bluuebunny/crossref_metadata_2025 huggingface dataset:
The pro-tumorigenic activity of p38γ overexpression in nasopharyngeal carcinoma
Authors: Yin De-Pei , Zheng Yu-Fan , Sun Peng , Yao Ming-Yu , Xie Li-xiao , Dou Xun-Wu , Tian Ye , Liu Ji-Sheng
Published: March 2022

It is urgent to identify and validate biomarkers for early diagnosis and efficient treatment of nasopharyngeal carcinoma (NPC). Recent studies have proposed p38 gamma (p38γ) as a cyclin-dependent kinase (CDK)-like kinase that phosphorylates retinoblastoma (Rb) to promote cyclins expression and tumorigenesis. Here the Gene Expression Profiling Interactive Analysis (GEPIA) database and results from the local NPC tissues demonstrate that p38γ is significantly upregulated in NPC tissues, correlating with poor overall survival. Furthermore, p38γ mRNA and protein expression is elevated in established NPC cell lines (CNE-1 HONE-1 and CNE-2) and primary human NPC cells, but low expression detected in human nasal epithelial cells. In established and primary NPC cells, p38γ depletion, using the shRNA strategy or the CRISPR/Cas9 gene-editing method, largely inhibited cell growth, proliferation and migration, and induced significant apoptosis activation. Contrarily, ectopic p38γ overexpression exerted opposite activity and promoted NPC cell proliferation and migration. Retinoblastoma (Rb) phosphorylation and cyclin E1/A expression were decreased in NPC cells with p38γ silencing or knockout, but increased after p38γ overexpression. Moreover, mitochondrial subcellular p38γ localization was detected in NPC cells. Significantly, p38γ depletion disrupted mitochondrial functions, causing mitochondrial depolarization, reactive oxygen species production, oxidative injury and ATP depletion in NPC cells. In vivo, intratumoral injection of adeno-associated virus-packed p38γ shRNA potently inhibited primary human NPC xenograft growth in nude mice. In p38γ shRNA virus-injected NPC xenograft tissues, p38γ expression, Rb phosphorylation, cyclin E1/A expression and ATP levels were dramatically decreased. Taken together, we conclude that p38γ overexpression is required for NPC cell growth, acting as a promising therapeutic target of NPC.
A drug repurposing strategy for overcoming human multiple myeloma resistance to standard-of-care treatment
Authors: Chroma Katarina , Skrott Zdenek , Gursky Jan , Bacovsky Jaroslav , Moudry Pavel , Buchtova Tereza , Mistrik Martin , Bartek Jiri
Published: March 2022

Despite several approved therapeutic modalities, multiple myeloma (MM) remains an incurable blood malignancy and only a small fraction of patients achieves prolonged disease control. The common anti-MM treatment targets proteasome with specific inhibitors (PI). The resulting interference with protein degradation is particularly toxic to MM cells as they typically accumulate large amounts of toxic proteins. However, MM cells often acquire resistance to PIs through aberrant expression or mutations of proteasome subunits such as PSMB5, resulting in disease recurrence and further treatment failure. Here we propose CuET—a proteasome-like inhibitor agent that is spontaneously formed in-vivo and in-vitro from the approved alcohol-abuse drug disulfiram (DSF), as a readily available treatment effective against diverse resistant forms of MM. We show that CuET efficiently kills also resistant MM cells adapted to proliferate under exposure to common anti-myeloma drugs such as bortezomib and carfilzomib used as the first-line therapy, as well as to other experimental drugs targeting protein degradation upstream of the proteasome. Furthermore, CuET can overcome also the adaptation mechanism based on reduced proteasome load, another clinically relevant form of treatment resistance. Data obtained from experimental treatment-resistant cellular models of human MM are further corroborated using rather unique advanced cytotoxicity experiments on myeloma and normal blood cells obtained from fresh patient biopsies including newly diagnosed as well as relapsed and treatment-resistant MM. Overall our findings suggest that disulfiram repurposing particularly if combined with copper supplementation may offer a promising and readily available treatment option for patients suffering from relapsed and/or therapy-resistant multiple myeloma.
Elevated nuclear localization of glycolytic enzyme TPI1 promotes lung adenocarcinoma and enhances chemoresistance
Authors: Liu Peng , Sun Si-Jia , Ai Ying-Jie , Feng Xu , Zheng Yi-Min , Gao Yun , Zhang Jin-Ye , Zhang Lei , Sun Yi-Ping , Xiong Yue , Lin Miao , Yuan Hai-Xin
Published: March 2022

Increased glycolysis is a hallmark of tumor, which can provide tumor cells with energy and building blocks to promote cell proliferation. Recent studies have shown that not only the expression of glycolytic genes but also their subcellular localization undergoes a variety of changes to promote development of different types of tumors. In this study, we performed a comprehensive analysis of glycolysis and gluconeogenesis genes based on data from TCGA to identify those with significant tumor-promoting potential across 14 types of tumors. This analysis not only confirms genes that are known to be involved in tumorigenesis, but also reveals a significant correlation of triosephosphate isomerase 1 (TPI1) with poor prognosis, especially in lung adenocarcinoma (LUAD). TPI1 is a glycolytic enzyme that interconverts dihydroxyacetone phosphate (DHAP) to glyceraldehyde 3-phosphate (GAP). We confirm the upregulation of TPI1 expression in clinical LUAD samples and an inverse correlation with the overall patient survival. Knocking down of TPI1 in lung cancer cells significantly reduced cell migration, colony formation, and xenograft tumor growth. Surprisingly, we found that the oncogenic function of TPI1 depends on its translocation to cell nucleus rather than its catalytic activity. Significant accumulation of TPI1 in cell nucleus was observed in LUAD tumor tissues compared with the cytoplasm localization in adjacent normal tissues. Moreover, nuclear translocation of TPI1 is induced by extracellular stress (such as chemotherapy agents and peroxide), which facilitates the chemoresistance of cancer cells. Our study uncovers a novel function of the glycolytic enzyme TPI1 in the LUAD.
Leptin secreted from testicular microenvironment modulates hedgehog signaling to augment the endogenous function of Leydig cells
Authors: Arora Himanshu , Qureshi Rehana , Khodamoradi Kajal , Seetharam Deepa , Parmar Madhumita , Van Booven Derek J. , Issa Isabelle Catherine , Sackstein Robert , Lamb Dolores , Hare Joshua M. , Ramasamy Ranjith
Published: March 2022

