarity. A physical model incorporating both cell geometry and intraluminal pressure can account for our observations as well as cases in which pressure plays a dominant role.
Soft gamma rays from low accreting supermassive black holes and connection to energetic neutrinos
Authors: Kimura Shigeo S. , Murase Kohta , Mészáros Péter
Published: September 2021

The Universe is filled with a diffuse background of MeV gamma-rays and PeV neutrinos, whose origins are unknown. Here, we propose a scenario that can account for both backgrounds simultaneously. Low-luminosity active galactic nuclei have hot accretion flows where thermal electrons naturally emit soft gamma rays via Comptonization of their synchrotron photons. Protons there can be accelerated via turbulence or reconnection, producing high-energy neutrinos via hadronic interactions. We demonstrate that our model can reproduce the gamma-ray and neutrino data. Combined with a contribution by hot coronae in luminous active galactic nuclei, these accretion flows can explain the keV – MeV photon and TeV – PeV neutrino backgrounds. This scenario can account for the MeV background without non-thermal electrons, suggesting a higher transition energy from the thermal to nonthermal Universe than expected. Our model is consistent with X-ray data of nearby objects, and testable by future MeV gamma-ray and high-energy neutrino detectors.
Dissecting transition cells from single-cell transcriptome data through multiscale stochastic dynamics
Authors: Zhou Peijie , Wang Shuxiong , Li Tiejun , Nie Qing
Published: September 2021

Advances in single-cell technologies allow scrutinizing of heterogeneous cell states, however, detecting cell-state transitions from snap-shot single-cell transcriptome data remains challenging. To investigate cells with transient properties or mixed identities, we present MuTrans, a method based on multiscale reduction technique to identify the underlying stochastic dynamics that prescribes cell-fate transitions. By iteratively unifying transition dynamics across multiple scales, MuTrans constructs the cell-fate dynamical manifold that depicts progression of cell-state transitions, and distinguishes stable and transition cells. In addition, MuTrans quantifies the likelihood of all possible transition trajectories between cell states using coarse-grained transition path theory. Downstream analysis identifies distinct genes that mark the transient states or drive the transitions. The method is consistent with the well-established Langevin equation and transition rate theory. Applying MuTrans to datasets collected from five different single-cell experimental platforms, we show its capability and scalability to robustly unravel complex cell fate dynamics induced by transition cells in systems such as tumor EMT, iPSC differentiation and blood cell differentiation. Overall, our method bridges data-driven and model-based approaches on cell-fate transitions at single-cell resolution.
Atomic layer deposition triggered Fe-In-S cluster and gradient energy band in ZnInS photoanode for improved oxygen evolution reaction
Authors: Meng Linxing , He Jinlu , Zhou Xiaolong , Deng Kaimo , Xu Weiwei , Kidkhunthod Pinit , Long Run , Tang Yongbing , Li Liang
Published: September 2021

Vast bulk recombination of photo-generated carriers and sluggish surface oxygen evolution reaction (OER) kinetics severely hinder the development of photoelectrochemical water splitting. Herein, through constructing a vertically ordered ZnInS nanosheet array with an interior gradient energy band as photoanode, the bulk recombination of photogenerated carriers decreases greatly. We use the atomic layer deposition technology to introduce Fe-In-S clusters into the surface of photoanode. First-principles calculations and comprehensive characterizations indicate that these clusters effectively lower the electrochemical reaction barrier on the photoanode surface and promote the surface OER reaction kinetics through precisely affecting the second and third steps (forming processes of O* and OOH*) of the four-electron reaction. As a result, the optimal photoanode exhibits the high performance with a significantly enhanced photocurrent of 5.35 mA cm−2 at 1.23 VRHE and onset potential of 0.09 VRHE. Present results demonstrate a robust platform for controllable surface modification, nanofabrication, and carrier transport.
Turn-key constrained parameter space exploration for particle accelerators using Bayesian active learning
Authors: Roussel Ryan , Gonzalez-Aguilera Juan Pablo , Kim Young-Kee , Wisniewski Eric , Liu Wanming , Piot Philippe , Power John , Hanuka Adi , Edelen Auralee
Published: September 2021

