bluuebunny/crossref_metadata_2025 huggingface dataset:
Remote control of neural function by X-ray-induced scintillation
Authors: Matsubara Takanori , Yanagida Takayuki , Kawaguchi Noriaki , Nakano Takashi , Yoshimoto Junichiro , Sezaki Maiko , Takizawa Hitoshi , Tsunoda Satoshi P. , Horigane Shin-ichiro , Ueda Shuhei , Takemoto-Kimura Sayaka , Kandori Hideki , Yamanaka Akihiro , Yamashita Takayuki
Published: July 2021

Scintillators emit visible luminescence when irradiated with X-rays. Given the unlimited tissue penetration of X-rays, the employment of scintillators could enable remote optogenetic control of neural functions at any depth of the brain. Here we show that a yellow-emitting inorganic scintillator, Ce-doped Gd3(Al,Ga)5O12 (Ce:GAGG), can effectively activate red-shifted excitatory and inhibitory opsins, ChRmine and GtACR1, respectively. Using injectable Ce:GAGG microparticles, we successfully activated and inhibited midbrain dopamine neurons in freely moving mice by X-ray irradiation, producing bidirectional modulation of place preference behavior. Ce:GAGG microparticles are non-cytotoxic and biocompatible, allowing for chronic implantation. Pulsed X-ray irradiation at a clinical dose level is sufficient to elicit behavioral changes without reducing the number of radiosensitive cells in the brain and bone marrow. Thus, scintillator-mediated optogenetics enables minimally invasive, wireless control of cellular functions at any tissue depth in living animals, expanding X-ray applications to functional studies of biology and medicine.
S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis
Authors: Chao Meng-Lin , Luo Shanshan , Zhang Chao , Zhou Xuechun , Zhou Miao , Wang Junyan , Kong Chuiyu , Chen Jiyu , Lin Zhe , Tang Xin , Sun Shixiu , Tang Xinlong , Chen Hongshan , Wang Hong , Wang Dongjin , Sun Jin-Peng , Han Yi , Xie Liping , Ji Yong
Published: July 2021

Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.
Vulnerability of the North Water ecosystem to climate change
Authors: Ribeiro Sofia , Limoges Audrey , Massé Guillaume , Johansen Kasper L. , Colgan William , Weckström Kaarina , Jackson Rebecca , Georgiadis Eleanor , Mikkelsen Naja , Kuijpers Antoon , Olsen Jesper , Olsen Steffen M. , Nissen Martin , Andersen Thorbjørn J. , Strunk Astrid , Wetterich Sebastian , Syväranta Jari , Henderson Andrew C. G. , Mackay Helen , Taipale Sami , Jeppesen Erik , Larsen Nicolaj K. , Crosta Xavier , Giraudeau Jacques , Wengrat Simone , Nuttall Mark , Grønnow Bjarne , Mosbech Anders , Davidson Thomas A.
Published: July 2021

High Arctic ecosystems and Indigenous livelihoods are tightly linked and exposed to climate change, yet assessing their sensitivity requires a long-term perspective. Here, we assess the vulnerability of the North Water polynya, a unique seaice ecosystem that sustains the world’s northernmost Inuit communities and several keystone Arctic species. We reconstruct mid-to-late Holocene changes in sea ice, marine primary production, and little auk colony dynamics through multi-proxy analysis of marine and lake sediment cores. Our results suggest a productive ecosystem by 4400–4200 cal yrs b2k coincident with the arrival of the first humans in Greenland. Climate forcing during the late Holocene, leading to periods of polynya instability and marine productivity decline, is strikingly coeval with the human abandonment of Greenland from c. 2200–1200 cal yrs b2k. Our long-term perspective highlights the future decline of the North Water ecosystem, due to climate warming and changing sea-ice conditions, as an important climate change risk.
Massive carbon storage in convergent margins initiated by subduction of limestone
Authors: Chen Chunfei , Förster Michael W. , Foley Stephen F. , Liu Yongsheng
Published: July 2021

Remobilization of sedimentary carbonate in subduction zones modulates arc volcanism emissions and thus Earth’s climate over geological timescales. Although limestones (or chalk) are thought to be the major carbon reservoir subducted to subarc depths, their fate is still unclear. Here we present high-pressure reaction experiments between impure limestone (7.4 wt.% clay) and dunite at 1.3–2.7 GPa to constrain the melting behaviour of subducted natural limestone in contact with peridotite. The results show that although clay impurities significantly depress the solidus of limestone, melting will not occur whilst limestones are still part of the subducting slab. Buoyancy calculations suggest that most of these limestones would form solid-state diapirs intruding into the mantle wedge, resulting in limited carbon flux to the deep mantle (< ~10 Mt C y−1). Less than 20% melting within the mantle wedge indicates that most limestones remain stable and are stored in subarc lithosphere, resulting in massive carbon storage in convergent margins considering their high carbon flux (~21.4 Mt C y−1). Assimilation and outgassing of these carbonates during arc magma ascent may dominate the carbon flux in volcanic arcs.
Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism
Authors: Fu Zheng , Dean Joseph W. , Xiong Lifeng , Dougherty Michael W. , Oliff Kristen N. , Chen Zong-ming E. , Jobin Christian , Garrett Timothy J. , Zhou Liang
Published: July 2021