Although testosterone deficiency (TD) may be present in one out of five men 40 years or older, the factors responsible for TD remain largely unknown. Leydig stem cells (LSCs) differentiate into adult Leydig cells (ALC) and produce testosterone in the testes under the pulsatile control of luteinizing hormone (LH) from the pituitary gland. However, recent studies have suggested that the testicular microenvironment (TME), which is comprised of Sertoli and peritubular myoid cells (PMC), plays an instrumental role in LSC differentiation and testosterone production under the regulation of the desert hedgehog signaling pathway (DHH). It was hypothesized that the TME releases paracrine factors to modulate LSC differentiation. For this purpose, cells (Sertoli, PMCs, LSCs, and ALCs) were extracted from men undergoing testis biopsies for sperm retrieval and were evaluated for the paracrine factors in the presence or absence of the TME (Sertoli and PMC). The results demonstrated that TME secretes leptin, which induces LSC differentiation and increases testosterone production. Leptin’s effects on LSC differentiation and testosterone production, however, are inversely concentration-dependent: positive at low doses and negative at higher doses. Mechanistically, leptin binds to the leptin receptor on LSCs and induces DHH signaling to modulate LSC differentiation. Leptin-DHH regulation functions unidirectionally insofar as DHH gain or loss of function has no effect on leptin levels. Taken together, these findings identify leptin as a key paracrine factor released by cells within the TME that modulates LSC differentiation and testosterone release from mature Leydig cells, a finding with important clinical implications for TD.
SIRT6 mediates MRTF-A deacetylation in vascular endothelial cells to antagonize oxLDL-induced ICAM-1 transcription
Authors: Huang Shan , Shao Tinghui , Liu Hong , Wang Qianyun , Li Tianfa , Zhao Qianwen
Published: March 2022

Oxidized low-density lipoprotein (oxLDL), a known risk factor for atherosclerosis, activates the transcription of adhesion molecules (ICAM-1) in endothelial cells. We previously showed that myocardin-related transcription factor A (MRTF-A) mediates oxLDL-induced ICAM-1 transcription. Here we confirm that ICAM-1 transactivation paralleled dynamic alterations in MRTF-A acetylation. Since treatment with the antioxidant NAC dampened MRTF-A acetylation, MRTF-A acetylation appeared to be sensitive to cellular redox status. Of interest, silencing of SIRT6, a lysine deacetylase, restored MRTF-A acetylation despite the addition of NAC. SIRT6 directly interacted with MRTF-A to modulate MRTF-A acetylation. Deacetylation of MRTF-A by SIRT6 led to its nuclear expulsion thus dampening MRTF-A occupancy on the ICAM-1 promoter. Moreover, SIRT6 expression was downregulated with oxLDL stimulation likely owing to promoter hypermethylation in endothelial cells. DNA methyltransferase 1 (DNMT1) was recruited to the SIRT6 promoter and mediated SIRT6 repression. The ability of DNMT1 to repress SIRT6 promoter partly was dependent on ROS-sensitive serine 154 phosphorylation. In conclusion, our data unveil a novel DNMT1-SIRT6 axis that contributes to the regulation of MRTF-A acetylation and ICAM-1 transactivation in endothelial cells.
Long noncoding RNA LINC00518 contributes to proliferation and metastasis in lung adenocarcinoma via the miR-335-3p/CTHRC1 Axis
Authors: Shen Ruoyi , Cai Xin , Shen Dan , Zhang Ruochen , Zhang Weijie , Zhang Yang , Li Yue , Wang Anqi , Zeng Yuanyuan , Zhu Jianjie , Liu Zeyi , Huang Jian-an
Published: March 2022

Long intergenic nonprotein coding RNA 518 (LINC00518) is recognized to impart cancer proliferation and metastasis in lung adenocarcinoma (LUAD). However, the study about the relationship between LINC00518 and LUAD is shallow so far. In our work, LINC00518 was predicted to be a negative regulator in LUAD based on the TCGA database. It was further verified that the cell proliferation, colony formation, migration, and invasion of LUAD could be obviously inhibited by the knockdown of LINC00518. Moreover, miR-335-3p/CTHRC1 axis was intensively possible to be a critical regulator in the effect of LINC00518 on LUAD via visual ceRNA network. Importantly the progress of LUAD was relevant to the active CTHRC1 which was realized by the target of LINC00518 to miR-335-3p. Furthermore, the knockdown of LINC00518 exhibited a synergistic effect with VS6063, an inhibitor of FAK protein, in the suppression of LUAD indicating that miR-335-3p/CTHRC1 axis was potentially exploitable as a targeted intervention to integrin β3/FAK signal pathway in LUAD. All the collective results demonstrated that LINC00518 could be a promising biomarker of the prognosis of LUAD and possibly a therapeutic target via miR-335-3p/CTHRC1 axis.
Unravelling a new many-body large-hole polaron in a transition metal oxide that promotes high photocatalytic activity
Authors: Chi Xiao , Mandal Lily , Liu Cuibo , Fauzi Angga Dito , Chaudhuri Anindita , Whitcher Thomas J. , Jani Hariom Kirit , Chen Zhongxin , Xi Shibo , Diao Caozheng , Naradipa Muhammad Avicenna , Yu Xiaojiang , Yang Ping , Castro-Neto Antonio Helio , Breese Mark B. H. , Loh Kian Ping , Venkatesan Thirumalai Venky , Rusydi Andrivo
Published: March 2022