Particle accelerators are invaluable discovery engines in the chemical, biological and physical sciences. Characterization of the accelerated beam response to accelerator input parameters is often the first step when conducting accelerator-based experiments. Currently used techniques for characterization, such as grid-like parameter sampling scans, become impractical when extended to higher dimensional input spaces, when complicated measurement constraints are present, or prior information known about the beam response is scarce. Here in this work, we describe an adaptation of the popular Bayesian optimization algorithm, which enables a turn-key exploration of input parameter spaces. Our algorithm replaces  the need for parameter scans while minimizing prior information needed about the measurement’s behavior and associated measurement constraints. We experimentally demonstrate that our algorithm autonomously conducts an adaptive, multi-parameter exploration of input parameter space, potentially orders of magnitude faster than conventional grid-like parameter scans, while making highly constrained, single-shot beam phase-space measurements and accounts for costs associated with changing input parameters. In addition to applications in accelerator-based scientific experiments, this algorithm addresses challenges shared by many scientific disciplines, and is thus applicable to autonomously conducting experiments over a broad range of research topics.
Collaborative management of the Grand Ethiopian Renaissance Dam increases economic benefits and resilience
Authors: Basheer Mohammed , Nechifor Victor , Calzadilla Alvaro , Siddig Khalid , Etichia Mikiyas , Whittington Dale , Hulme David , Harou Julien J.
Published: September 2021

The landscape of water infrastructure in the Nile Basin is changing with the construction of the Grand Ethiopian Renaissance Dam. Although this dam could improve electricity supply in Ethiopia and its neighbors, there is a lack of consensus between Ethiopia, Sudan, and Egypt on the dam operation. We introduce a new modeling framework that simulates the Nile River System and Egypt’s macroeconomy, with dynamic feedbacks between the river system and the macroeconomy. Because the two systems “coevolve” throughout multi-year simulations, we term this a “coevolutionary” modeling framework. The framework is used to demonstrate that a coordinated operating strategy could allow the Grand Ethiopian Renaissance Dam to help meet water demands in Egypt during periods of water scarcity and increase hydropower generation and storage in Ethiopia during high flows. Here we show the hydrological and macroeconomic performance of this coordinated strategy compared to a strategy that resembles a recent draft proposal for the operation of the dam discussed in Washington DC.
Peering into lunar permanently shadowed regions with deep learning
Authors: Bickel V. T. , Moseley B. , Lopez-Francos I. , Shirley M.
Published: September 2021

The lunar permanently shadowed regions (PSRs) are expected to host large quantities of water-ice, which are key for sustainable exploration of the Moon and beyond. In the near future, NASA and other entities plan to send rovers and humans to characterize water-ice within PSRs. However, there exists only limited information about the small-scale geomorphology and distribution of ice within PSRs because the orbital imagery captured to date lacks sufficient resolution and/or signal. In this paper, we develop and validate a new method of post-processing LRO NAC images of PSRs. We show that our method is able to reveal previously unseen geomorphological features such as boulders and craters down to 3 meters in size, whilst not finding evidence for surface frost or near-surface ice. Our post-processed images significantly facilitate the exploration of PSRs by reducing the uncertainty of target selection and traverse/mission planning.
9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy
Authors: Han Guangchun , Yang Guoliang , Hao Dapeng , Lu Yang , Thein Kyaw , Simpson Benjamin S. , Chen Jianfeng , Sun Ryan , Alhalabi Omar , Wang Ruiping , Dang Minghao , Dai Enyu , Zhang Shaojun , Nie Fengqi , Zhao Shuangtao , Guo Charles , Hamza Ameer , Czerniak Bogdan , Cheng Chao , Siefker-Radtke Arlene , Bhat Krishna , Futreal Andrew , Peng Guang , Wargo Jennifer , Peng Weiyi , Kadara Humam , Ajani Jaffer , Swanton Charles , Litchfield Kevin , Ahnert Jordi Rodon , Gao Jianjun , Wang Linghua
Published: September 2021

