bluuebunny/crossref_metadata_2025 huggingface dataset:
Stromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
Authors: Wang Wenyu , Tang Yen-An , Xiao Qian , Lee Wee Chyan , Cheng Bing , Niu Zhitong , Oguz Gokce , Feng Min , Lee Puay Leng , Li Baojie , Yang Zi-huan , Chen Yu-feng , Lan Ping , Wu Xiao-Jian , Yu Qiang
Published: July 2021

BRD4, a Bromodomain and Extraterminal (BET) protein family member, is a promising anti-cancer drug target. However, resistance to BET inhibitors targeting BRD4 is common in solid tumors. Here, we show that cancer-associated fibroblast (CAF)-activated stromal signaling, interleukin-6/8-JAK2, induces BRD4 phosphorylation at tyrosine 97/98 in colorectal cancer, resulting in BRD4 stabilization due to interaction with the deubiquitinase UCHL3. BRD4 phosphorylation at tyrosine 97/98 also displays increased binding to chromatin but reduced binding to BET inhibitors, resulting in resistance to BET inhibitors. We further show that BRD4 phosphorylation promotes interaction with STAT3 to induce chromatin remodeling through concurrent binding to enhancers and super-enhancers, supporting a tumor-promoting transcriptional program. Inhibition of IL6/IL8-JAK2 signaling abolishes BRD4 phosphorylation and sensitizes BET inhibitors in vitro and in vivo. Our study reveals a stromal mechanism for BRD4 activation and BET inhibitor resistance, which provides a rationale for developing strategies to treat CRC more effectively.
Small RNA mediated gradual control of lipopolysaccharide biosynthesis affects antibiotic resistance in Helicobacter pylori
Authors: Pernitzsch Sandy R. , Alzheimer Mona , Bremer Belinda U. , Robbe-Saule Marie , De Reuse Hilde , Sharma Cynthia M.
Published: July 2021

The small, regulatory RNA RepG (Regulator of polymeric G-repeats) regulates the expression of the chemotaxis receptor TlpB in Helicobacter pylori by targeting a variable G-repeat in the tlpB mRNA leader. Here, we show that RepG additionally controls lipopolysaccharide (LPS) phase variation by also modulating the expression of a gene (hp0102) that is co-transcribed with tlpB. The hp0102 gene encodes a glycosyltransferase required for LPS O-chain biosynthesis and in vivo colonization of the mouse stomach. The G-repeat length defines a gradual (rather than ON/OFF) control of LPS biosynthesis by RepG, and leads to gradual resistance to a membrane-targeting antibiotic. Thus, RepG-mediated modulation of LPS structure might impact host immune recognition and antibiotic sensitivity, thereby helping H. pylori to adapt and persist in the host.
Increasing the Hilbert space dimension using a single coupled molecular spin
Authors: Biard Hugo , Moreno-Pineda Eufemio , Ruben Mario , Bonet Edgar , Wernsdorfer Wolfgang , Balestro Franck
Published: July 2021

Quantum technologies are expected to introduce revolutionary changes in information processing in the near future. Nowadays, one of the main challenges is to be able to handle a large number of quantum bits (qubits), while preserving their quantum properties. Beyond the usual two-level encoding capacity of qubits, multi-level quantum systems are a promising way to extend and increase the amount of information that can be stored in the same number of quantum objects. Recent work (Kues et al. 2017), has shown the possibility to use devices based on photonic integrated circuits to entangle two qudits (with “d” being the number of available states). In the race to develop a mature quantum technology with real-world applications, many possible platforms are being investigated, including those that use photons, trapped ions, superconducting and silicon circuits and molecular magnets. In this work, we present the electronic read-out of a coupled molecular multi-level quantum systems, carried by a single Tb2Pc3 molecular magnet. Owning two magnetic centres, this molecular magnet architecture permits a 16 dimensions Hilbert space, opening the possibility of performing more complex quantum algorithms.
3-hydroxy-L-kynurenamine is an immunomodulatory biogenic amine
Authors: Clement Cristina C. , D’Alessandro Angelo , Thangaswamy Sangeetha , Chalmers Samantha , Furtado Raquel , Spada Sheila , Mondanelli Giada , Ianni Federica , Gehrke Sarah , Gargaro Marco , Manni Giorgia , Cara Luisa Carlota Lopez , Runge Peter , Tsai Wanxia Li , Karaman Sinem , Arasa Jorge , Fernandez-Rodriguez Ruben , Beck Amanda , Macchiarulo Antonio , Gadina Massimo , Halin Cornelia , Fallarino Francesca , Skobe Mihaela , Veldhoen Marc , Moretti Simone , Formenti Silvia , Demaria Sandra , Soni Rajesh K. , Galarini Roberta , Sardella Roccaldo , Lauvau Gregoire , Putterman Chaim , Alitalo Kari , Grohmann Ursula , Santambrogio Laura
Published: July 2021