RORγt+lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion ofTfamin RORγt+lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.
Structure and function of an Arabidopsis thaliana sulfate transporter
Authors: Wang Lie , Chen Kehan , Zhou Ming
Published: July 2021

Plant sulfate transporters (SULTR) mediate absorption and distribution of sulfate (SO42−) and are essential for plant growth; however, our understanding of their structures and functions remains inadequate. Here we present the structure of a SULTR from Arabidopsis thaliana, AtSULTR4;1, in complex with SO42− at an overall resolution of 2.8 Å. AtSULTR4;1 forms a homodimer and has a structural fold typical of the SLC26 family of anion transporters. The bound SO42− is coordinated by side-chain hydroxyls and backbone amides, and further stabilized electrostatically by the conserved Arg393 and two helix dipoles. Proton and SO42− are co-transported by AtSULTR4;1 and a proton gradient significantly enhances SO42− transport. Glu347, which is ~7 Å from the bound SO42−, is required for H+-driven transport. The cytosolic STAS domain interacts with transmembrane domains, and deletion of the STAS domain or mutations to the interface compromises dimer formation and reduces SO42− transport, suggesting a regulatory function of the STAS domain.
Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis
Authors: Ye Bo , Fan Dandan , Xiong Weiwei , Li Min , Yuan Jian , Jiang Qi , Zhao Yuting , Lin Jianxiang , Liu Jie , Lv Yilv , Wang Xiongjun , Li Zhigang , Su Jianzhong , Qiao Yunbo
Published: July 2021

The role of cis-elements and their aberrations remains unclear in esophageal squamous cell carcinoma (ESCC, further abbreviated EC). Here we survey 28 H3K27ac-marked active enhancer profiles and 50 transcriptomes in primary EC, metastatic lymph node cancer (LNC), and adjacent normal (Nor) esophageal tissues. Thousands of gained or lost enhancers and hundreds of altered putative super-enhancers are identified in EC and LNC samples respectively relative to Nor, with a large number of common gained or lost enhancers. Moreover, these differential enhancers contribute to the transcriptomic aberrations in ECs and LNCs. We also reveal putative driver onco-transcription factors, depletion of which diminishes cell proliferation and migration. The administration of chemical inhibitors to suppress the predicted targets of gained super-enhances reveals HSP90AA1 and PDE4B as potential therapeutic targets for ESCC. Thus, our epigenomic profiling reveals a compendium of reprogrammed cis-regulatory elements during ESCC carcinogenesis and metastasis for uncovering promising targets for cancer treatment.
Hearing difficulty is linked to Alzheimer’s disease by common genetic vulnerability, not shared genetic architecture
Authors: Abidin Fatin N. Zainul , Wells Helena R. R. , Altmann Andre , Dawson Sally J.
Published: July 2021

Age-related hearing loss was recently established as the largest modifiable risk factor for Alzheimer’s disease (AD), however, the reasons for this link remain unclear. We investigate shared underlying genetic associations using results from recent large genome-wide association studies (GWAS) on adult hearing difficulty and AD. Genetic correlation and Mendelian randomization (MR) analysis do not support a genetic correlation between the disorders, but suggest a direct causal link from AD genetic risk to hearing difficulty, driven by APOE. Systematic MR analyses on the effect of other traits revealed shared effects of glutamine, gamma-glutamylglutamine, and citrate levels on reduced risk of both hearing difficulty and AD. In addition, pathway analysis on GWAS risk variants suggests shared function in neuronal signalling pathways as well as etiology of diabetes and cardiovascular disease. However, after multiple testing corrections, neither analysis led to statistically significant associations. Altogether, our genetic-driven analysis suggests hearing difficulty and AD are linked by a shared vulnerability in molecular pathways rather than by a shared genetic architecture.
Altered oral and gut microbiota and its association with SARS-CoV-2 viral load in COVID-19 patients during hospitalization
Authors: Wu Yongjian , Cheng Xiaomin , Jiang Guanmin , Tang Huishu , Ming Siqi , Tang Lantian , Lu Jiahai , Guo Cheng , Shan Hong , Huang Xi
Published: July 2021

The human oral and gut commensal microbes play vital roles in the development and maintenance of immune homeostasis, while its association with susceptibility and severity of SARS-CoV-2 infection is barely understood. In this study, we investigated the dynamics of the oral and intestinal flora before and after the clearance of SARS-CoV-2 in 53 COVID-19 patients, and then examined their microbiome alterations in comparison to 76 healthy individuals. A total of 140 throat swab samples and 81 fecal samples from these COVID-19 patients during hospitalization, and 44 throat swab samples and 32 fecal samples from sex and age-matched healthy individuals were collected and then subjected to 16S rRNA sequencing and viral load inspection. We found that SARS-CoV-2 infection was associated with alterations of the microbiome community in patients as indicated by both alpha and beta diversity indexes. Several bacterial taxa were identified related to SARS-CoV-2 infection, wherein elevated Granulicatella and Rothia mucilaginosa were found in both oral and gut microbiome. The SARS-CoV-2 viral load in those samples was also calculated to identify potential dynamics between COVID-19 and the microbiome. These findings provide a meaningful baseline for microbes in the digestive tract of COVID-19 patients and will shed light on new dimensions for disease pathophysiology, potential microbial biomarkers, and treatment strategies for COVID-19.
Restructured single parabolic band model for quick analysis in thermoelectricity
Authors: Zhu Jianbo , Zhang Xuemei , Guo Muchun , Li Jingyu , Hu Jinsuo , Cai Songting , Cai Wei , Zhang Yongsheng , Sui Jiehe
Published: July 2021