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers “cold” tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A “response score” was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B
Authors: Yoo Chan Yul , He Jiangman , Sang Qing , Qiu Yongjian , Long Lingyun , Kim Ruth Jean-Ae , Chong Emily G. , Hahm Joseph , Morffy Nicholas , Zhou Pei , Strader Lucia C. , Nagatani Akira , Mo Beixin , Chen Xuemei , Chen Meng
Published: September 2021

Photoactivated phytochrome B (PHYB) binds to antagonistically acting PHYTOCHROME-INTERACTING transcription FACTORs (PIFs) to regulate hundreds of light responsive genes in Arabidopsis by promoting PIF degradation. However, whether PHYB directly controls the transactivation activity of PIFs remains ambiguous. Here we show that the prototypic PIF, PIF3, possesses a p53-like transcription activation domain (AD) consisting of a hydrophobic activator motif flanked by acidic residues. A PIF3mAD mutant, in which the activator motif is replaced with alanines, fails to activate PIF3 target genes in Arabidopsis, validating the functions of the PIF3 AD in vivo. Intriguingly, the N-terminal photosensory module of PHYB binds immediately adjacent to the PIF3 AD to repress PIF3’s transactivation activity, demonstrating a novel PHYB signaling mechanism through direct interference of the transactivation activity of PIF3. Our findings indicate that PHYB, likely also PHYA, controls the stability and activity of PIFs via structurally separable dual signaling mechanisms.
Lattice reconstruction induced multiple ultra-flat bands in twisted bilayer WSe2
Authors: Li En , Hu Jin-Xin , Feng Xuemeng , Zhou Zishu , An Liheng , Law Kam Tuen , Wang Ning , Lin Nian
Published: September 2021

Moiré superlattices in van der Waals heterostructures provide a tunable platform to study emergent properties that are absent in the natural crystal form. Twisted bilayer transition metal dichalcogenides (TB-TMDs) can host moiré flat bands over a wide range of twist angles. For twist angle close to 60°, it was predicted that TB-TMDs undergo a lattice reconstruction which causes the formation of ultra-flat bands. Here, by using scanning tunneling microscopy and spectroscopy, we show the emergence of multiple ultra-flat bands in twisted bilayer WSe2 when the twist angle is within 3° of 60°. The ultra-flat bands are manifested as narrow tunneling conductance peaks with estimated bandwidth less than 10 meV, which is only a fraction of the estimated on-site Coulomb repulsion energy. The number of these ultra-flat bands and spatial distribution of the wavefunctions match well with the theoretical predictions, strongly evidencing that the observed ultra-flat bands are induced by lattice reconstruction. Our work provides a foundation for further study of the exotic correlated phases in TB-TMDs.
SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms
Authors: Fröberg Janeri , Gillard Joshua , Philipsen Ria , Lanke Kjerstin , Rust Joyce , van Tuijl Diana , Teelen Karina , Bousema Teun , Simonetti Elles , van der Gaast-de Jongh Christa E. , Bos Mariska , van Kuppeveld Frank J. , Bosch Berend-Jan , Nabuurs-Franssen Marrigje , van der Geest-Blankert Nannet , van Daal Charlotte , Huynen Martijn A. , de Jonge Marien I. , Diavatopoulos Dimitri A.
Published: September 2021