Tryptophan catabolism is a major metabolic pathway utilized by several professional and non-professional antigen presenting cells to maintain immunological tolerance. Here we report that 3-hydroxy-l-kynurenamine (3-HKA) is a biogenic amine produced via an alternative pathway of tryptophan metabolism. In vitro, 3-HKA has an anti-inflammatory profile by inhibiting the IFN-γ mediated STAT1/NF-κΒ pathway in both mouse and human dendritic cells (DCs) with a consequent decrease in the release of pro-inflammatory chemokines and cytokines, most notably TNF, IL-6, and IL12p70. 3-HKA has protective effects in an experimental mouse model of psoriasis by decreasing skin thickness, erythema, scaling and fissuring, reducing TNF, IL-1β, IFN-γ, and IL-17 production, and inhibiting generation of effector CD8+ T cells. Similarly, in a mouse model of nephrotoxic nephritis, besides reducing inflammatory cytokines, 3-HKA improves proteinuria and serum urea nitrogen, overall ameliorating immune-mediated glomerulonephritis and renal dysfunction. Overall, we propose that this biogenic amine is a crucial component of tryptophan-mediated immune tolerance.
IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer
Authors: Tulotta Claudia , Lefley Diane V. , Moore Charlotte K. , Amariutei Ana E. , Spicer-Hadlington Amy R. , Quayle Lewis A. , Hughes Russell O. , Ahmed Khawla , Cookson Victoria , Evans Catherine A. , Vadakekolathu Jayakumar , Heath Paul , Francis Sheila , Pinteaux Emmanuel , Pockley A. Graham , Ottewell Penelope D.
Published: July 2021

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients.
Quantum phases and spin liquid properties of 1T-TaS2
Authors: Mañas-Valero Samuel , Huddart Benjamin M. , Lancaster Tom , Coronado Eugenio , Pratt Francis L.
Published: July 2021

Quantum materials exhibiting magnetic frustration are connected to diverse phenomena, including high Tc superconductivity, topological order, and quantum spin liquids (QSLs). A QSL is a quantum phase (QP) related to a quantum-entangled fluid-like state of matter. Previous experiments on QSL candidate materials are usually interpreted in terms of a single QP, although theories indicate that many distinct QPs are closely competing in typical frustrated spin models. Here we report on combined temperature-dependent muon spin relaxation and specific heat measurements for the triangular-lattice QSL candidate material 1T-TaS2 that provide evidence for competing QPs. The measured properties are assigned to arrays of individual QSL layers within the layered charge density wave structure of 1T-TaS2 and their characteristic parameters can be interpreted as those of distinct Z2 QSL phases. The present results reveal that a QSL description can extend beyond the lowest temperatures, offering an additional perspective in the search for such materials.
Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers
Authors: Caushi Justina X. , Zhang Jiajia , Ji Zhicheng , Vaghasia Ajay , Zhang Boyang , Hsiue Emily Han-Chung , Mog Brian J. , Hou Wenpin , Justesen Sune , Blosser Richard , Tam Ada , Anagnostou Valsamo , Cottrell Tricia R. , Guo Haidan , Chan Hok Yee , Singh Dipika , Thapa Sampriti , Dykema Arbor G. , Burman Poromendro , Choudhury Begum , Aparicio Luis , Cheung Laurene S. , Lanis Mara , Belcaid Zineb , El Asmar Margueritta , Illei Peter B. , Wang Rulin , Meyers Jennifer , Schuebel Kornel , Gupta Anuj , Skaist Alyza , Wheelan Sarah , Naidoo Jarushka , Marrone Kristen A. , Brock Malcolm , Ha Jinny , Bush Errol L. , Park Bernard J. , Bott Matthew , Jones David R. , Reuss Joshua E. , Velculescu Victor E. , Chaft Jamie E. , Kinzler Kenneth W. , Zhou Shibin , Vogelstein Bert , Taube Janis M. , Hellmann Matthew D. , Brahmer Julie R. , Merghoub Taha , Forde Patrick M. , Yegnasubramanian Srinivasan , Ji Hongkai , Pardoll Drew M. , Smith Kellie N.
Published: July 2021

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThighTRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.
Aerosol emission in professional singing of classical music
Authors: Mürbe Dirk , Kriegel Martin , Lange Julia , Rotheudt Hansjörg , Fleischer Mario
Published: July 2021

In this study, emission rates of aerosols emitted by professional singers were measured with a laser particle counter under cleanroom conditions. The emission rates during singing varied between 753 and 6093 particles/sec with a median of 1537 particles/sec. Emission rates for singing were compared with data for breathing and speaking. Significantly higher emission rates were found for singing. The emission enhancements between singing and speaking were between 4.0 and 99.5 with a median of 17.4, largely due to higher sound pressure levels when singing. Further, significant effects of vocal loudness were found, whereas there were no significant differences between the investigated voice classifications. The present study supports the efforts to improve the risk management in cases of possible aerogenic virus transmission, especially for choir singing.
Comparison of two novel swept-source optical coherence tomography devices to a partial coherence interferometry-based biometer
Authors: Chan Tommy C. Y. , Yu Marco C. Y. , Chiu Vivian , Lai Gilda , Leung Christopher K. S. , Chan Poemen P. M.
Published: July 2021