The single parabolic band (SPB) model has been widely used to preliminarily elucidate inherent transport behaviors of thermoelectric (TE) materials, such as their band structure and electronic thermal conductivity, etc. However, in the SPB calculation, it is necessary to determine some intermediate variables, such as Fermi level or the complex Fermi-Dirac integrals. In this work, we establish a direct carrier-concentration-dependent restructured SPB model, which eliminates Fermi-Dirac integrals and Fermi level calculation and emerges stronger visibility and usability in experiments. We have verified the reliability of such restructured model with 490 groups of experimental data from state-of-the-art TE materials and the relative error is less than 2%. Moreover, carrier effective mass, intrinsic carrier mobility and optimal carrier concentration of these materials are systematically investigated. We believe that our work can provide more convenience and accuracy for thermoelectric data analysis as well as instructive understanding on future optimization design.
The complexity of mental health care for people with COPD: a qualitative study of clinicians’ perspectives
Authors: Wang Juliet , Willis Karen , Barson Elizabeth , Smallwood Natasha
Published: July 2021

Anxiety and depression are common mental health illnesses in people with chronic obstructive pulmonary disease (COPD). However, patients often decline formal mental health care with barriers identified at the patient, health provider and health system levels. Currently clinicians’ perspectives on this issue are not well understood. A qualitative study using semi-structured interviews was undertaken to explore clinician perceived barriers and facilitators to acceptance of psychological care amongst people with COPD. Twenty-four Australian respiratory health professionals participated. Interview transcripts were analysed thematically. An overarching theme of ‘complexity’ was identified, which was evident across five domains: (1) physical and mental health illnesses; (2) psychosocial circumstances; (3) community views and stigma; (4) educational needs and knowledge gaps; (5) navigating the health system. Targeted patient education around psychological interventions and integration of mental health clinicians within multidisciplinary outpatient respiratory services are needed to address the current challenges.
Links between fecal microbiota and the response to vaccination against influenza A virus in pigs
Authors: Borey Marion , Blanc Fany , Lemonnier Gaëtan , Leplat Jean-Jacques , Jardet Deborah , Rossignol Marie-Noëlle , Ravon Laure , Billon Yvon , Bernard Maria , Estellé Jordi , Rogel-Gaillard Claire
Published: July 2021

This study describes the associations between fecal microbiota and vaccine response variability in pigs, using 98 piglets vaccinated against the influenza A virus at 28 days of age (D28) with a booster at D49. Immune response to the vaccine is measured at D49, D56, D63, and D146 by serum levels of IAV-specific IgG and assays of hemagglutination inhibition (HAI). Analysis of the pre-vaccination microbiota characterized by 16S rRNA gene sequencing of fecal DNA reveals a higher vaccine response in piglets with a richer microbiota, and shows that 23 operational taxonomic units (OTUs) are differentially abundant between high and low IAV-specific IgG producers at D63. A stronger immune response is linked with OTUs assigned to the genus Prevotella and family Muribaculaceae, and a weaker response is linked with OTUs assigned to the genera Helicobacter and Escherichia-Shigella. A set of 81 OTUs accurately predicts IAV-specific IgG and HAI titer levels at all time points, highlighting early and late associations between pre-vaccination fecal microbiota composition and immune response to the vaccine.
A single dose of replication-competent VSV-vectored vaccine expressing SARS-CoV-2 S1 protects against virus replication in a hamster model of severe COVID-19
Authors: Malherbe Delphine C. , Kurup Drishya , Wirblich Christoph , Ronk Adam J. , Mire Chad , Kuzmina Natalia , Shaik Noor , Periasamy Sivakumar , Hyde Matthew A. , Williams Julie M. , Shi Pei-Yong , Schnell Matthias J. , Bukreyev Alexander
Published: July 2021

The development of effective countermeasures against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal models of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine.
A multi-site, year-round turbulence microstructure atlas for the deep perialpine Lake Garda
Authors: Piccolroaz Sebastiano , Fernández-Castro Bieito , Toffolon Marco , Dijkstra Henk A.
Published: July 2021