Although serological studies have shown that antibodies against SARS-CoV-2 play an important role in protection against (re)infection, the dynamics of mucosal antibodies during primary infection and their potential impact on viral load and the resolution of disease symptoms remain unclear. During the first pandemic wave, we assessed the longitudinal nasal antibody response in index cases with mild COVID-19 and their household contacts. Nasal and serum antibody responses were analysed for up to nine months. Higher nasal receptor binding domain and spike protein-specific antibody levels at study inclusion were associated with lower viral load. Older age was correlated with more frequent COVID-19 related symptoms. Receptor binding domain and spike protein-specific mucosal antibodies were associated with the resolution of systemic, but not respiratory symptoms. Finally, receptor binding domain and spike protein-specific mucosal antibodies remained elevated up to nine months after symptom onset.
Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions
Authors: Gómez Xavier , Sanon Serena , Zambrano Kevin , Asquel Samira , Bassantes Mariuxi , Morales Julián E. , Otáñez Gabriela , Pomaquero Core , Villarroel Sarah , Zurita Alejandro , Calvache Carlos , Celi Kathlyn , Contreras Terry , Corrales Dylan , Naciph María Belén , Peña José , Caicedo Andrés
Published: September 2021

Exposure to microgravity and ionizing radiation during spaceflight missions causes excessive reactive oxygen species (ROS) production that contributes to cellular stress and damage in astronauts. Average spaceflight mission time is expected to lengthen as humanity aims to visit other planets. However, longer missions or spaceflights will undoubtedly lead to an increment in microgravity, ionizing radiation and ROS production. Strategies to minimize ROS damage are necessary to maintain the health of astronauts, future space colonists, and tourists during and after spaceflight missions. An antioxidant cocktail formulated to prevent or mitigate ROS damage during space exploration could help maintain the health of space explorers. We propose key points to consider when developing an antioxidant cocktail. We discuss how ROS damages our body and organs, the genetic predisposition of astronauts to its damage, characteristics and evidence of the effectiveness of antioxidants to combat excess ROS, differences in drug metabolism when on Earth and in space that could modify antioxidant effects, and the characteristics and efficacy of common antioxidants. Based on this information we propose a workflow for assessing astronaut resistance to ROS damage, infight monitoring of ROS production, and an antioxidant cocktail. Developing an antioxidant cocktail represents a big challenge to translate current medical practices from an Earth setting to space. The key points presented in this review could promote the development of different antioxidant formulations to maintain space explorers’ health in the future.
Quantifying the optimal strategy of population control of quorum sensing network in Escherichia coli
Authors: Li Xiang , Jin Jun , Zhang Xiaocui , Xu Fei , Zhong Jinjin , Yin Zhiyong , Qi Hong , Wang Zhaoshou , Shuai Jianwei
Published: September 2021

Biological functions of bacteria can be regulated by monitoring their own population density induced by the quorum sensing system. However, quantitative insight into the system’s dynamics and regulatory mechanism remain challenging. Here, we construct a comprehensive mathematical model of the synthetic quorum sensing circuit that controls population density in Escherichia coli. Simulations agree well with experimental results obtained under different ribosome-binding site (RBS) efficiencies. We present a quantitative description of the component dynamics and show how the components respond to isopropyl-β-D-1-thiogalactopyranoside (IPTG) induction. The optimal IPTG-induction range for efficiently controlling population density is quantified. The controllable area of population density by acyl-homoserine lactone (AHL) permeability is quantified as well, indicating that high AHL permeability should be treated with a high dose of IPTG, while low AHL permeability should be induced with low dose for efficiently controlling. Unexpectedly, an oscillatory behavior of the growth curve is observed with proper RBS-binding strengths and the oscillation is greatly restricted by the bacterial death induced by toxic metabolic by-products. Moreover, we identify that the mechanism underlying the emergence of oscillation is determined by the negative feedback loop structure within the signaling. Bifurcation analysis and landscape theory are further employed to study the stochastic dynamic and global stability of the system, revealing two faces of toxic metabolic by-products in controlling oscillatory behavior. Overall, our study presents a quantitative basis for understanding and new insights into the control mechanism of quorum sensing system, providing possible clues to guide the development of more rational control strategy.
Mass measurements of 99–101In challenge ab initio nuclear theory of the nuclide 100Sn
Authors: Mougeot M. , Atanasov D. , Karthein J. , Wolf R. N. , Ascher P. , Blaum K. , Chrysalidis K. , Hagen G. , Holt J. D. , Huang W. J. , Jansen G. R. , Kulikov I. , Litvinov Yu. A. , Lunney D. , Manea V. , Miyagi T. , Papenbrock T. , Schweikhard L. , Schwenk A. , Steinsberger T. , Stroberg S. R. , Sun Z. H. , Welker A. , Wienholtz F. , Wilkins S. G. , Zuber K.
Published: September 2021