A many-body large polaron, which is important for both fundamental physics and technological applications, has been predicted to occur in bismuth vanadate (BiVO4). Herein, using a combination of high-resolution spectroscopic ellipsometry, X-ray absorption spectroscopy at the V L3,2- and O K-edges, and high-resolution X-ray diffraction supported by theoretical calculations, we reveal a new many-body large-hole polaron in W-doped BiVO4 films and the interplay of the large-hole polaron and indirect bandgap when determining the photocatalytic activity. With various W doping concentrations and temperatures, anomalous spectral weight transfers in the complex dielectric function are observed, revealing electronic correlations, particularly the on-site Coulomb interactions of O p (Upp) and V d (Udd), and screening in BiVO4. Due to the distortion of BiO8 dodecahedra and Udd, Bi 6 s is lifted to the top of the valance band, which results in the formation of an indirect bandgap and a large-hole polaron. The large-hole polaron is found to form as a localized midgap state, consisting of O p hybridized with the V d and Bi sp orbitals, and this is important when determining the high photocatalytic activity of BiVO4. Our results show the importance of the interplay among the charge, orbital, and lattice degrees of freedom in forming the many-body large-hole polaron, which improves the conductivity and results in a transition metal oxide with high photocatalytic activity.
NSC-derived extracellular matrix-modified GelMA hydrogel fibrous scaffolds for spinal cord injury repair
Authors: Chen Zheng , Wang Lin , Chen Chichi , Sun Jie , Luo Junchao , Cui Wenguo , Zhu Can , Zhou Xiaozhong , Liu Xingzhi , Yang Huilin , Shi Qin
Published: March 2022

Cell-derived extracellular matrix (ECM) has been applied in spinal cord injury (SCI) regeneration because of its various biological functions. However, insufficient mechanical properties limit its wide application. Herein, we developed GelMA/ECM hydrogel fibrous scaffolds (GelMA/ECM scaffolds) that can recruit and enhance the differentiation of neural stem cells (NSCs) by electrospinning and decellularization techniques. Moreover, the GelMA/ECM scaffolds had good mechanical properties and reinforced cell adhesion and proliferation. Compared to GelMA hydrogel fibrous scaffolds (GelMA scaffolds), GelMA/ECM scaffolds promoted more NSCs toward neurons by markedly enhancing the expression of MAP-2 and Tuj-1 and decreasing GFAP expression. In addition, the GelMA/ECM scaffolds significantly reduced the proportion of M1-phenotype macrophages, which is favorable for SCI repair. In vivo, the GelMA/ECM scaffolds recruited NSCs at the injured site, promoted neuron regeneration, and reduced the formation of glial scars and the inflammatory response, which further led to a significant improvement in the functional recovery of SCI. Therefore, this scaffold shows potential in regenerative medicine, mainly in SCI.
Change and variability in Antarctic coastal exposure, 1979–2020
Authors: Reid P. A. , Massom R. A.
Published: March 2022

Increased exposure of Antarctica’s coastal environment to open ocean and waves due to loss of a protective sea-ice “buffer” has important ramifications for ice-shelf stability, coastal erosion, important ice-ocean-atmosphere interactions and shallow benthic ecosystems. Here, we introduce a climate and environmental metric based on the ongoing long-term satellite sea-ice concentration record, namely Coastal Exposure Length. This is a daily measure of change and variability in the length and incidence of Antarctic coastline lacking any protective sea-ice buffer offshore. For 1979–2020, ~50% of Antarctica’s ~17,850-km coastline had no sea ice offshore each summer, with minimal exposure in winter. Regional summer/maximum contributions vary from 45% (Amundsen-Bellingshausen seas) to 58% (Indian Ocean and Ross Sea), with circumpolar annual exposure ranging from 38% (2019) to 63% (1993). The annual maximum length of Antarctic coastal exposure decreased by ~30 km (~0.32%) per year for 1979–2020, composed of distinct regional and seasonal contributions.
White matter integrity in mice requires continuous myelin synthesis at the inner tongue
Authors: Meschkat Martin , Steyer Anna M. , Weil Marie-Theres , Kusch Kathrin , Jahn Olaf , Piepkorn Lars , Agüi-Gonzalez Paola , Phan Nhu Thi Ngoc , Ruhwedel Torben , Sadowski Boguslawa , Rizzoli Silvio O. , Werner Hauke B. , Ehrenreich Hannelore , Nave Klaus-Armin , Möbius Wiebke
Published: March 2022

Myelin, the electrically insulating sheath on axons, undergoes dynamic changes over time. However, it is composed of proteins with long lifetimes. This raises the question how such a stable structure is renewed. Here, we study the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survive recombination, continue to express myelin genes, but they fail to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualize myelin-like membranes failing to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicates degradation of existing myelin at the abaxonal side and the inner tongue of the sheath. Thinning of compact myelin and shortening of internodes result in the loss of about 50% of myelin and axonal pathology within 20 weeks post recombination. In summary, our data suggest that functional axon-myelin units require the continuous incorporation of new myelin membranes.
Associations between alcohol consumption and gray and white matter volumes in the UK Biobank
Authors: Daviet Remi , Aydogan Gökhan , Jagannathan Kanchana , Spilka Nathaniel , Koellinger Philipp D. , Kranzler Henry R. , Nave Gideon , Wetherill Reagan R.
Published: March 2022