A multi-site, year-round dataset comprising a total of 606 high-resolution turbulence microstructure profiles of shear and temperature gradient in the upper 100 m depth is made available for Lake Garda (Italy). Concurrent meteorological data were measured from the fieldwork boat at the location of the turbulence measurements. During the fieldwork campaign (March 2017-June 2018), four different sites were sampled on a monthly basis, following a standardized protocol in terms of time-of-day and locations of the measurements. Additional monitoring activity included a 24-h campaign and sampling at other sites. Turbulence quantities were estimated, quality-checked, and merged with water quality and meteorological data to produce a unique turbulence atlas for a lake. The dataset is open to a wide range of possible applications, including research on the variability of turbulent mixing across seasons and sites (demersal vs pelagic zones) and driven by different factors (lake-valley breezes vs buoyancy-driven convection), validation of hydrodynamic lake models, as well as technical studies on the use of shear and temperature microstructure sensors.
Chronic musculoskeletal pain, catastrophizing, and physical function in adult women were improved after 3-month aerobic-resistance circuit training
Authors: Sato Seira , Ukimoto Sho , Kanamoto Takashi , Sasaki Nao , Hashimoto Takao , Saito Hikaru , Hida Eisuke , Sato Tomoharu , Mae Tatsuo , Nakata Ken
Published: July 2021

Although exercise is beneficial for chronic musculoskeletal pain (CMP), the optimal type and amount of exercise are unclear. This study aimed to determine the impact of circuit training that combines aerobic and resistance exercises on adult women with CMP. A total of 139 women with CMP underwent circuit training for 3 months and were asked to complete the following questionnaires at baseline and 3 months later: Numeric Rating Scale (NRS), Pain Catastrophizing Scale (PCS), Roland-Morris Disability Questionnaire (RDQ), Shoulder36, and Knee injury and Osteoarthritis Outcome Score (KOOS). Significant improvements were observed in NRS, PCS, RDQ, and KOOS activities of daily living (ADL) scores after the intervention relative to baseline (p < 0.0001, p = 0.0013, 0.0004, and 0.0295, respectively), whereas shoulder function did not improve. When considering the impact of exercise frequency, NRS scores improved regardless of exercise frequency. Furthermore, PCS, RDQ, and KOOS scores improved in participants who exercised at least twice a week (24 sessions over the course of 3 months). In conclusion, CMP, pain catastrophizing, and physical function in adult female fitness club participants with CMP of NRS 4 or higher improved after 3 months of aerobic-resistance circuit training.
Analysis of variant-pairing tendencies in lenticular martensite microstructures based on rank-1 connection
Authors: Shinohara Yuri , Akabane Satomu , Inamura Tomonari
Published: July 2021

Herein, variant-pairing tendencies of lenticular martensite in an Fe–30Ni–0.3C (wt%) alloy are analyzed based on rank-1 connection at martensite/martensite junction planes (JPs) to facilitate the understanding of martensite microstructure. The degree of incompatibility (θ) at the JPs successfully explained their observed frequency; in the actual microstructure, variant pairs with a smallθform preferentially. The experimentally obtained JPs were consistent with theoretical ones. To the best of our knowledge, this is the first study to confirm the validity of variant-pair crystallography in steel based on rank-1 connection, both theoretically and experimentally. Diamond, composite-spear, and composite-kink clusters are considered. The cumulativeθat the JPs can suppress diamond cluster formation because it exceeds theθof a single variant pair, and the diamond cluster is not observed experimentally. However,θat the JPs cancel out in composite-spear (CS) and composite-kink (CK) clusters, but CK clusters are rarely observed experimentally, while a few CS clusters are observed. This demonstrates the analytical limitations of 2D approaches used to evaluate the frequency of variant pairs and clusters. These two variant clusters have a narrow window of 2D observation because the orientation relationships between JPs and intersection lines between two habit planes affect the areas of JPs.
Tyrosine and Tryptophan vibrational bands as markers of kidney injury: a renocardiac syndrome induced by renal ischemia and reperfusion study
Authors: Nepomuceno Gabrielle , Junho Carolina Victoria Cruz , Carneiro-Ramos Marcela Sorelli , da Silva Martinho Herculano
Published: July 2021

Renal injury caused by renal ischemia and reperfusion strongly influences heart morphology, electrophysiology, and redox unbalance. The so-called cardiorenal syndrome is an important class of dysfunction since heart and kidneys are responsible for hemodynamic stability and organ perfusion through a complex network. In the present work we investigate the vibrational spectral features probed by Fourier-Transform Raman (FT-Raman) spectroscopy due to physiological alterations induced by renal ischemic reperfusion aiming to detect molecular markers related to progression of acute to chronic kidney injury and mortality predictors as well. C57BL/6J mice were subjected to unilateral occlusion of the renal pedicle for 60 min and reperfusion for 5, 8, and 15 days. Biopsies of heart and kidney tissues were analyzed. Our findings indicated that cysteine/cystine, fatty acids, methyl groups of Collagen, α-form of proteins, Tyrosine, and Tryptophan were modulated during renal ischemia and reperfusion process. These changes are consistent with fibroblast growth factors and Collagen III contents changes. Interestingly, Tyrosine and Tryptophan, precursor molecules for the formation of uremic toxins such as indoxyl sulfate and p-cresyl sulfate were also modulated. They are markers of kidney injury and their increase is strongly correlated to cardiovascular mortality. Regarding this aspect, we notice that monitoring the Tyrosine and Tryptophan bands at 1558, 1616, and 1625 cm−1 is a viable and and advantageous way to predict fatality in cardiovascular diseases both “in vivo” or “in vitro”, using the real-time, multiplexing, and minimally invasive advantages of FT-Raman spectroscopy.
Human placental piwi-interacting RNA transcriptome is characterized by expression from the DLK1-DIO3 imprinted region
Authors: Martinez Victor D. , Sage Adam P. , Minatel Brenda C. , Marshall Erin A. , Price E. Magda , Becker-Santos Daiana D. , Robinson Wendy P. , Lam Wan L.
Published: July 2021