The tin isotope 100Sn is of singular interest for nuclear structure due to its closed-shell proton and neutron configurations. It is also the heaviest nucleus comprising protons and neutrons in equal numbers—a feature that enhances the contribution of the short-range proton–neutron pairing interaction and strongly influences its decay via the weak interaction. Decay studies in the region of 100Sn have attempted to prove its doubly magic character1 but few have studied it from an ab initio theoretical perspective2,3, and none of these has addressed the odd-proton neighbours, which are inherently more difficult to describe but crucial for a complete test of nuclear forces. Here we present direct mass measurements of the exotic odd-proton nuclide 100In, the beta-decay daughter of 100Sn, and of 99In, with one proton less than 100Sn. We use advanced mass spectrometry techniques to measure 99In, which is produced at a rate of only a few ions per second, and to resolve the ground and isomeric states in 101In. The experimental results are compared with ab initio many-body calculations. The 100-fold improvement in precision of the 100In mass value highlights a discrepancy in the atomic-mass values of 100Sn deduced from recent beta-decay results4,5.
Ligand recognition and G-protein coupling selectivity of cholecystokinin A receptor
Authors: Liu Qiufeng , Yang Dehua , Zhuang Youwen , Croll Tristan I. , Cai Xiaoqing , Dai Antao , He Xinheng , Duan Jia , Yin Wanchao , Ye Chenyu , Zhou Fulai , Wu Beili , Zhao Qiang , Xu H. Eric , Wang Ming-Wei , Jiang Yi
Published: September 2021

Cholecystokinin A receptor (CCKAR) belongs to family A G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal and metabolic diseases. One distinguishing feature of CCKAR is its ability to interact with a sulfated ligand and to couple with divergent G-protein subtypes, including Gs, Giand Gq. However, the basis for G-protein coupling promiscuity and ligand recognition by CCKAR remains unknown. Here, we present three cryo-electron microscopy structures of sulfated CCK-8-activated CCKAR in complex with Gs, Giand Gqheterotrimers, respectively. CCKAR presents a similar conformation in the three structures, whereas conformational differences in the ‘wavy hook’ of the Gα subunits and ICL3 of the receptor serve as determinants in G-protein coupling selectivity. Our findings provide a framework for understanding G-protein coupling promiscuity by CCKAR and uncover the mechanism of receptor recognition by sulfated CCK-8.
Light intensity and spectral composition drive reproductive success in the marine benthic diatom Seminavis robusta
Authors: Bilcke Gust , Van Craenenbroeck Lore , Castagna Alexandre , Osuna-Cruz Cristina Maria , Vandepoele Klaas , Sabbe Koen , De Veylder Lieven , Vyverman Wim
Published: September 2021