Heavy alcohol consumption has been associated with brain atrophy, neuronal loss, and poorer white matter fiber integrity. However, there is conflicting evidence on whether light-to-moderate alcohol consumption shows similar negative associations with brain structure. To address this, we examine the associations between alcohol intake and brain structure using multimodal imaging data from 36,678 generally healthy middle-aged and older adults from the UK Biobank, controlling for numerous potential confounds. Consistent with prior literature, we find negative associations between alcohol intake and brain macrostructure and microstructure. Specifically, alcohol intake is negatively associated with global brain volume measures, regional gray matter volumes, and white matter microstructure. Here, we show that the negative associations between alcohol intake and brain macrostructure and microstructure are already apparent in individuals consuming an average of only one to two daily alcohol units, and become stronger as alcohol intake increases.
Demonstration of non-destructive and isotope-sensitive material analysis using a short-pulsed laser-driven epi-thermal neutron source
Authors: Zimmer Marc , Scheuren Stefan , Kleinschmidt Annika , Mitura Nikodem , Tebartz Alexandra , Schaumann Gabriel , Abel Torsten , Ebert Tina , Hesse Markus , Zähter Şêro , Vogel Sven C. , Merle Oliver , Ahlers Rolf-Jürgen , Duarte Pinto Serge , Peschke Maximilian , Kröll Thorsten , Bagnoud Vincent , Rödel Christian , Roth Markus
Published: March 2022

Neutrons are a valuable tool for non-destructive material investigation as their interaction cross sections with matter are isotope sensitive and can be used complementary to x-rays. So far, most neutron applications have been limited to large-scale facilities such as nuclear research reactors, spallation sources, and accelerator-driven neutron sources. Here we show the design and optimization of a laser-driven neutron source in the epi-thermal and thermal energy range, which is used for non-invasive material analysis. Neutron resonance spectroscopy, neutron radiography, and neutron resonance imaging with moderated neutrons are demonstrated for investigating samples in terms of isotope composition and thickness. The experimental results encourage applications in non-destructive and isotope-sensitive material analysis and pave the way for compact laser-driven neutron sources with high application potential.
A programmable qudit-based quantum processor
Authors: Chi Yulin , Huang Jieshan , Zhang Zhanchuan , Mao Jun , Zhou Zinan , Chen Xiaojiong , Zhai Chonghao , Bao Jueming , Dai Tianxiang , Yuan Huihong , Zhang Ming , Dai Daoxin , Tang Bo , Yang Yan , Li Zhihua , Ding Yunhong , Oxenløwe Leif K. , Thompson Mark G. , O’Brien Jeremy L. , Li Yan , Gong Qihuang , Wang Jianwei
Published: March 2022

Controlling and programming quantum devices to process quantum information by the unit of quantum dit, i.e., qudit, provides the possibilities for noise-resilient quantum communications, delicate quantum molecular simulations, and efficient quantum computations, showing great potential to enhance the capabilities of qubit-based quantum technologies. Here, we report a programmable qudit-based quantum processor in silicon-photonic integrated circuits and demonstrate its enhancement of quantum computational parallelism. The processor monolithically integrates all the key functionalities and capabilities of initialisation, manipulation, and measurement of the two quantum quart (ququart) states and multi-value quantum-controlled logic gates with high-level fidelities. By reprogramming the configuration of the processor, we implemented the most basic quantum Fourier transform algorithms, all in quaternary, to benchmark the enhancement of quantum parallelism using qudits, which include generalised Deutsch-Jozsa and Bernstein-Vazirani algorithms, quaternary phase estimation and fast factorization algorithms. The monolithic integration and high programmability have allowed the implementations of more than one million high-fidelity preparations, operations and projections of qudit states in the processor. Our work shows an integrated photonic quantum technology for qudit-based quantum computing with enhanced capacity, accuracy, and efficiency, which could lead to the acceleration of building a large-scale quantum computer.
Ubiquitin and a charged loop regulate the ubiquitin E3 ligase activity of Ark2C
Authors: Paluda Andrej , Middleton Adam J. , Rossig Claudia , Mace Peter D. , Day Catherine L.
Published: March 2022

A large family of E3 ligases that contain both substrate recruitment and RING domains confer specificity within the ubiquitylation cascade. Regulation of RING E3s depends on modulating their ability to stabilise the RING bound E2~ubiquitin conjugate in the activated (or closed) conformation. Here we report the structure of the Ark2C RING bound to both a regulatory ubiquitin molecule and an activated E2~ubiquitin conjugate. The structure shows that the RING domain and non-covalently bound ubiquitin molecule together make contacts that stabilise the activated conformation of the conjugate, revealing why ubiquitin is a key regulator of Ark2C activity. We also identify a charged loop N-terminal to the RING domain that enhances activity by interacting with both the regulatory ubiquitin and ubiquitin conjugated to the E2. In addition, the structure suggests how Lys48-linked ubiquitin chains might be assembled by Ark2C and UbcH5b. Together this study identifies features common to RING E3s, as well elements that are unique to Ark2C and related E3s, which enhance assembly of ubiquitin chains.
Homotypic protection against influenza in a pediatric cohort in Managua, Nicaragua
Authors: Wraith Steph , Balmaseda Angel , Carrillo Fausto Andres Bustos , Kuan Guillermina , Huddleston John , Kubale John , Lopez Roger , Ojeda Sergio , Schiller Amy , Lopez Brenda , Sanchez Nery , Webby Richard , Nelson Martha I. , Harris Eva , Gordon Aubree
Published: March 2022