The placenta is vital to embryonic development and requires a finely-tuned pattern of gene expression, achieved in part by its unique epigenetic landscape. Piwi-interacting RNAs (piRNAs) are a class of small-non-coding RNA with established roles as epigenetic regulators of gene expression, largely via methylation of targeted DNA sequences. The expression of piRNAs have mainly been described in germ cells, but a fraction have been shown to retain expression in adult somatic tissues. To aid in understanding the contribution of these regulators in the placenta, we provide the first description of the piRNA transcriptome in human placentas. We find 297 piRNAs to be preferentially expressed in the human placenta, a subset of which are expressed at higher levels relative to testes samples. We also observed a large proportion of placental piRNAs to be expressed from a single locus, as distinct from canonical cluster locations associated with transposable element silencing. Finally, we find that 15 of the highest-expressed placental piRNAs maps to the DLK1-DIO3 locus, suggesting a link to placental biology. Our findings suggest that piRNAs could contribute to the molecular networks defining placental function in humans, and a biological impact of piRNA expression beyond germ cells.
Neutrophils are important for the development of pro-reparative macrophages after irreversible electroporation of the liver in mice
Authors: Lopez-Ichikawa Maya , Vu Ngan K. , Nijagal Amar , Rubinsky Boris , Chang Tammy T.
Published: July 2021

Irreversible electroporation (IRE) is a non-thermal tissue ablative technology that has emerging applications in surgical oncology and regenerative surgery. To advance its therapeutic usefulness, it is important to understand the mechanisms through which IRE induces cell death and the role of the innate immune system in mediating subsequent regenerative repair. Through intravital imaging of the liver in mice, we show that IRE produces distinctive tissue injury features, including delayed yet robust recruitment of neutrophils, consistent with programmed necrosis. IRE treatment converts the monocyte/macrophage balance from pro-inflammatory to pro-reparative populations, and depletion of neutrophils inhibits this conversion. Reduced generation of pro-reparative Ly6CloF4/80hi macrophages correlates with lower numbers of SOX9+ hepatic progenitor cells in areas of macrophage clusters within the IRE injury zone. Our findings suggest that neutrophils play an important role in promoting the development of pro-reparative Ly6Clo monocytes/macrophages at the site of IRE injury, thus establishing conditions of regenerative repair.
A comparison of alternative selection methods for reporting spirometric parameters in healthy adults
Authors: Therkorn Jennifer H. , Toto Daniella R. , Falvo Michael J.
Published: July 2021

Alternative methods have been proposed to report spirometry indices from test sessions (forced expiratory volume 1 s, FEV1; forced vital capacity, FVC). However, most use the American and European Societies’ standard (ATS/ERS) which stops sessions once a repeatability threshold is met which may not accurately represent intra-session variability. Our goal was to repeat trials beyond the repeatability threshold and evaluate alternative reporting methods. 130 adults performed spirometry across two visits. Spirometry indices were reported using the ATS/ERS standard and four alternatives. 78 participants (60%) had valid data for all methods and visits. Intra-session coefficients of variation were low (FEV1: 3.1–3.7%; FVC: 2.3–2.8%). Our four alternative methods yielded FEV1 and FVC values ≤ 0.08 L different from ATS/ERS standard, which is not clinically meaningful. Intraclass correlation coefficients were ≥ 0.97 indicating consistency across repeated measures. The smallest real differences ranged from FEV1: 0.20–0.27 L and FVC: 0.18–0.24 L indicating consistency and low measurement error. Overall, all methods for reporting FEV1 and FVC demonstrated similar measurement error, precision, and stability within- and between-visits. These results suggest that once ATS/ERS repeatability is achieved, which approach is used for reporting spirometric variables may be of low clinical significance in a healthy population.
Safety evaluation of a clinical focused ultrasound system for neuronavigation guided blood-brain barrier opening in non-human primates
Authors: Pouliopoulos Antonios N. , Kwon Nancy , Jensen Greg , Meaney Anna , Niimi Yusuke , Burgess Mark T. , Ji Robin , McLuckie Alicia J. , Munoz Fabian A. , Kamimura Hermes A. S. , Teich Andrew F. , Ferrera Vincent P. , Konofagou Elisa E.
Published: July 2021