To evaluate the repeatability and agreement of corneal and biometry measurements obtained with two swept-source optical coherence tomography (SSOCT) and a partial coherence interferometry-based device. This is a cross-sectional study. Forty-eight eyes of 48 patients had three consecutive measurements for ANTERION (Heidelberg Engineering, Germany), CASIAII (Tomey, Japan) and IOLMaster500 (Carl Zeiss Meditec, USA) on the same visit. Mean keratometry (Km), central corneal thickness (CCT), anterior chamber depth (ACD) and axial length (AL) were recorded. Corneal astigmatic measurements were converted into vector components—J0 and J45. Intra-device repeatability and agreements of measurements amongst the devices were evaluated using repeatability coefficients (RCs) and Bland–Altman plots, respectively. All devices demonstrated comparable repeatability for Km (p ≥ 0.138). ANTERION had the lowest RC for J0 amongst the devices (p ≤ 0.039). Systematic difference was found for the Km and J0 obtained with IOLMaster500 compared to either SSOCTs (p ≤ 0.010). The ACD and AL measured by IOLMaster500 showed a higher RC compared with either SSOCTs (p < 0.002). Systematic difference was found in CCT and ACD between the two SSOCTs (p < 0.001), and in AL between ANTERION and IOLMaster500 (p < 0.001), with a mean difference of 1.6 µm, 0.022 mm and 0.021 mm, respectively. Both SSOCTs demonstrated smaller test–retest variability for measuring ACD and AL compared with IOLMaster500. There were significant disagreement in keratometry and AL measurements between the SSOCTs and PCI-based device; their measurements should not be considered as interchangeable.
Anticancer effects of the combined Thai noni juice ethanolic extracts and 5-fluorouracil against cholangiocarcinoma cells in vitro and in vivo
Authors: Prompipak Jeerati , Senawong Thanaset , Sripa Banchob , Ketterman Albert J. , Utaiwat Suppawit , Woranam Khanutsanan , Jeeunngoi Jarckrit , Senawong Gulsiri
Published: July 2021

Application of 5-fluorouracil (5-FU) in cholangiocarcinoma (CCA) is limited by adverse side effects and chemoresistance. Therefore, the combination therapy of 5-FU with other substances, especially natural products may provide a new strategy for CCA treatment. The aim of this study was to evaluate the combination effects of 5-FU and two ethanolic extracts of Thai noni juice (TNJ) products on CCA cell lines and nude mice xenografts. The results of antiproliferative assay showed the combination treatment of 5-FU and each TNJ ethanolic extract exerted more cytotoxicity on CCA cells than either single agent treatment. Synergistic effects of drug combinations can enable the dose reduction of 5-FU. The mechanism underlying a combination treatment was apoptosis induction through an activation of p53 and Bax proteins. In the nude mouse xenograft model, combination treatments of 5-FU with each TNJ ethanolic extract suppressed the growth of CCA cells implanted mice more than single agent treatments with no effects on mouse body weight, kidney, and spleen. Moreover, low doses of TNJ ethanolic extracts reduced the hepatotoxicity of 5-FU in nude mice. Taken together, these data suggested that the ethanolic extracts of TNJ products can enhance the anti-CCA effect and reduce toxicity of 5-FU.
Inhibition of the canonical Wnt signaling pathway by a β-catenin/CBP inhibitor prevents heart failure by ameliorating cardiac hypertrophy and fibrosis
Authors: Methatham Thanachai , Tomida Shota , Kimura Natsuka , Imai Yasushi , Aizawa Kenichi
Published: July 2021

In heart failure (HF) caused by hypertension, the myocyte size increases, and the cardiac wall thickens. A low-molecular-weight compound called ICG001 impedes β-catenin-mediated gene transcription, thereby protecting both the heart and kidney. However, the HF-preventive mechanisms of ICG001 remain unclear. Hence, we investigated how ICG001 can prevent cardiac hypertrophy and fibrosis induced by transverse aortic constriction (TAC). Four weeks after TAC, ICG001 attenuated cardiac hypertrophy and fibrosis in the left ventricular wall. The TAC mice treated with ICG001 showed a decrease in the following: mRNA expression of brain natriuretic peptide (Bnp), Klf5, fibronectin, β-MHC, and β-catenin, number of cells expressing the macrophage marker CD68 shown in immunohistochemistry, and macrophage accumulation shown in flow cytometry. Moreover, ICG001 may mediate the substrates in the glycolysis pathway and the distinct alteration of oxidative stress during cardiac hypertrophy and HF. In conclusion, ICG001 is a potential drug that may prevent cardiac hypertrophy and fibrosis by regulating KLF5, immune activation, and the Wnt/β-catenin signaling pathway and inhibiting the inflammatory response involving macrophages.
The interactions between genetics and early childhood nutrition influence adult cardiometabolic risk factors
Authors: Wang Carol A. , Attia John R. , Lye Stephen J. , Oddy Wendy H. , Beilin Lawrence , Mori Trevor A. , Meyerkort Claire , Pennell Craig E.
Published: July 2021

It is well established that genetics, environment, and interplay between them play a crucial role in adult disease. We aimed to evaluate the role of genetics, early life nutrition, and the interaction between them, on optimal adult health. As part of a large international consortium (n ~ 154,000), we identified 60 SNPs associated with both birthweight and adult disease. Utilising the Raine Study, we developed a birthweight polygenic score (BW-PGS) based on the 60 SNPs and examined relationships between BW-PGS and adulthood cardiovascular risk factors, specifically evaluating interactions with early life nutrition. Healthy nutrition was beneficial for all individuals; longer duration of any breastfeeding was particularly associated with lower BMI and lower Systolic Blood Pressure in those with higher BW-PGS. Optimal breastfeeding offers the greatest benefit to reduce adult obesity and hypertension in those genetically predisposed to high birthweight. This provides an example of how precision medicine in early life can improve adult health.
Observed three dimensional distributions of enhanced turbulence near the Luzon Strait
Authors: Wang Jianfeng , Yu Fei , Nan Feng , Ren Qiang , Chen Zifei , Zheng Tongtong
Published: July 2021