The properties of incident light play a crucial role in the mating process of diatoms, a group of ecologically important microalgae. While species-specific requirements for light intensity and photoperiod have been observed in several diatom species, little is known about the light spectrum that allows sexual reproduction. Here, we study the effects of spectral properties and light intensity on the initiation and progression of sexual reproduction in the model benthic diatom Seminavis robusta. We found that distinct stages of the mating process have different requirements for light. Vigorous mating pair formation occurred under a broad range of light intensities, ranging from 10 to 81 µE m−2 s−1, while gametogenesis and subsequent stages were strongly affected by moderate light intensities of 27 µE m−2 s−1 and up. In addition, light of blue or blue–green wavelengths was required for the formation of mating pairs. Combining flow cytometric analysis with expression profiling of the diatom-specific cyclin dsCyc2 suggests that progression through a blue light-dependent checkpoint in the G1 cell cycle phase is essential for induction of sexual reproduction. Taken together, we expand the current model of mating in benthic pennate diatoms, which relies on the interplay between light, cell cycle and sex pheromone signaling.
Transcriptional expression of ZICs as an independent indicator of survival in gliomas
Authors: Han Zhaocheng , Jia Jingnan , Lv Yangting , Wang Rongyanqi , Cao Kegang
Published: September 2021

The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas (HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyzes were performed with Metascape. PPI networks were constructed using STRING. The expression levels of ZIC1/3/4/5 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined was related to favorable OS in glioblastoma multiforme (GBM). ZIC alterations were associated with poor prognosis in LGG patients and related to favorable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving Neuroactive ligand-receptor interaction (hsa04080). The PPI network revealed that some proteins coexpressed with ZICs played a role in the pathogenesis of gliomas. Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.
Trends and age-period-cohort effects on hypertension mortality rates from 1998 to 2018 in Mexico
Authors: Castro-Porras Lilia V. , Rojas-Martínez Rosalba , Aguilar-Salinas Carlos A. , Bello-Chavolla Omar Yaxmehen , Becerril-Gutierrez Carlos , Escamilla-Nuñez Consuelo
Published: September 2021

Arterial hypertension is a major global health problem. It is the main risk factor for preventable death and the leading cause of premature death in the world. This study aims to describe the changes in hypertension-related mortality in Mexico between 1998 and 2018. Using death certificates and national population public data sets, a total of 335,863 deaths due to hypertension were found in Mexico, disaggregated by sex and age, during the time period covered in this study. An age-period-cohort analysis was conducted to show trends in hypertension mortality rates. Mortality due to hypertension in Mexico affects more women than men. In the most recent cohorts, the risk of dying from hypertension is two times higher in men compared to women. Hypertensive kidney disease is found to be the main underlying cause, with an average increase throughout the period studied. Our results indicate that mortality rates due to hypertension continue to grow and point to an alarming trend of mortality shifting towards younger ages, with sex-based disparities in absolute numbers and in changing trends.
Combining multi-site magnetic resonance imaging with machine learning predicts survival in pediatric brain tumors
Authors: Grist James T. , Withey Stephanie , Bennett Christopher , Rose Heather E. L. , MacPherson Lesley , Oates Adam , Powell Stephen , Novak Jan , Abernethy Laurence , Pizer Barry , Bailey Simon , Clifford Steven C. , Mitra Dipayan , Arvanitis Theodoros N. , Auer Dorothee P. , Avula Shivaram , Grundy Richard , Peet Andrew C.
Published: September 2021

Brain tumors represent the highest cause of mortality in the pediatric oncological population. Diagnosis is commonly performed with magnetic resonance imaging. Survival biomarkers are challenging to identify due to the relatively low numbers of individual tumor types. 69 children with biopsy-confirmed brain tumors were recruited into this study. All participants had perfusion and diffusion weighted imaging performed at diagnosis. Imaging data were processed using conventional methods, and a Bayesian survival analysis performed. Unsupervised and supervised machine learning were performed with the survival features, to determine novel sub-groups related to survival. Sub-group analysis was undertaken to understand differences in imaging features. Survival analysis showed that a combination of diffusion and perfusion imaging were able to determine two novel sub-groups of brain tumors with different survival characteristics (p < 0.01), which were subsequently classified with high accuracy (98%) by a neural network. Analysis of high-grade tumors showed a marked difference in survival (p = 0.029) between the two clusters with high risk and low risk imaging features. This study has developed a novel model of survival for pediatric brain tumors. Tumor perfusion plays a key role in determining survival and should be considered as a high priority for future imaging protocols.