The period of protection from repeat infection following symptomatic influenza is not well established due to limited availability of longitudinal data. Using data from a pediatric cohort in Managua, Nicaragua, we examine the effects of natural influenza virus infection on subsequent infection with the same influenza virus subtype/lineage across multiple seasons, totaling 2,170 RT-PCR-confirmed symptomatic influenza infections. Logistic regression models assessed whether infection in the prior influenza season protected against homologous reinfection. We sequenced viruses from 2011–2019 identifying dominant clades and measuring antigenic distances between hemagglutinin clades. We observe homotypic protection from repeat infection in children infected with influenza A/H1N1pdm (OR 0.12, CI 0.02–0.88), A/H3N2 (OR 0.41, CI 0.24–0.73), and B/Victoria (OR 0.00, CI 0.00–0.14), but not with B/Yamagata viruses (OR 0.60, CI 0.09–2.10). Overall, protection wanes as time or antigenic distance increases. Individuals infected with one subtype or lineage of influenza virus have significantly lower odds of homologous reinfection for the following one to two years; after two years this protection wanes. This protection is demonstrated across multiple seasons, subtypes, and lineages among children.
Unsupervised machine learning for discovery of promising half-Heusler thermoelectric materials
Authors: Jia Xue , Deng Yanshuai , Bao Xin , Yao Honghao , Li Shan , Li Zhou , Chen Chen , Wang Xinyu , Mao Jun , Cao Feng , Sui Jiehe , Wu Junwei , Wang Cuiping , Zhang Qian , Liu Xingjun
Published: March 2022

Thermoelectric materials can be potentially applied to waste heat recovery and solid-state cooling because they allow a direct energy conversion between heat and electricity and vice versa. The accelerated materials design based on machine learning has enabled the systematic discovery of promising materials. Herein we proposed a successful strategy to discover and design a series of promising half-Heusler thermoelectric materials through the iterative combination of unsupervised machine learning with the labeled known half-Heusler thermoelectric materials. Subsequently, optimized zT values of ~0.5 at 925 K for p-type Sc0.7Y0.3NiSb0.97Sn0.03 and ~0.3 at 778 K for n-type Sc0.65Y0.3Ti0.05NiSb were experimentally achieved on the same parent ScNiSb.
TiO2 nanotube electrode for organic degradation coupled with flow-electrode capacitive deionization for brackish water desalination
Authors: Lim Jihun , Shin Yong-Uk , Son Aseom , Hong Seok Won , Hong Seungkwan
Published: March 2022

A photoelectrochemical (PEC) oxidation and flow-electrode capacitive deionization (FCDI) dual system was explored for the effective treatment of brackish water. Two anodic electrodes with electrochemically self-doped TiO2 arrays (blue-mesh/ blue-plate TiO2 nanotube arrays (BM-TNA & BP-TNA)) were fabricated by annealing at 600 °C, and applied for the treatment of a water system. Specifically, the BM-TNA confirmed lower electrical resistance and superior performance under multiple light source (UV-A, -B, and -C). Furthermore, the system generated powerful oxidizing reactive oxygen species (ROS), which were assessed via degradation of eight organic pollutants: bisphenol-A, 4-chlorophenol, cimetidine, sulfamethoxazole, benzoic acid, phenol, nitrobenzene, and acetaminophen. Decomposition efficiency was stable throughout a wide range of pH, and durability of the BM-TNA electrode was demonstrated through long-term operation. Concurrently, optimization of the FCDI process via key operational parameters (electrode mass loading, and applied voltage) achieved superior desalination performance, and specific energy consumption (SEC). In particular, increased mass loading enhanced charge transportation through the formation of stable charge-percolation pathways, leading to improved solution conductance. Finally, the feasibility of the dual system (PEC-FCDI) was verified through complete degradation of the organic substrates and successful desalination of the brackish water.
A reference set of clinically relevant adverse drug-drug interactions
Authors: Kontsioti Elpida , Maskell Simon , Dutta Bhaskar , Pirmohamed Munir
Published: March 2022

The accurate and timely detection of adverse drug-drug interactions (DDIs) during the postmarketing phase is an important yet complex task with potentially major clinical implications. The development of data mining methodologies that scan healthcare databases for drug safety signals requires appropriate reference sets for performance evaluation. Methodologies for establishing DDI reference sets are limited in the literature, while there is no publicly available resource simultaneously focusing on clinical relevance of DDIs and individual behaviour of interacting drugs. By automatically extracting and aggregating information from multiple clinical resources, we provide a scalable approach for generating a reference set for DDIs that could support research in postmarketing safety surveillance. CRESCENDDI contains 10,286 positive and 4,544 negative controls, covering 454 drugs and 179 adverse events mapped to RxNorm and MedDRA concepts, respectively. It also includes single drug information for the included drugs (i.e., adverse drug reactions, indications, and negative drug-event associations). We demonstrate usability of the resource by scanning a spontaneous reporting system database for signals of DDIs using traditional signal detection algorithms.
In silico identification of single nucleotide variations at CpG sites regulating CpG island existence and size
Authors: Shyamala Nivas , Kongettira Chaitra Lava , Puranam Kaushik , Kupsal Keerthi , Kummari Ramanjaneyulu , Padala Chiranjeevi , Hanumanth Surekha Rani
Published: March 2022