Ocean turbulence can impact the transfer of heat, nutrients, momentum and sea level rise, which are crucially important to climate systems. The Luzon Strait, one of the mixing hotspots, is important for water exchange between the northeastern South China Sea and West Pacific. Here, for the first time, we carry out full-depth direct microstructure measurements surrounding the Luzon Strait to clarify the three-dimensional distributions of turbulence. We demonstrate that the turbulent kinetic energy dissipation rates in the upper and middle layers of the northeastern South China Sea are on the same order of magnitude as those in the West Pacific. The dissipation rates are only bottom enhanced near the rough topography of the South China Sea slope and Luzon Strait which is one order of magnitude larger than those at smooth area. The relevant bottom diapycnal diffusivity in the South China Sea is elevated in the West Pacific by a factor of three, instead of by two orders of magnitude as overestimated by indirect parameterization. These results may appear surprising in light of previous studies but are in fact consistent with predictions from internal wave-topography interaction theory.
Rapid in vitro quantification of TDP-43 and FUS mislocalisation for screening of gene variants implicated in frontotemporal dementia and amyotrophic lateral sclerosis
Authors: Oyston Lisa J. , Ubiparipovic Stephanie , Fitzpatrick Lauren , Hallupp Marianne , Boccanfuso Lauren M. , Kwok John B. , Dobson-Stone Carol
Published: July 2021

Identified genetic mutations cause 20% of frontotemporal dementia (FTD) and 5-10% of amyotrophic lateral sclerosis (ALS) cases: however, for the remainder of patients the origin of disease is uncertain. The overlap in genetic, clinical and pathological presentation of FTD and ALS suggests these two diseases are related. Post-mortem, ~ 95% of ALS and ~ 50% of FTD patients show redistribution of the nuclear protein TDP-43 to the cytoplasm within affected neurons, while ~ 5% ALS and ~ 10% FTD show mislocalisation of FUS protein. We exploited these neuropathological features to develop an unbiased method for the in vitro quantification of cytoplasmic TDP-43 and FUS. Utilising fluorescently-tagged cDNA constructs and immunocytochemistry, the fluorescence intensity of TDP-43 or FUS was measured in the nucleus and cytoplasm of cells, using the freely available software CellProfiler. Significant increases in the amount of cytoplasmic TDP-43 and FUS were detectable in cells expressing known FTD/ALS-causative TARDBP and FUS gene mutations. Pharmacological intervention with the apoptosis inducer staurosporine and mutation in a secondary gene (CYLD) also induced measurable cytoplasmic mislocalisation of endogenous FUS and TDP-43, respectively. These findings validate this methodology as a novel in vitro technique for the quantification of TDP-43 or FUS mislocalisation that can be used for initial prioritisation of predicted FTD/ALS-causative mutations.
Brown banded bamboo shark (Chiloscyllium punctatum) shows high genetic diversity and differentiation in Malaysian waters
Authors: Lim Kean Chong , Then Amy Yee-Hui , Wee Alison Kim Shan , Sade Ahemad , Rumpet Richard , Loh Kar-Hoe
Published: July 2021

The demersal brown banded bamboo shark Chiloscyllium punctatum is a major component of sharks landed in Malaysia. However, little is known about their population structure and the effect of high fishing pressure on these weak swimming sharks. Both mitochondrial DNA control region (1072 bp) and NADH dehydrogenase subunit 2 (1044 bp) were used to elucidate the genetic structure and connectivity of C. punctatum among five major areas within the Sundaland region. Our findings revealed (i) strong genetic structure with little present day mixing between the major areas, (ii) high intra-population genetic diversity with unique haplotypes, (iii) significant correlation between genetic differentiation and geographical distance coupled with detectable presence of fine scale geographical barriers (i.e. the South China Sea), (iv) historical directional gene flow from the east coast of Peninsular Malaysia towards the west coast and Borneo, and (v) no detectable genetic differentiation along the coastline of east Peninsular Malaysia. Genetic patterns inferred from the mitochondrial DNA loci were consistent with the strong coastal shelf association in this species, the presence of contemporary barriers shaped by benthic features, and limited current-driven egg dispersal. Fine scale population structure of C. punctatum highlights the need to improve genetic understanding for fishery management and conservation of other small-sized sharks.
Compression-rate dependence of pressure-induced phase transitions in Bi
Authors: Husband Rachel J. , O’Bannon Earl F. , Liermann Hanns-Peter , Lipp Magnus J. , Méndez Alba S. J. , Konôpková Zuzana , McBride Emma E. , Evans William J. , Jenei Zsolt
Published: July 2021