An emerging approach with potential in improving the treatment of neurodegenerative diseases and brain tumors is the use of focused ultrasound (FUS) to bypass the blood–brain barrier (BBB) in a non-invasive and localized manner. A large body of pre-clinical work has paved the way for the gradual clinical implementation of FUS-induced BBB opening. Even though the safety profile of FUS treatments in rodents has been extensively studied, the histological and behavioral effects of clinically relevant BBB opening in large animals are relatively understudied. Here, we examine the histological and behavioral safety profile following localized BBB opening in non-human primates (NHPs), using a neuronavigation-guided clinical system prototype. We show that FUS treatment triggers a short-lived immune response within the targeted region without exacerbating the touch accuracy or reaction time in visual-motor cognitive tasks. Our experiments were designed using a multiple-case-study approach, in order to maximize the acquired data and support translation of the FUS system into human studies. Four NHPs underwent a single session of FUS-mediated BBB opening in the prefrontal cortex. Two NHPs were treated bilaterally at different pressures, sacrificed on day 2 and 18 post-FUS, respectively, and their brains were histologically processed. In separate experiments, two NHPs that were earlier trained in a behavioral task were exposed to FUS unilaterally, and their performance was tracked for at least 3 weeks after BBB opening. An increased microglia density around blood vessels was detected on day 2, but was resolved by day 18. We also detected signs of enhanced immature neuron presence within areas that underwent BBB opening, compared to regions with an intact BBB, confirming previous rodent studies. Logistic regression analysis showed that the NHP cognitive performance did not deteriorate following BBB opening. These preliminary results demonstrate that neuronavigation-guided FUS with a single-element transducer is a non-invasive method capable of reversibly opening the BBB, without substantial histological or behavioral impact in an animal model closely resembling humans. Future work should confirm the observations of this multiple-case-study work across animals, species and tasks.
Quantification of measurable residual disease in patients with multiple myeloma based on the IMWG response criteria
Authors: Narita Kentaro , Miura Daisuke , Tsushima Takafumi , Terao Toshiki , Kuzume Ayumi , Tabata Rikako , Takeuchi Masami , Matsue Kosei
Published: July 2021

Stringent complete response (sCR) is defined as a deeper response than complete response (CR) in multiple myeloma. Whether achieving sCR correlates with better survival remains controversial. We evaluated the outcomes in patients with intact immunoglobulin multiple myeloma (IIMM) and light chain multiple myeloma (LCMM) who achieved a very good partial response (VGPR) or better. Multicolour flow cytometry was used to assess the depth of response. LCMM patients with sCR had significantly lower measurable residual disease (MRD) levels than those with CR (median MRD: 7.9 × 10–4 vs. 5.6 × 10–5, P < 0.01). Nonetheless, no significant difference was observed in MRD levels across the responses in groups of patients with IIMM (VGPR vs. CR: 3.5 × 10–4 vs. 7.0 × 10–5, P = 0.07; CR vs. sCR: 7.0 × 10–5 vs. 5.4 × 10–5, P = 0.81. In accordance with MRD levels, the median overall survival of patients with sCR was significantly longer (sCR, CR, VGPR; not reached, 41 months, and 58 months, respectively; VGPR vs. CR, P = 0.83; CR vs. sCR, P = 0.04) in LCMM, but not in IIMM (sCR, CR, VGPR; not reached, 41 months, and not reached, respectively; VGPR vs. CR, P = 0.59; CR vs. sCR; P = 0.10). Our results show that sCR represents a deeper response that correlates with longer survival in patients with LCMM, but not IIMM.
Expression patterns and prognostic value of RUNX genes in kidney cancer
Authors: Gao Ke , Zhang Fang , Chen Ke , Li Wei , Guan Yi-Bing , Xu Meng-Lu , Chong Tie , Dai Zhi-Ming
Published: July 2021

Kidney cancer is the third most common malignancy of the urinary system, of which, kidney renal clear cell carcinoma (KIRC) accounts for the vast majority. Runt-related transcription factors (RUNX) are involved in multiple cellular functions. However, the diverse expression patterns and prognostic values of RUNX genes in kidney cancer remained to be elucidated. In our study, we mined the DNA methylation, transcriptional and survival data of RUNX genes in patients with different kinds of kidney cancer through Oncomine, Gene Expression Profiling Interactive Analysis, UALCAN, Kaplan–Meier Plotter, cBioPortal and LinkedOmics. We found that RUNX1 and RUNX3 were upregulated in KIRC tissues compared with those in normal tissues. The survival analysis results indicated a high transcription level of RUNX1 was associated with poor overall survival (OS) in KIRC patients. Furthermore, KIRC tumor tissues had significantly lower levels of RUNX1 promoter methylation than that in paracancerous tissues, with decreased DNA methylation of RUNX1 notably associated with poor OS in KIRC. In conclusion, our results revealed that RUNX1 may be a potential therapeutic target for treating KIRC, and RUNX1 promoter methylation level shows promise as a novel diagnostic and prognostic biomarker, which laid a foundation for further study.
The recent advances, drawbacks, and the future directions of CMRI in the diagnosis of IHD
Authors: Fagiry Moram A. , Abdelaziz Ikhlas , Davidson Rob , Mahmoud Mustafa Z.
Published: July 2021