Genetic and epigenetic modifications of genes involved in the key regulatory pathways play a significant role in the pathophysiology and progression of multifactorial diseases. The present study is an attempt to identify single nucleotide variations (SNVs) at CpG sites of promoters of ACAT1, APOB, APOE, CYBA, FAS, FLT1, KSR2, LDLR, MMP9, PCSK9, PHOX2A, REST, SH2B3, SORT1 and TIMP1 genes influencing CpG island (CGI) existence and size associated with the pathophysiology of Diabetes mellitus, Coronary artery disease and Cancers. Promoter sequences located between −2000 to + 2000 bp were retrieved from the EPDnew database and predicted the CpG island using MethPrimer. Further, SNVs at CpG sites were accessed from NCBI, Ensembl while transcription factor (TF) binding sites were accessed using AliBaba2.1. CGI existence and size were determined for each SNV at CpG site with respect to wild type and variant allele by MethPrimer. A total of 200 SNVs at CpG sites were analyzed from the promoters of ACAT1, APOB, APOE, CYBA, FAS, FLT1, KSR2, LDLR, MMP9, PCSK9, PHOX2A, REST, SH2B3, SORT1 and TIMP1 genes. Of these, only 17 (8.5%) SNVs were found to influence the loss of CGI while 70 (35%) SNVs were found to reduce the size of CGI. It has also been found that 59% (10) of CGI abolishing SNVs are showing differences in binding of TFs. The findings of the study suggest that the candidate SNVs at CpG sites regulating CGI existence and size might influence the DNA methylation status and expression of genes involved in molecular pathways associated with several diseases. The insights of the present study may pave the way for new experimental studies to undertake challenges in DNA methylation, gene expression and protein assays.
Human infrapatellar fat pad mesenchymal stem cells show immunomodulatory exosomal signatures
Authors: Kouroupis Dimitrios , Kaplan Lee D. , Best Thomas M.
Published: March 2022

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases. Our hypothesis is that IFP-derived mesenchymal stem cells (IFP-MSC) robust immunomodulatory therapeutic effects are largely exerted via their exosomal (IFP-MSC EXOs) secretome by attenuating synoviocytes and macrophages pro-inflammatory activation. IFP-MSC EXOs showed distinct miRNA and protein immunomodulatory profiles. Reactome analysis of 24 miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, including immune system. Exosomes were enriched for immunomodulatory and reparative proteins that are involved in positive regulation of cell proliferation, response to stimulus, signal transduction, signal receptor activity, and protein phosphorylation. Stimulated synoviocytes or macrophages exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation, altered inflammation-related molecular profiles, and reduced secretion of pro-inflammatory molecules compared to stimulated alone. In an acute synovial/IFP inflammation rat model, IFP-MSC EXOs therapeutic treatment resulted in robust macrophage polarization towards an anti-inflammatory therapeutic M2 phenotype within the synovium/IFP tissues. Based on these findings, we propose a viable cell-free alternative to MSC-based therapeutics as an alternative approach to treating synovitis and IFP fibrosis.
Branch-like enhancement on contrast enhanced MRI is a specific finding of cerebellar lymphoma compared with other pathologies
Authors: Yokoyama Kota , Oyama Jun , Tsuchiya Junichi , Karakama Jun , Tamura Kaoru , Inaji Motoki , Tanaka Yoji , Kobayashi Daisuke , Maehara Taketoshi , Tateishi Ukihide
Published: March 2022

Branch-like enhancement (BLE) on contrast-enhanced (CE) magnetic resonance imaging (MRI) was found to be effective in differentiating primary central nervous system lymphoma (PCNSL) from high-grade glioma (HGG) in the cerebellum. However, whether it can be applied to assessments of secondary central nervous system lymphoma (SCNSL), or other cerebellar lesions is unknown. Hence, we retrospectively reviewed cerebellar masses to investigate the use of BLE in differentiating cerebellar lymphoma (CL), both primary and secondary, from other lesions. Two reviewers qualitatively evaluated the presence and degree of BLE on CE-T1 weighted imaging (T1WI). If multiple views were available, we determined the view in which BLE was the most visible. Seventy-five patients with the following pathologies were identified:17 patients with CL, 30 patients with metastasis, 12 patients with hemangioblastoma, 9 patients with HGG, and 7 patients with others. Twelve patients presented with PCNSL and five with SCNSL. Of 17 patients with CL, 15 (88%) had BLE, whereas three (5%) out of 58 patients in the non-CL group showed BLE. In patients who underwent three-dimensional-CE-T1WI, BLE was the most visible on the sagittal image. In conclusion, BLE is a highly specific finding for CL and the sagittal image is important in evaluating this finding.
Spatial distribution of live gut microbiota and bile acid metabolism in various parts of human large intestine
Authors: Chinda Daisuke , Takada Toshihiko , Mikami Tatsuya , Shimizu Kensuke , Oana Kosuke , Arai Tetsu , Akitaya Kazuki , Sakuraba Hirotake , Katto Miyuki , Nagara Yusuke , Makino Hiroshi , Fujii Daichi , Oishi Kenji , Fukuda Shinsaku
Published: March 2022

Gut microbiomics is based on analysis of both live and dead cells in the stool. However, to understand the ecology of gut microbiota and their symbiotic relationships with hosts, spatial distribution of live bacteria must be examined. Here, we analyzed the live composition of luminal microbiota (LM) and mucosa-associated microbiota (MAM) in the ascending and descending colons and the rectums of 10 healthy adults and compared it with the total composition. The abundance of Lachnospiraceae in live LM decreased along the gut length and was significantly lower than that in total LM. Contrastingly, the abundance of Bacteroidaceae and Bifidobacteriaceae in live LM was higher than that in total LM, suggesting differences in death rate during gut migration. Live Enterobacteriaceae levels in MAM were significantly higher in rectum than in the ascending and descending colons and in LM. High-performance liquid chromatographic analysis of luminal bile acids revealed that 7α-dehydroxylation occurred towards the rectum. In live LM where a bile acid-inducible gene could be detected, 7α-dehydroxylation rates were higher than those in the group without the gene. Overall, we showed differences in live bacteria composition among three gut sites and between LM and MAM, highlighting the importance of understanding their spatial distribution.
Temporal properties of positive and negative defocus on emmetropization
Authors: Zhu Xiaoying , Kang Pauline , Troilo David , Benavente-Perez Alexandra
Published: March 2022