It is qualitatively well known that kinetics related to nucleation and growth can shift apparent phase boundaries from their equilibrium value. In this work, we have measured this effect in Bi using time-resolved X-ray diffraction with unprecedented 0.25 ms time resolution, accurately determining phase transition pressures at compression rates spanning five orders of magnitude (10–2–103 GPa/s) using the dynamic diamond anvil cell. An over-pressurization of the Bi-III/Bi-V phase boundary is observed at fast compression rates for different sample types and stress states, and the largest over-pressurization that is observed is ΔP = 2.5 GPa. The work presented here paves the way for future studies of transition kinetics at previously inaccessible compression rates.
Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration
Authors: Pita-Thomas Wolfgang , Gonçalves Tassia Mangetti , Kumar Ajeet , Zhao Guoyan , Cavalli Valeria
Published: July 2021

Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.
Joint analysis of D-dimer, N-terminal pro b-type natriuretic peptide, and cardiac troponin I on predicting acute pulmonary embolism relapse and mortality
Authors: Liu Xiaoyu , Zheng Liying , Han Jing , Song Lu , Geng Hemei , Liu Yunqiu
Published: July 2021

Previous studies on the adverse events of acute pulmonary embolism (APE) were mostly limited to single marker, and short follow-up duration, from hospitalization to up to 30 days. We aimed to predict the long-term prognosis of patients with APE by joint assessment of D-dimer, N-Terminal Pro-Brain Natriuretic Peptide (NT-ProBNP), and troponin I (cTnI). Newly diagnosed patients of APE from January 2011 to December 2015 were recruited from three hospitals. Medical information of the patients was collected retrospectively by reviewing medical records. Adverse events (APE recurrence and all-cause mortality) of all enrolled patients were followed up via telephone. D-dimer > 0.50 mg/L, NT-ProBNP > 500 pg/mL, and cTnI > 0.40 ng/mL were defined as the abnormal. Kaplan–Meier curve was used to compare the cumulative survival rate between patients with different numbers of abnormal markers. Cox proportional hazard regression model was used to further test the association between numbers of abnormal markers and long-term prognosis of patients with APE after adjusting for potential confounding. During follow-up, APE recurrence and all-cause mortality happened in 78 (30.1%) patients. The proportion of APE recurrence and death in one abnormal marker, two abnormal markers, and three abnormal markers groups were 7.69%, 28.21%, and 64.10% respectively. Patients with three abnormal markers had the lowest survival rate than those with one or two abnormal markers (Log-rank test, P < 0.001). After adjustment, patients with two or three abnormal markers had a significantly higher risk of the total adverse event compared to those with one abnormal marker. The hazard ratios (95% confidence interval) were 6.27 (3.24, 12.12) and 10.7 (4.1, 28.0), respectively. Separate analyses for APE recurrence and all-cause death found similar results. A joint test of abnormal D-dimer, NT-ProBNP, and cTnI in APE patients could better predict the long-term risk of APE recurrence and all-cause mortality.
Intranasal plus subcutaneous prime vaccination with a dual antigen COVID-19 vaccine elicits T-cell and antibody responses in mice
Authors: Rice Adrian , Verma Mohit , Shin Annie , Zakin Lise , Sieling Peter , Tanaka Shiho , Balint Joseph , Dinkins Kyle , Adisetiyo Helty , Morimoto Brett , Higashide Wendy , Anders Olson C. , Mody Shivani , Spilman Patricia , Gabitzsch Elizabeth , Safrit Jeffrey T. , Rabizadeh Shahrooz , Niazi Kayvan , Soon-Shiong Patrick
Published: July 2021

We have developed a COVID-19 vaccine, hAd5 S-Fusion + N-ETSD, that expresses SARS-CoV-2 spike (S) and nucleocapsid (N) proteins with modifications to increase immune responses delivered using a human adenovirus serotype 5 (hAd5) platform. Here, we demonstrate subcutaneous (SC) prime and SC boost vaccination of CD-1 mice with this dual-antigen vaccine elicits T-helper cell 1 (Th1) biased T-cell and humoral responses to both S and N that are greater than those seen with hAd5 S wild type delivering only unmodified S. We then compared SC to intranasal (IN) prime vaccination with SC or IN boosts and show that an IN prime with an IN boost is as effective at generating Th1 biased humoral responses as the other combinations tested, but an SC prime with an IN or SC boost elicits greater T cell responses. Finally, we used a combined SC plus IN (SC + IN) prime with or without a boost and found the SC + IN prime alone to be as effective in generating humoral and T-cell responses as the SC + IN prime with a boost. The finding that SC + IN prime-only delivery has the potential to provide broad immunity—including mucosal immunity—against SARS-CoV-2 supports further testing of this vaccine and delivery approach in animal models of viral challenge.
The prevalence and clinical features associated of hypothyroidism among Thai systemic sclerosis patients
Authors: Paolee Yathao , Foocharoen Chingching , Charoensri Suranut , Mayxay Mayfong , Mahakkanukrauh Ajanee , Suwannaroj Siraphop , Nanagara Ratanavadee
Published: July 2021