Ischemic heart disease (IHD), also known as coronary artery disease (CAD), is a leading cause of morbidity and mortality in adults. The aims of this research were to study the recent advances on the prognostic and diagnostic value, drawbacks, and the future directions of cardiac magnetic resonance imaging (CMRI) in the diagnosis of IHD. One hundred patients with IHD who had been clinically diagnosed were enrolled in this study prospectively. CMRI; Siemens Magnetom Sola 1.5 T MRI scanner was used to examine the patients. To confirm the diagnosis, conventional coronary angiography was used. CMRI revealed that the left ventricular (LV) volumes and systolic function of male and female patients differed by age decile were 28.9 ± 3.5%; 32 ± 1.7%, 53.3 ± 11.2; 58 ± 6.6 ml, 100.6 ± 7.1; 98.3 ± 14.7 bpm, 5.4 ± 1.4; 5.8 ± 1.5 L/min, 189 ± 14.3; 180 ± 10.9 ml, and 136 ± 3.1; 123 ± 4.4 ml for the left ventricle ejection fraction (LVEF), stroke volume (SV), heart rate, cardiac output, end diastolic volume (EDV), and end systolic volume (ESV), respectively. CMRI has sensitivity, specificity, and accuracy of 97%, 33.33%, and 95.15%, respectively. Finally, CMRI provides a comprehensive assessment of LV function, myocardial perfusion, and viability, as well as coronary anatomy.
Modest changes in Spi1 dosage reveal the potential for altered microglial function as seen in Alzheimer’s disease
Authors: Jones Ruth E. , Andrews Robert , Holmans Peter , Hill Matthew , Taylor Philip R.
Published: July 2021

Genetic association studies have identified multiple variants at the SPI1 locus that modify risk and age of onset for Alzheimer’s Disease (AD). Reports linking risk variants to gene expression suggest that variants denoting higher SPI1 expression are likely to have an earlier AD onset, and several other AD risk genes contain PU.1 binding sites in the promoter region. Overall, this suggests the level of SPI1 may alter microglial phenotype potentially impacting AD. This study determined how the microglial transcriptome was altered following modest changes to Spi1 expression in primary mouse microglia. RNA-sequencing was performed on microglia with reduced or increased Spi1/PU.1 expression to provide an unbiased approach to determine transcriptomic changes affected by Spi1. In summary, a reduction in microglial Spi1 resulted in the dysregulation of transcripts encoding proteins involved in DNA replication pathways while an increased Spi1 results in an upregulation of genes associated with immune response pathways. Additionally, a subset of 194 Spi1 dose-sensitive genes was identified and pathway analysis suggests that several innate immune and interferon response pathways are impacted by the concentration of Spi1. Together these results suggest Spi1 levels can alter the microglial transcriptome and suggests interferon pathways may be altered in individuals with AD related Spi1 risk SNPs.
Melting line of calcium characterized by in situ LH-DAC XRD and first-principles calculations
Authors: Anzellini Simone , Alfé Dario , Pozzo Monica , Errandonea Daniel
Published: July 2021

In this work, the melting line of calcium has been characterized both experimentally, using synchrotron X-ray diffraction in laser-heated diamond-anvil cells, and theoretically, using first-principles calculations. In the investigated pressure and temperature range (pressure between 10 and 40 GPa and temperature between 300 and 3000 K) it was possible to observe the face-centred phase of calcium and to confirm (and characterize for the first time at these conditions) the presence of the body-centred cubic and the simple cubic phase of calcium. The melting points obtained with the two techniques are in excellent agreement. Furthermore, the present results agree with the only existing melting line of calcium obtained in laser-heated diamond anvil cells, using the speckle method as melting detection technique. They also confirm a flat slope of the melting line in the pressure range between 10 and 30 GPa. The flat melting curve is associated with the presence of the solid high-temperature body-centered cubic phase of calcium and to a small volume change between this phase and the liquid at melting. Reasons for the stabilization of the body-centered face at high-temperature conditions will be discussed.
Management of biliary diseases after the failure of initial needle knife precut sphincterotomy for biliary cannulation
Authors: Lo Min-Hao , Lin Cheng-Hui , Wu Chi-Huan , Tsou Yung-Kuan , Lee Mu-Hsien , Sung Kai-Feng , Liu Nai-Jen
Published: July 2021