Studying the temporal integration of visual signals is crucial to understand how time spent on different visual tasks can affect emmetropization and refractive error development. In this study we assessed the effect of interrupting positive and negative lens-imposed defocus with brief periods of unrestricted vision or darkness. A total of forty-six marmosets were treated monocularly with soft contact lenses for 4 weeks from 10 weeks of age (OD: + 5D or − 5D; OS: plano). Two control groups wore + 5D (n = 5) or − 5D (n = 13) lenses continuously for 9 h/day. Two experimental groups had lens-wear interrupted for 30 min twice/day at noon and mid-afternoon by removing lenses and monitoring vision while marmosets sat at the center of a viewing cylinder (normal vision interruption, + 5D: n = 7; − 5D: n = 8) or while they were in the dark (dark interruption, + 5D: n = 7; − 5D: n = 6). The interruption period (30 min/day) represented approx. 10% of the total stimulation time (9 h/day). On-axis refractive error (RE) and vitreous chamber depth (VCD) were measured using an autorefractor and high frequency A-scan ultrasound at baseline and after treatment. Wearing + 5D lenses continuously 9 h/day for 4 weeks induced slowed eye growth and hyperopic shifts in RE in treated relative to contralateral control eyes (relative change, VCD: − 25 ± 11 μm, p > 0.05; RE: + 1.24 ± 0.58 D, p > 0.05), whereas − 5D lens wear resulted in larger and myopic eyes (relative change, VCD: + 109 ± 24 μm, p < 0.001; RE: − 2.03 ± 0.56 D, p < 0.05), significantly different from those in the + 5D lens-treated animals (p < 0.01 for both). Interrupting lens induced defocus with periods of normal vision or darkness for approx. 10% of the treatment time affected the resulting compensation differently for myopic and hyperopic defocus. Interrupting defocus with unrestricted vision reduced − 5D defocus compensation but enhanced + 5D defocus compensation (− 5D, VCD: + 18 ± 33 μm; RE: − 0.93 ± 0.50 D, both p > 0.05; + 5D, VCD: − 86 ± 30 μm; RE: + 1.93 ± 0.50 D, both p < 0.05). Interrupting defocus with darkness also decreased − 5D defocus compensation, but had little effect on + 5D defocus compensation (− 5D, VCD: + 73 ± 34 μm, RE: − 1.13 ± 0.77 D, p > 0.05 for both; + 5D, VCD: − 10 ± 28 μm, RE: + 1.22 ± 0.50 D, p > 0.05 for both). These findings in a non-human primate model of emmetropization are similar to those described in other species and confirm a non-linear model of visual signal integration over time. This suggests a mechanism that is conserved across species and may have clinical implications for myopia management in school-aged children.
Expression profiling of TaARGOS homoeologous drought responsive genes in bread wheat
Authors: Ahmed Kashif , Shabbir Ghulam , Ahmed Mukhtar , Noor Sabahat , Mohi Ud Din Atta , Qamar Maqsood , Rehman Nazia
Published: March 2022

Drought tolerant germplasm is needed to increase crop production, since water scarcity is a critical bottleneck in crop productivity worldwide. Auxin Regulated Gene involved in Organ Size (ARGOS) is a large protein family of transcription factors that plays a vital role in organ size, plant growth, development, and abiotic stress responses in plants. Although, the ARGOS gene family has been discovered and functionalized in a variety of crop plants, but a comprehensive and systematic investigation of ARGOS genes in locally used commercial wheat cultivars is still yet to be reported. The relative expression of three highly conserved TaARGOS homoeologous genes (TaARGOS-A, TaARGOS-B, TaARGOS-D) was studied in three drought-tolerant (Pakistan-2013, NARC-2009 and NR-499) and three sensitive (Borlaug-2016, NR-514 and NR-516) wheat genotypes under osmotic stress, induced by PEG-6000 at 0 (exogenous control), 2, 4, 6, and 12 h. The normalization of target genes was done using β-actin as endogenous control, whereas DREB3, as a marker gene was also transcribed, reinforcing the prevalence of dehydration in all stress treatments. Real-time quantitative PCR revealed that osmotic stress induced expression of the three TaARGOS transcripts in different wheat seedlings at distinct timepoints. Overall, all genes exhibited significantly higher expression in the drought-tolerant genotypes as compared to the sensitive ones. For instance, the expression profile of TaARGOS-A and TaARGOS-D showed more than threefold increase at 2 h and six to sevenfold increase after 4 h of osmotic stress. However, after 6 h of osmotic stress these genes started to downregulate, and the lowest gene expression was noticed after 12 h of osmotic stress. Among all the homoeologous genes, TaARGOS-D, in particular, had a more significant influence on controlling plant growth and drought tolerance as it showed the highest expression. Altogether, TaARGOSs are involved in seedling establishment and overall plant growth. In addition, the tolerant group of genotypes had a much greater relative fold expression than the sensitive genotypes. Ultimately, Pakistan-2013 showed the highest relative expression of the studied genes than other genotypes which shows its proficiency to mitigate osmotic stress. Therefore, it could be cultivated in arid and semi-arid regions under moisture-deficient regimes. These findings advocated the molecular mechanism and regulatory roles of TaARGOS genes in plant growth and osmotic stress tolerance in contrasting groups of wheat genotypes, accompanied by the genetic nature of identified genotypes in terms of their potential for drought tolerance.
Author Correction: Understanding contagion dynamics through microscopic processes in active Brownian particles
Authors: Norambuena Ariel , Valencia Felipe J. , Guzmán‑Lastra Francisca
Published: March 2022

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Rap1 prevents colitogenic Th17 cell expansion and facilitates Treg cell differentiation and distal TCR signaling
Authors: Ishihara Sayaka , Sato Tsuyoshi , Fujikado Noriyuki , Miyazaki Haruka , Yoshimoto Takayuki , Yamamoto Hiromitsu , Fukuda Shinji , Katagiri Koko
Published: March 2022

T-cell-specific Rap1 deletion causes spontaneous colitis in mice. In the present study, we revealed that Rap1 deficiency in T cells impaired the preceding induction of intestinal RORγt+Treg cells. In the large intestinal lamina propria (LILP) of T-cell-specific Rap1-knockout mice (Rap1KO mice), Th17 cells were found to increase in a microbiota-dependent manner, and the inhibition of IL-17A production prevented the development of colitis. In the LILP of Rap1KO mice, RORγt+Treg cells were scarcely induced by 4 weeks of age. The expression of CTLA-4 on Rap1-deficient Treg cells was reduced and the expression of CD80 and CD86 on dendritic cells was consequently elevated in Rap1KO mice. When cultured under each polarizing condition, Rap1-deficient naïve CD4+T cells did not show biased differentiation into Th17 cells; their differentiation into Treg cells as well as Th1 and Th2 cells was lesser than that of wild-type cells. Rap1-deficient naïve CD4+T cells were found to exhibit the defective nuclear translocation of NFAT and formation of actin foci in response to TCR engagement. These data suggest that Rap1 amplifies the TCR signaling required for Treg-mediated control of intestinal colitogenic Th17 responses.
A leafhopper saliva protein mediates horizontal transmission of viral pathogens from insect vectors into rice phloem
Authors: Wu Wei , Yi Ge , Lv Xinwei , Mao Qianzhuo , Wei Taiyun
Published: March 2022

Numerous insects transmit viruses together with saliva to plant phloem, but the roles of saliva components remain elusive. Here, we report that calcium-binding protein (CBP), a universal insect saliva protein, is modified to benefit horizontal transmission of a devastating rice reovirus into plant phloem. CBP effectively competes with virus-induced filaments to target and traverse actin-based apical plasmalemma into saliva-stored cavities in salivary glands of leafhopper vector. Thus, the inhibition of CBP expression by viral infection facilitates filament-mediated viral secretion into salivary cavities and then into plant phloem. Furthermore, virus-mediated reduction of CBP secretion causes an increase of cytosolic Ca2+ levels in rice, triggering substantial callose deposition and H2O2 production. Thus, viruliferous vectors encounter stronger feeding barriers, probe more frequently, and secrete more saliva into plants, ultimately enhancing viral transmission. We thus conclude that the inhibition of CBP secretion facilitates viral secretion and increases host defense response to benefit viral transmission.
The evolution of biogeochemical recycling by persistence-based selection
Authors: Boyle Richard A. , Lenton Timothy M.
Published: March 2022

Darwinian evolution operates at more restricted scales than the feedback processes within the Earth system, precluding the development of any systematic relationship between the organism-level traits favored by natural selection and the impact of these traits upon Earth’s long-term average habitability for life. “It’s-the-song-not-the-singer” theory proposes an extended understanding of natural selection to encompass differential persistence of non-replicating entities, potentially allowing for a quasi-Darwinian understanding of biogeochemical cycles. Here we use a simple stochastic model to demonstrate how persistence selection of the form invoked by “It’s-the-song-not-the-singer” can stabilize a generic nutrient recycling loop, despite its dependence upon genotypes with relatively low organism-level fitness. We present an evolutionary trajectory plausibly representative of aspects of Precambrian biogeochemical cycles, involving persistence-based selection for recycling via fluctuations in abiotic boundary conditions and strong genetic drift. We illustrate how self-perpetuating life-environment correlation patterns, as opposed to specific state-values, may help empirically distinguish “It’s-the-song-not-the-singer” from conventional Earth-system feedbacks.
Tracing the migration and transformation of metabolites in xylem during wood growth by mass spectrometry imaging
Authors: Hu Wenya , Nie Honggang , Wang Yinghao , Li Na , Di Shuangshuang , Pan Qiong , Liu Jikun , Han Yehua
Published: March 2022

MALDI MSI was used to explore the rule of metabolite migration and transformation for the first time. The rules of heartwood formation and resin secretion were visualized and fully explored.
A physics-inspired neural network to solve partial differential equations – application in diffusion-induced stress
Authors: Xue Yuan , Li Yong , Zhang Kai , Yang Fuqian
Published: March 2022

A physics-inspired deep neural network is used to numerically solve diffusion induced stress (DIS) in an elastic spherical electrode, and the accuracies are above 97.98% and 92.56% for decoupling and coupling problems, respectively.
Platycodon grandiflorum root fermentation broth reduces inflammation in a mouse IBD model through the AMPK/NF-κB/NLRP3 pathway
Authors: Wang Zhe , Li Chunhai , He Xi , Xu Kang , Xue Zhipeng , Wang Ting , Xu Zhenshang , Liu Xinli
Published: March 2022

Schematic graph of PGRFB affecting DSS-induced UC through the AMPK/NF-κB/NLRP3 signaling pathway.
Oxygen vacancies in oxidized and reduced vertically aligned α-MoO3 nanoblades
Authors: Noby Sohaila Z. , Fakharuddin Azhar , Schupp Stefan , Sultan Muhammad , Krumova Marina , Drescher Malte , Azarkh Mykhailo , Boldt Klaus , Schmidt-Mende Lukas
Published: March 2022

Oxidation states of MoO3 alter the electronic properties by several orders of magnitude. Oxygen vacancy-mediated intrinsic defects in vertically aligned α-MoO3 crystals are systematically tuned and their impact on optoelectronic properties analyzed.
N-gene-complementary antisense-oligonucleotide directed molecular aggregation of dual-colour carbon dots, leading to efficient fluorometric sensing of SARS-COV-2 RNA
Authors: Sheffield Zach , Alafeef Maha , Moitra Parikshit , Ray Priyanka , Pan Dipanjan
Published: March 2022

Herein, we report that a pair of complementary antisense oligonucleotide (ASO) sequences can lead to a highly specific molecular aggregation of dual colour carbon dots (CDs) in the presence of SARS-CoV-2 RNA.