Thyroid disease, particularly hypothyroidism, has been reported in systemic sclerosis (SSc). Some clinical features of SSc can also present in hypothyroidism. Our aims were to determine the prevalence of, and describe clinical features associated with, hypothyroidism in SSc patients. We conducted a historical cohort study of adult SSc patients who underwent screening thyroid function tests at the Scleroderma Clinic, Khon Kaen University, Thailand, between 2009 and 2018. The patients who had any thyroid disorders before the onset of SSc and were diagnosed as an overlap syndrome were excluded. A total of 200 SSc were included according to sample size calculation, among whom the female to male ratio was 2:1. The majority of cases (137; 69.5%) were diffuse cutaneous SSc subset. The mean age was 55.8 ± 10.7 years and the median duration of disease 4.9 (IQR 1.6–9.9) years. Of the total, 9 had primary hypothyroidism (prevalence 4.5%; 95%CI 2.1–8.4) and 22 had subclinical hypothyroidism (prevalence 11%; 95%CI 7.0–16.2). Of the latter 22, 71% had dcSSc. Logistic regression analysis indicated that unexplained anemia was significantly associated with either subclinical hypothyroid or hypothyroidism (OR 2.74; 95% CI 1.17–6.47), whereas Raynaud’s phenomenon had a negative association (OR 0.28; 95% CI 0.11–0.66). Neither severity of skin tightness nor internal organ involvement were associated with hypothyroidism among SSc patients. Clinical-subclinical hypothyroidism is uncommon among SSc patients, it is frequently associated with anemia, and less so Raynaud’s phenomenon. Clinical-subclinical hypothyroidism should thus be considered in cases of unexplained anemia in SSc patients.
Low alanine aminotransferase as a risk factor for chronic obstructive pulmonary disease in males
Authors: Choi Yong Jun , Kwon Do Sun , Kim Taehee , Cho Jae Hwa , Kim Hyung Jung , Byun Min Kwang , Park Hye Jung
Published: July 2021

Alanine aminotransferase (ALT) levels reflect skeletal muscle volume and general performance, which are associated with chronic obstructive pulmonary disease (COPD) development and prognosis. This study aimed to investigate ALT levels as a risk factor for COPD development. This 13-year population-based retrospective observational cohort study included 422,452 participants for analysis. We classified groups according to the baseline ALT levels (groups 1–5: ALT (IU/L) < 10; 10–19; 20–29; 30–39; and ≥ 40, respectively). The incidence of COPD was the highest in group 1, decreasing as the group number increased in males, but not in females. The Cox regression analysis in males revealed that a lower ALT level, as a continuous variable, was a significant risk factor for COPD development [univariable, hazard ratio (HR): 0.992, 95% confidence interval (CI): 0.991–0.994; multivariable, HR: 0.998, 95% CI: 0.996–0.999]. In addition, COPD was more likely to develop in the lower ALT level groups (groups 1–4; < 40 IU/L), than in the highest ALT level group (group 5; ≥ 40 IU/L) (univariable, HR: 1.341, 95% CI: 1.263–1.424; multivariable, HR: 1.097, 95% CI: 1.030–1.168). Our findings suggest that males with low ALT levels should be carefully monitored for COPD development.
Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice
Authors: Wang Lixiang , Li Xin , Hanada Yuki , Hasuzawa Nao , Moriyama Yoshinori , Nomura Masatoshi , Yamamoto Ken
Published: July 2021

Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.
3D tumor spheroid microarray for high-throughput, high-content natural killer cell-mediated cytotoxicity
Authors: Gopal Sneha , Kwon Seok-Joon , Ku Bosung , Lee Dong Woo , Kim Jungeun , Dordick Jonathan S.
Published: July 2021

Immunotherapy has emerged as a promising approach to treating several forms of cancer. Use of immune cells, such as natural killer (NK) cells, along with small molecule drugs and antibodies through antibody dependent cell-mediated cytotoxicity (ADCC) has been investigated as a potential combination therapy for some difficult to treat solid tumors. Nevertheless, there remains a need to develop tools that support co-culture of target cancer cells and effector immune cells in a contextually relevant three-dimensional (3D) environment to provide a rapid means to screen for and optimize ADCC-drug combinations. To that end, here we have developed a high throughput 330 micropillar-microwell sandwich platform that enables 3D co-culture of NK92-CD16 cells with pancreatic (MiaPaCa-2) and breast cancer cell lines (MCF-7 and MDA-MB-231). The platform successfully mimicked hypoxic conditions found in a tumor microenvironment and was used to demonstrate NK-cell mediated cell cytotoxicity in combination with two monoclonal antibodies; Trastuzumab and Atezolizumab. The platform was also used to show dose response behavior of target cancer cells with reduced EC50 values for paclitaxel (an anti-cancer chemotherapeutic) when treated with both NK cells and antibody. Such a platform may be used to develop more personalized cancer therapies using patient-derived cancer cells.
The Horseshoe Abyssal plain Thrust could be the source of the 1755 Lisbon earthquake and tsunami
Authors: Martínez-Loriente Sara , Sallarès Valentí , Gràcia Eulàlia
Published: July 2021

The southwest Iberia margin is widely believed to have hosted the 1755 Great Lisbon earthquake and ensuing tsunami, one of the most destructive natural events in European history. Here we combine geophysical data and numerical tsunami modelling to investigate the source and mechanism responsible for this event. We find that an intra-plate, lithospheric¬-scale thrust fault located at the Horseshoe Abyssal Plain coincides with the location and focal mechanisms of the largest regional earthquakes and is likely to have suitable dimensions and fault-rock properties to account for the magnitude of the 1755 event. We present tsunami simulations with this fault as the source, and find that they reproduce reported tsunami energy propagation patterns, arrival-times and run up heights more successfully than other modelled sources. We propose that a reverse dip-slip mechanism on the northwest verging Horseshoe Abyssal plain Thrust, combined with the two-state mechanical behaviour of serpentinite, is the most likely candidate for the source of the 1755 Great Lisbon earthquake and for other recent large regional earthquakes.
Single-digit Salmonella detection with the naked eye using bio-barcode immunoassay coupled with recombinase polymerase amplification and a CRISPR-Cas12a system
Authors: Cai Qiqi , Wang Rui , Qiao Zhaohui , Yang Wenge
Published: July 2021

An ultrasensitive, rapid, and visual detection platform for Salmonella Typhimurium based on the bio-barcode assay and recombinase polymerase amplification (RPA) coupled with a CRISPR-Cas12a cleavage system is presented.
Iridium(iii) complexes as mitochondrial topoisomerase inhibitors against cisplatin-resistant cancer cells
Authors: He Liting , Xiong Kai , Wang Lili , Guan Ruilin , Chen Yu , Ji Liangnian , Chao Hui
Published: July 2021

Iridium(iii) complexes, Ir1–Ir2, were developed to act as poisons of mitochondrial topoisomerase and achieve an effective therapeutic outcome for the therapy of cisplatin-resistant tumour cells.
Dinitrosyl iron complexes (DNICs) as inhibitors of the SARS-CoV-2 main protease
Authors: Pectol D. Chase , DeLaney Christopher R. , Zhu Jiyun , Mellott Drake M. , Katzfuss Ardala , Taylor Zane W. , Meek Thomas D. , Darensbourg Marcetta Y.
Published: July 2021

By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay.
Strong anisotropic optical properties of 8-Pmmn borophene: a many-body perturbation study
Authors: Deily Nazar N. , Vazifehshenas T. , Ebrahimi M. R. , Peeters F. M.
Published: July 2021

Based on first-principles calculations, robust and highly anisotropic excitonic effects are obtained in 8-Pmmn borophene, a new 2D Dirac material with semimetallic nature.
Electronic-vibrational density evolution in a perylene bisimide dimer: mechanistic insights into excitation energy transfer
Authors: Kundu Sohang , Makri Nancy
Published: July 2021

Mechanistic picture of excitation energy transfer through the time evolution of electronic-vibrational densities in a perylene bisimide dimer from all-mode real-time path integral calculations.
Investigation of the complex vibronic structure in the first excited and ionic ground states of 3-chloropyridine by means of REMPI and MATI spectroscopy and Franck–Condon analysis
Authors: Helle Niklas , Raeker Tim , Grotemeyer Juergen
Published: July 2021

3-Chloropyridine has been investigated by means of REMPI and MATI spectroscopy to elucidate the effect of m-chlorine substitution on the vibronic structure of the first electronically excited and ionic ground states.
X-Ray induced desorption and photochemistry in CO ice
Authors: Dupuy R. , Bertin M. , Féraud G. , Romanzin C. , Putaud T. , Philippe L. , Michaut X. , Jeseck P. , Cimino R. , Baglin V. , Fillion J.-H.
Published: July 2021

We report an investigation of X-ray induced desorption of neutrals, cations and anions from CO ice.
Impact of vibronic coupling effects on light-driven charge transfer in pyrene-functionalized middle and large-sized metalloid gold nanoclusters from Ehrenfest dynamics
Authors: Domínguez-Castro Adrian , Frauenheim Thomas
Published: July 2021

Ehrenfest dynamics study describing the photoinduced charge transfer in metalloid gold nanoclusters.
Role of additives and solvents in the synthesis of chiral isoreticular MOF-74 topologies
Authors: Gheorghe Andreea , Reus Suzanne , Koenis Mark , Dubbeldam David , Woutersen Sander , Tanase Stefania
Published: July 2021

Strongly interacting chiral additives play a complex role during the crystallisation of chiral isoreticular MOF-74. They can coordinate to the open sites of the metal ions and induce strain on the framework, leading to a local twisting of the organic linker.
A metal-radical hetero-tri-spin SCM with methyl–pyrazole–nitronyl nitroxide bridges
Authors: Huang Xiaohui , Wang Kang , Han Jing , Xie Junfang , Li Licun , Sutter Jean-Pascal
Published: July 2021

A novel 2p–3d–4f SCM has been successfully achieved using a pyrazole substituted nitronyl nitroxide which exhibits dual relaxation processes.
Insights into HONO sources from observations during a solar eclipse
Authors: Singh Ajit , Crilley Leigh R. , Pope Francis D. , Bloss William J.
Published: July 2021

Nitrous acid (HONO) is a key precursor to the principal atmospheric oxidant OH. HONO measurements during a solar eclipse show little variation, implying the main HONO sources are photolytic, approximately balancing removal through photolysis.
Understanding the toxicity mechanism of CuO nanoparticles: the intracellular view of exposed earthworm cells
Authors: Navarro Pacheco Natividad Isabel , Roubalova Radka , Dvorak Jiri , Benada Oldrich , Pinkas Dominik , Kofronova Olga , Semerad Jaroslav , Pivokonsky Martin , Cajthaml Tomas , Bilej Martin , Prochazkova Petra
Published: July 2021

The originality of the present study is the description of CuO NP interaction with earthworm immune cells and subsequent physiological response from thein vitroperspective.
Enhanced fluorescence of mercaptopropionic acid-capped zinc sulfide quantum dots with moxifloxacin in food and water samplesviareductive photoinduced electron transfer
Authors: Sajwan Reena K. , Pandey Shailja , Kumar Rahul , Dhiman Tarun Kumar , Eremin Sergei A. , Solanki Pratima R.
Published: July 2021

MZS QDs based fluorometric nanosensor for the detection of MOXIviaphotoinduced electron transfer.
Exopolysaccharides produced by Lactobacillus rhamnosus GG alleviate hydrogen peroxide-induced intestinal oxidative damage and apoptosis through the Keap1/Nrf2 and Bax/Bcl-2 pathways in vitro
Authors: Li Jinze , Li Qiuke , Gao Nan , Wang Zhihua , Li Feng , Li Jianping , Shan Anshan
Published: July 2021

The exopolysaccharides of Lactobacillus rhamnosus GG extracted by the ethanol precipitation method could alleviate oxidative damage and apoptosis induced by hydrogen peroxide in IPEC-J2 cells by regulating Bax/Bcl-2 and Keap1/Nrf2 signaling pathways.
Inhibition and interactions of alpha-amylase by daucosterol from the peel of Chinese water chestnut (Eleocharis dulcis)
Authors: Gu Yipeng , Yang Xiaomei , Shang Chaojie , Thao Truong Thi Phuong , Koyama Tomoyuki
Published: July 2021

Daucosterol fromEleocharis dulcispeel exhibits potent effective inhibitory activity against alpha-amylase.
Gut and liver metabolic responses to dietary fructose – are they reversible or persistent after switching to a healthy diet?
Authors: Mazzoli Arianna , Gatto Cristina , Crescenzo Raffaella , Spagnuolo Maria Stefania , Nazzaro Martina , Iossa Susanna , Cigliano Luisa
Published: July 2021

Metabolic derangement elicited by a fructose-rich diet, even after a brief period of intake, is fully reversed in the liver by a period of fructose withdrawal, while gut dysfunction persists.
IgE epitope analysis of sarcoplasmic-calcium-binding protein, a heat-resistant allergen in Crassostrea angulata
Authors: Han Tian-Jiao , Huan Fei , Liu Meng , Li Meng-Si , Yang Yang , Chen Gui-Xia , Lai Dong , Cao Min-Jie , Liu Guang-Ming
Published: July 2021

The heat-resistant allergen Cra a 4 was detected to have significant allergenicity. Additionally, five linear epitopes and two conformational epitopes of Cra a 4 were identified.
Different types of components obtained from Monascus purpureus with neuroprotective and anti-inflammatory potentials
Authors: Wu Ho-Cheng , Chen Yih-Fung , Cheng Ming-Jen , Wu Ming-Der , Chen Yen-Lin , Chang Hsun-Shuo
Published: July 2021

Seven new and ten known compounds were isolated from a citrinin-free strain: M. purpureus BCRC 38110. The bioactivity results indicated that this strain possessed potentials against inflammatory osteoarthritis and paclitaxel-induced neurotoxicity.
Pyran based bipodal D–π–A systems: colorimetric and ratiometric sensing of mercury – experimental and theoretical approach
Authors: Vineetha Pookalavan Karicherry , Krishnan Aravind , Aswathy Ajayakumar , Chandrasekaran Parvathy O. , Manoj Narayanapillai
Published: July 2021

Reversible and selective Hg2+ ion complexation of the two pyran based colorimetric and fluorescent ratiometric probes.
Modeling the interaction of SARS-CoV-2 binding to the ACE2 receptor via molecular theory of solvation
Authors: Kobryn Alexander E. , Maruyama Yutaka , Velázquez-Martínez Carlos A. , Yoshida Norio , Gusarov Sergey
Published: July 2021

The angiotensin-converting enzyme 2 (ACE2) protein is a cell gate receptor for the SARS-CoV-2 virus, responsible for the development of symptoms associated with the Covid-19 disease.
A review of low-temperature H2S gas sensors: fabrication and mechanism
Authors: Ghaderahmadi Sara , Kamkar Milad , Tasnim Nishat , Arjmand Mohammad , Hoorfar Mina
Published: July 2021

Reduced detection temperature of hazardous gases such as H2S can lower power consumption and increase the long-term stability. The decreased operating temperature can be achieved via physical and chemical modification of the sensing layer.
Ultra-low background signaling cascade amplifiers for in vivo fluorescence imaging of hydroxyl radical production induced by testosterone
Authors: Nan Yanxia , Gu Yu , Zhou Qiulan , Zhao Wenjie , Zhang Jun
Published: July 2021

A novel ultra-low background signal cascade amplifier was developed to understand the production mechanism of ˙OH pools in situ stimulated by testosterone.
Double magnetic tunnel junctions with a switchable assistance layer for improved spin transfer torque magnetic memory performance
Authors: Sanchez Hazen Daniel , Auffret Stéphane , Joumard Isabelle , Vila Laurent , Buda-Prejbeanu Liliana D. , Sousa Ricardo C. , Prejbeanu Lucian , Dieny Bernard
Published: July 2021

This paper reports the first experimental demonstration of a new concept of double magnetic tunnel junctions comprising a magnetically switchable assistance layer.