Endoscopic retrograde cholangiopancreatography is not always successful even with needle knife precut sphincterotomy (NKPS). How to manage these patients with initial NKPS failure has not been well studied. We report the outcomes of patients who received endoscopic and non-endoscopic rescue treatment after the initial NKPS failure. During the 15 years from 2004 to 2018, 87 patients with initial NKPS failure received interval endoscopic treatment (IET group, n = 43), percutaneous transhepatic biliary drainage (PTBD group, n = 25), or bile duct surgery (BDS group, n = 19) were retrospectively studied. Compared with the PTBD group, the prevalence of choledocholithiasis was higher (69.8% vs. 16.0%, p < 0.001), and malignant bile duct stricture were lower (20.9% vs. 76.0%, p < 0.001) in the IET group. Furthermore, the IET group had a significantly longer time interval between the first and second treatment procedures (4 days vs. 2 days, p = 0.001), a lower technique success rate (79.1% vs. 100%, p = 0.021), and a shorter length of hospital stay (7 days vs. 18 days, p < 0.001). Compared to the BDS group, the only significant finding was that the patients in the IET group were older. Although not statistically significant, the complication rate was lowest in the IET group (7.0%) while highest in the BDS group (15.8%). Complications in the IET group were also mild, as compared with the other two groups. In conclusion, IET should be considered after initial failed NKPS for deep biliary cannulation before contemplating more invasive treatment such as BDS. PTBD may be the alternative therapy for patients with malignant biliary obstruction.
Prevalence of low birth weight and macrosomia estimates based on heaping adjustment method in China
Authors: Shen Liping , Wang Jie , Duan Yifan , Yang Zhenyu
Published: July 2021

Low birth weight (< 2500 g; LBW) and macrosomia (> 4000 g) are both adverse birth outcomes with high health risk in short- or long-term period. However, national prevalence estimates of LBW and macrosomia varied partially due to methodology limits in China. The aim of this study is to estimate the prevalence of LBW and macrosomia after taking potential birth weight heaping into consideration in Chinese children under 6 years in 2013. The data were from a nationally representative cross-sectional survey in mainland China in 2013, which consists of 32,276 eligible records. Birth weight data and socio-demographic information was collected using standard questionnaires. Birth weight distributions were examined and LBW and macrosomia estimates were adjusted for potential heaping. The overall prevalence of LBW of Chinese children younger than 6 years was 5.15% in 2013, with 4.57% in boys and 5.68% in girls. LBW rate was higher for children who were minority ethnicity, had less educated mothers, mothers aged over 35 years or under 20 years, or were in lower income household than their counterparts. The overall prevalence of macrosomia of Chinese children younger than 6 years was 7.35% in 2013, with 8.85% in boys and 5.71% in girls. The prevalence of macrosomia increased with increasing maternal age, educational level and household income level. Both LBW and macrosomia varied among different regions and socio-economic groups around China. It is found that estimates based on distribution adjustment might be more accurate and could be used as the foundation for policy-decision and health resource allocation. It would be needed to take potential misclassification of birth weight data arising from heaping into account in future studies.
An epigenetic GPI anchor defect impairs TLR4 signaling in the B cell transdifferentiation model for primary human monocytes BLaER1
Authors: Wegner Julia , Zillinger Thomas , Schlee-Guimaraes Thais Marina , Bartok Eva , Schlee Martin
Published: July 2021

Antigen-presenting myeloid cells like monocytes detect invading pathogens via pattern recognition receptors (PRRs) and initiate adaptive and innate immune responses. As analysis of PRR signaling in primary human monocytes is hampered by their restricted expandability, human monocyte models like THP-1 cells are commonly used for loss-of-function studies, such as with CRISPR-Cas9 editing. A recently developed transdifferentiation cell culture system, BLaER1, enables lineage conversion from malignant B cells to monocytes and was found superior to THP-1 in mimicking PRR signaling, thus being the first model allowing TLR4 and inflammasome pathway analysis. Here, we identified an important caveat when investigating TLR4-driven signaling in BLaER1 cells. We show that this model contains glycosylphosphatidylinositol (GPI) anchor-deficient cells, which lack CD14 surface expression when differentiated to monocytes, resulting in diminished LPS/TLR4 but not TLR7/TLR8 responsiveness. This GPI anchor defect is caused by epigenetic silencing of PIGH, leading to a random distribution of intact and PIGH-deficient clones after single-cell cloning. Overexpressing PIGH restored GPI-anchored protein (including CD14) expression and LPS responsiveness. When studying CD14- or other GPI-anchored protein-dependent pathways, researchers should consider this anomaly and ensure equal GPI-anchored protein expression when comparing cells that have undergone single-cell cloning, e. g. after CRISPR-Cas9 editing.
VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, induces cell cycle arrest and apoptosis in breast cancer cells by inhibiting the Wnt/β-catenin pathway
Authors: Li Hongling , Dang Chunyan , Tai Xiaohui , Xue Li , Meng Yuna , Ma Shuping , Zhang Jing
Published: July 2021

Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. In this study, we investigated the cytotoxic and apoptotic effects of VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, on human breast cancer cells and the possible underlying mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test was used to observe the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells induced by VALD-3. Flow cytometry analysis showed that VALD-3 triggered cell cycle arrest and induced apoptosis of breast cancer cells. Western blot analysis revealed that VALD-3 upregulated pro-apoptotic proteins (Bad and Bax), downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin and XIAP) and increased the expression of cleaved caspase-3, cleaved caspase-8, Cyto-c and cleaved PARP. VALD-3 also regulated the Wnt/β-catenin signaling pathway in breast cancer cells, inhibiting the activation of downstream molecules. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. In addition, survival analysis showed that VALD-3 can significantly prolong the survival time of mice (P = 0.036). This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/β-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer.