bluuebunny/crossref_metadata_2025 huggingface dataset:
New phosphosite-specific antibodies to unravel the role of GRK phosphorylation in dopamine D2 receptor regulation and signaling
Authors: Mann Anika , Keen Alastair C. , Mark Hanka , Dasgupta Pooja , Javitch Jonathan A. , Canals Meritxell , Schulz Stefan , Robert Lane J.
Published: April 2021

The dopamine D2 receptor (D2R) is the target of drugs used to treat the symptoms of Parkinson’s disease and schizophrenia. The D2R is regulated through its interaction with and phosphorylation by G protein receptor kinases (GRKs) and interaction with arrestins. More recently, D2R arrestin-mediated signaling has been shown to have distinct physiological functions to those of G protein signalling. Relatively little is known regarding the patterns of D2R phosphorylation that might control these processes. We aimed to generate antibodies specific for intracellular D2R phosphorylation sites to facilitate the investigation of these mechanisms. We synthesised double phosphorylated peptides corresponding to regions within intracellular loop 3 of the hD2R and used them to raise phosphosite-specific antibodies to capture a broad screen of GRK-mediated phosphorylation. We identify an antibody specific to a GRK2/3 phosphorylation site in intracellular loop 3 of the D2R. We compared measurements of D2R phosphorylation with other measurements of D2R signalling to profile selected D2R agonists including previously described biased agonists. These studies demonstrate the utility of novel phosphosite-specific antibodies to investigate D2R regulation and signalling.
A previously unknown way of heme detoxification in the digestive tract of cats
Authors: Duzhak Alexandr B. , Sherin Petr S. , Yanshole Vadim V. , Veber Sergey L. , Baiborodin Sergey I. , Sinitsyna Olga I. , Tsentalovich Yuri P.
Published: April 2021

Free heme is a highly toxic molecule for a living organism and its detoxification is a very important process, especially for carnivorous animals. Here we report the discovery of a previously unknown process for neutralizing free heme in the digestive tract of domestic cats. The cornerstone of this process is the encapsulation of heme into carbonated hydroxyapatite nanoparticles, followed by their excretion with faeces. This way of heme neutralization resembles the formation of insoluble heme-containing particles in the digestive tracts of other hematophagous species (for example, the formation of insoluble hemozoin crystals in malaria-causing Plasmodium parasites). Our findings suggest that the encapsulation of heme molecules into a hydroxyapatite matrix occurs during the transition from the acidic gastric juice to the small intestine with neutral conditions. The formation of these particles and their efficiency to include heme depends on the bone content in a cat’s diet. In vitro experiments with heme-hydroxyapatite nanoparticles confirm the proposed scenario.
Novel, non-invasive markers for detecting therapy induced neuroendocrine differentiation in castration-resistant prostate cancer patients
Authors: Bhagirath Divya , Liston Michael , Akoto Theresa , Lui Byron , Bensing Barbara A. , Sharma Ashok , Saini Sharanjot
Published: April 2021

Neuroendocrine prostate cancer (NEPC), a highly aggressive variant of castration-resistant prostate cancer (CRPC), often emerges upon treatment with androgen pathway inhibitors, via neuroendocrine differentiation. Currently, NEPC diagnosis is challenging as available markers are not sufficiently specific. Our objective was to identify novel, extracellular vesicles (EV)-based biomarkers for diagnosing NEPC. Towards this, we performed small RNA next generation sequencing in serum EVs isolated from a cohort of CRPC patients with adenocarcinoma characteristics (CRPC-Adeno) vs CRPC-NE and identified significant dysregulation of 182 known and 4 novel miRNAs. We employed machine learning algorithms to develop an ‘EV-miRNA classifier’ that could robustly stratify ‘CRPC-NE’ from ‘CRPC-Adeno’. Examination of protein repertoire of exosomes from NEPC cellular models by mass spectrometry identified thrombospondin 1 (TSP1) as a specific biomarker. In view of our results, we propose that a miRNA panel and TSP1 can be used as novel, non-invasive tools to identify NEPC and guide treatment decisions. In conclusion, our study identifies for the first time, novel non-invasive exosomal/extracellular vesicle based biomarkers for detecting neuroendocrine differentiation in advanced castration resistant prostate cancer patients with important translational implications in clinical management of these patients that is currently extremely challenging.
Transcriptional profiles in Strongyloides stercoralis males reveal deviations from the Caenorhabditis sex determination model
Authors: Gonzalez Akimori Damia , Dalessandro Emily J. , Nolan Thomas J. , Stieha Christopher R. , Lok James B. , Stoltzfus Jonathan D. C.
Published: April 2021

The human and canine parasitic nematode Strongyloides stercoralis utilizes an XX/XO sex determination system, with parasitic females reproducing by mitotic parthenogenesis and free-living males and females reproducing sexually. However, the genes controlling S. stercoralis sex determination and male development are unknown. We observed precocious development of rhabditiform males in permissive hosts treated with corticosteroids, suggesting that steroid hormones can regulate male development. To examine differences in transcript abundance between free-living adult males and other developmental stages, we utilized RNA-Seq. We found two clusters of S. stercoralis-specific genes encoding predicted transmembrane proteins that are only expressed in free-living males. We additionally identified homologs of several genes important for sex determination in Caenorhabditis species, including mab-3, tra-1, fem-2, and sex-1, which may have similar functions. However, we identified three paralogs of gld-1; Ss-qki-1 transcripts were highly abundant in adult males, while Ss-qki-2 and Ss-qki-3 transcripts were highly abundant in adult females. We also identified paralogs of pumilio domain-containing proteins with sex-specific transcripts. Intriguingly, her-1 appears to have been lost in several parasite lineages, and we were unable to identify homologs of tra-2 outside of Caenorhabditis species. Together, our data suggest that different mechanisms control male development in S. stercoralis and Caenorhabditis species.
Boosting the signal-to-noise of low-field MRI with deep learning image reconstruction
Authors: Koonjoo N. , Zhu B. , Bagnall G. Cody , Bhutto D. , Rosen M. S.
Published: April 2021

Recent years have seen a resurgence of interest in inexpensive low magnetic field (< 0.3 T) MRI systems mainly due to advances in magnet, coil and gradient set designs. Most of these advances have focused on improving hardware and signal acquisition strategies, and far less on the use of advanced image reconstruction methods to improve attainable image quality at low field. We describe here the use of our end-to-end deep neural network approach (AUTOMAP) to improve the image quality of highly noise-corrupted low-field MRI data. We compare the performance of this approach to two additional state-of-the-art denoising pipelines. We find that AUTOMAP improves image reconstruction of data acquired on two very different low-field MRI systems: human brain data acquired at 6.5 mT, and plant root data acquired at 47 mT, demonstrating SNR gains above Fourier reconstruction by factors of 1.5- to 4.5-fold, and 3-fold, respectively. In these applications, AUTOMAP outperformed two different contemporary image-based denoising algorithms, and suppressed noise-like spike artifacts in the reconstructed images. The impact of domain-specific training corpora on the reconstruction performance is discussed. The AUTOMAP approach to image reconstruction will enable significant image quality improvements at low-field, especially in highly noise-corrupted environments.
Genetic variability, cryptic species and phylogenetic relationship of six cyathostomin species based on mitochondrial and nuclear sequences
Authors: Louro Mariana , Kuzmina Tetiana A. , Bredtmann Christina M. , Diekmann Irina , de Carvalho Luís M. Madeira , von Samson-Himmelstjerna Georg , Krücken Jürgen
Published: April 2021

Cyathostomins are important intestinal nematode parasites of equines and include 50 accepted species. Their taxonomy has been frequently revised and the presence of cryptic species suggested. Furthermore, usually molecular- and morphology-based phylogenetic analyses give divergent results. In this study, the nucleotide sequences of the nuclear second internal transcribed spacer (ITS-2) and the mitochondrial partial cytochrome c oxidase subunit I (COI) were determined for adults of six cyathostomin species (Coronocyclus coronatus, Coronocyclus labiatus, Cylicocyclus nassatus, Cylicostephanus calicatus, Cylicostephanus longibursatus, Cylicostephanus minutus) collected from different equine species within two geographic regions. Maximum likelihood trees were calculated for ITS-2, COI, and concatenated data. No obvious differentiation was observed between geographic regions or equine host species. As previously reported, Coronocyclus coronatus and Cylicostephanus calicatus revealed a close relationship. Cryptic species were detected in Cylicostephanus minutus and Cylicostephanus calicatus. Cylicocyclus nassatus and Coronocyclus labiatus showed diverse mitochondrial and nuclear haplotypes occurring in different combinations, while Cylicostephanus longibursatus was comparatively homogenous. In conclusion, a combined analysis of nuclear and mitochondrial haplotypes improved resolution of the phylogeny and should be applied to the remaining cyathostomin species and across additional equine host species and geographic regions.
The VH framework region 1 as a target of efficient mutagenesis for generating a variety of affinity-matured scFv mutants
Authors: Kiguchi Yuki , Oyama Hiroyuki , Morita Izumi , Nagata Yasuhiro , Umezawa Naoko , Kobayashi Norihiro
Published: April 2021

In vitro affinity-maturation potentially generates antibody fragments with enhanced antigen-binding affinities that allow for developing more sensitive diagnostic systems and more effective therapeutic agents. Site-directed mutagenesis targeting “hot regions,” i.e., amino acid substitutions therein frequently increase the affinities, is desirable for straightforward discovery of valuable mutants. We here report two “designed” site-directed mutagenesis (A and B) targeted theN-terminal 1–10 positions of the VHframework region 1 that successfully improved an anti-cortisol single-chain Fv fragment (Ka, 3.6 × 108 M−1). Mutagenesis A substituted the amino acids at the position 1–3, 5–7, 9 and 10 with a limited set of substitutions to generate only 1,536 different members, while mutagenesis B inserted 1–6 random residues between the positions 6 and 7. Screening the resulting bacterial libraries as scFv-phage clones with a clonal array profiling system provided 21 genetically unique scFv mutants showing 17–31-fold increased affinity with > 109 M−1Kavalues. Among the mutants selected from the library A and B, scFv mA#18 (with five-residue substitutions) and mB1-3#130 (with a single residue insertion) showed the greatestKavalue, 1.1 × 1010 M−1.
Changes in the gene expression profile during spontaneous migraine attacks
Authors: Kogelman Lisette J. A. , Falkenberg Katrine , Buil Alfonso , Erola Pau , Courraud Julie , Laursen Susan Svane , Michoel Tom , Olesen Jes , Hansen Thomas F.
Published: April 2021

Migraine attacks are delimited, allowing investigation of changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore, we hypothesized that changes in RNA expression during and outside a spontaneous migraine attack exist which are specific to migraine. Twenty-seven migraine patients were assessed during a spontaneous migraine attack, including headache characteristics and treatment effect. Blood samples were taken during attack, two hours after treatment, on a headache-free day and after a cold pressor test. RNA-Sequencing, genotyping, and steroid profiling were performed. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and genomic and transcriptomic data were integrated. We found 29 differentially expressed genes between ‘attack’ and ‘after treatment’, after subtracting non-migraine specific genes, that were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed mechanisms affected by changes in gene interactions, e.g. ‘ion transmembrane transport’. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. ‘5HT1 type receptor mediated signaling pathway’. In conclusion, we uniquely investigated intra-individual changes in gene expression during a migraine attack. We revealed both genes and pathways potentially involved in the pathophysiology of migraine and/or migraine treatment.
Tadalafil ameliorates bladder overactivity by restoring insulin-activated detrusor relaxation via the bladder mucosal IRS/PI3K/AKT/eNOS pathway in fructose-fed rats
Authors: Lee Wei-Chia , Leu Steve , Wu Kay L. H. , Tain You-Lin , Chuang Yao-Chi , Chan Julie Y. H.
Published: April 2021

The pathophysiologies of metabolic syndrome (MS) and overactive bladder (OAB) might overlap. Using fructose-fed rats (FFRs) as a rodent model of MS we investigated the effects of tadalafil (a phosphodiesterase type 5 inhibitor) on the dysregulated insulin signalling in the bladder mucosa and bladder overactivity. Micturition behaviour was evaluated. Concentration–response curves on detrusor relaxation to insulin stimulation were examined. Expression and phosphorylation of proteins in the insulin signalling pathway were evaluated by Western blotting. Levels of detrusor cGMP and urinary nitrite and nitrate (NOx) were measured. We observed FFRs exhibited metabolic traits of MS, bladder overactivity, and impaired insulin-activated detrusor relaxation in organ bath study. A high-fructose diet also impeded insulin signalling, reflected by overexpression of IRS1/pIRS1Ser307 and pIRS2Ser731 and downregulation of PI3K/pPI3KTyr508, AKT/pAKTSer473, and eNOS/peNOSSer1177 in the bladder mucosa, alongside decreased urinary NOx and detrusor cGMP levels. Tadalafil treatment restored the reduced level of mucosal peNOS, urinary NOx, and detrusor cGMP, improved the insulin-activated detrusor relaxation, and ameliorated bladder overactivity in FFRs. These results suggest tadalafil may ameliorate MS-associated bladder overactivity by restoring insulin-activated detrusor relaxation via molecular mechanisms that are associated with preservation of IR/IRS/PI3K/AKT/eNOS pathway in the bladder mucosa and cGMP production in the bladder detrusor.
Chemical characterization (LC–MS–ESI), cytotoxic activity and intracellular localization of PAMAM G4 in leukemia cells
Authors: Flores-Mejía R. , Fragoso-Vázquez M. J. , Pérez-Blas L. G. , Parra-Barrera A. , Hernández-Castro S. S. , Estrada-Pérez A. R. , Rodrígues J. , Lara-Padilla E. , Ortiz-Morales A. , Correa-Basurto J.
Published: April 2021

Generation 4 of polyamidoamine dendrimer (G4-PAMAM) has several biological effects due to its tridimensional globular structure, repetitive branched amides, tertiary amines, and amino-terminal subunit groups liked to a common core. G4-PAMAM is cytotoxic due to its positive charges. However, its cytotoxicity could increase in cancer cells due to the excessive intracellular negative charges in these cells. Furthermore, this work reports G4-PAMAM chemical structural characterization using UHPLC-QTOF-MS/MS (LC–MS) by electrospray ionization to measure its population according to its positive charges. Additionally, the antiproliferative effects and intracellular localization were explored in the HMC-1 and K-562 cell lines by confocal microscopy. The LC–MS results show that G4-PAMAM generated multivalent mass spectrum values, and its protonated terminal amino groups produced numerous positive charges, which allowed us to determine its exact mass despite having a high molecular weight. Additionally, G4-PAMAM showed antiproliferative activity in the HMC-1 tumor cell line after 24 h (IC50 = 16.97 µM), 48 h (IC50 = 7.02 µM) and 72 h (IC50 = 5.98 µM) and in the K-562 cell line after 24 h (IC50 = 15.14 µM), 48 h (IC50 = 14.18 µM) and 72 h (IC50 = 9.91 µM). Finally, our results showed that the G4-PAMAM dendrimers were located in the cytoplasm and nucleus in both tumor cell lines studied.
Activation of creER recombinase in the mouse calvaria induces local recombination without effects on distant skeletal segments
Authors: Hou Jue , Lin Charles P. , Intini Giuseppe
Published: April 2021

Conditional creER-mediated gene inactivation or gene induction has emerged as a robust tool for studying gene functions in mouse models of tissue development, homeostasis, and regeneration. Here, we present a method to conditionally induce cre recombination in the mouse calvarial bone while avoiding systemic recombination in distal bones. To test our method, we utilized Prx1creER-egfp;td-Tomato mice and delivered 4-hydroxytamoxifen (4-OHT) to the mouse calvaria, subperiosteally. First, we showed that two calvaria subperiosteal injections of 10 µg of 4-OHT (3.3 mg of 4-OHT/kg of body weight) can induce local recombination as efficiently as two intraperitoneal systemic injections of 200 μg of tamoxifen (70 mg of tamoxifen/kg of body weight). Then, we studied the recombination efficiency of various subperiosteal calvaria dosages and found that two subperiosteal injections of 5 µg 4-OHT (1.65 mg of 4-OHT/kg of body weight) uphold the same recombination efficiency observed with higher dosages. Importantly, the result indicated that the low dosage does not induce significant systemic recombination in remote skeletal tissues. With the proposed local low dosage protocol, the recombination efficiency at the injection site (calvarial bone) reached 94%, while the recombination efficiency at the mandible and the digits was as low as the efficiency measured in control animals.
Low-temperature synthesis and growth model of thin Mo2C crystals on indium
Authors: Caylan Omer Refet , Cambaz Buke Goknur
Published: April 2021

Chemical vapor deposition is a promising technique to produce Mo2C crystals with large area, controlled thickness, and reduced defect density. Typically, liquid Cu is used as a catalyst substrate; however, its high melting temperature (1085 °C) prompted research groups to search for alternatives. In this study, we report the synthesis of large-area thin Mo2C crystals at lower temperatures using liquid In, which is also advantageous with respect to the transfer process due to its facile etching. SEM, EDS, Raman spectroscopy, XPS, and XRD studies show that hexagonal Mo2C crystals, which are orthorhombic, grow along the [100] direction together with an amorphous carbon thin film on In. The growth mechanism is examined and discussed in detail, and a model is proposed. AFM studies agree well with the proposed model, showing that the vertical thickness of the Mo2C crystals decreases inversely with the thickness of In for a given reaction time.
Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells
Authors: Dong Yi Na , Hsu Fu-Chun , Koziol-White Cynthia J. , Stepanova Victoria , Jude Joseph , Gritsiuta Andrei , Rue Ryan , Mott Rosalind , Coulter Douglas A. , Panettieri Reynold A. , Krymskaya Vera P. , Takano Hajime , Goncharova Elena A. , Goncharov Dmitry A. , Cines Douglas B. , Lynch David R.
Published: April 2021

N-methyl-d-aspartate (NMDA) receptors are widely expressed in the central nervous system. However, their presence and function at extraneuronal sites is less well characterized. In the present study, we examined the expression of NMDA receptor subunit mRNA and protein in human pulmonary artery (HPA) by quantitative polymerase chain reaction (PCR), immunohistochemistry and immunoblotting. We demonstrate that both GluN1 and GluN2 subunit mRNAs are expressed in HPA. In addition, GluN1 and GluN2 (A–D) subunit proteins are expressed by human pulmonary artery smooth muscle cells (HPASMCs) in vitro and in vivo. These subunits localize on the surface of HPASMCs and form functional ion channels as evidenced by whole-cell patch-clamp electrophysiology and reduced phenylephrine-induced contractile responsiveness of human pulmonary artery by the NMDA receptor antagonist MK801 under hypoxic condition. HPASMCs also express high levels of serine racemase and vesicular glutamate transporter 1, suggesting a potential source of endogenous agonists for NMDA receptor activation. Our findings show HPASMCs express functional NMDA receptors in line with their effect on pulmonary vasoconstriction, and thereby suggest a novel therapeutic target for pharmacological modulations in settings associated with pulmonary vascular dysfunction.
Comparative analysis of histone H3K4me3 modifications between blastocysts and somatic tissues in cattle
Authors: Ishibashi Mao , Ikeda Shuntaro , Minami Naojiro
Published: April 2021

Epigenetic changes induced in the early developmental stages by the surrounding environment can have not only short-term but also long-term consequences throughout life. This concept constitutes the “Developmental Origins of Health and Disease” (DOHaD) hypothesis and encompasses the possibility of controlling livestock health and diseases by epigenetic regulation during early development. As a preliminary step for examining changes of epigenetic modifications in early embryos and their long-lasting effects in fully differentiated somatic tissues, we aimed to obtain high-throughput genome-wide histone H3 lysine 4 trimethylation (H3K4me3) profiles of bovine blastocysts and to compare these data with those from adult somatic tissues in order to extract common and typical features between these tissues in terms of H3K4me3 modifications. Bovine blastocysts were produced in vitro and subjected to chromatin immunoprecipitation-sequencing analysis of H3K4me3. Comparative analysis of the blastocyst-derived H3K4me3 profile with publicly available data from adult liver and muscle tissues revealed that the blastocyst profile could be used as a “sieve” to extract somatic tissue-specific modifications in genes closely related to tissue-specific functions. Furthermore, principal component analysis of the level of common modifications between blastocysts and somatic tissues in meat production-related and imprinted genes well characterized inter- and intra-tissue differences. The results of this study produced a referential genome-wide H3K4me3 profile of bovine blastocysts within the limits of their in vitro source and revealed its common and typical features in relation to the profiles of adult tissues.
Predicting anthropometric and metabolic traits with a genetic risk score for obesity in a sample of Pakistanis
Authors: Rana Sobia , Bhatti Adil Anwar
Published: April 2021

Obesity is an outcome of multiple factors including environmental and genetic influences. Common obesity is a polygenic trait indicating that multiple genetic variants act synergistically to influence its expression. We constructed a genetic risk score (GRS) based on five genetic variants (MC4Rrs17782313,BDNFrs6265,FTOrs1421085,TMEM18rs7561317, andNEGR1rs2815752) and examined its association with obesity-related traits in a sample of Pakistanis. The study involved 306 overweight/obese (OW/OB) and 300 normal-weight (NW) individuals. The age range of the study participants was 12–63 years. All anthropometric and metabolic parameters were measured for each participant via standard procedures and biochemical assays, respectively. The genetic variants were genotyped by allelic discrimination assays. The age- and gender-adjusted associations between the GRS and obesity-related anthropometric and metabolic measures were determined using linear regression analyses. The results showed that OW/OB individuals had significantly higher mean ranks of GRS than NW individuals. Moreover, a significant association of the GRS with obesity-related anthropometric traits was seen. However, the GRS did not appear to affect any obesity-related metabolic parameter. In conclusion, our findings indicate the combined effect of multiple genetic variants on the obesity-related anthropometric phenotypes in Pakistanis.
Methamphetamine facilitates pulmonary and splenic tissue injury and reduces T cell infiltration in C57BL/6 mice after antigenic challenge
Authors: Hernandez-Santini Adriana C. , Mitha Anum N. , Chow Daniela , Hamed Mohamed F. , Gucwa Azad L. , Vaval Valerie , Martinez Luis R.
Published: April 2021

Methamphetamine (METH) is a strong addictive central nervous system stimulant. METH abuse can alter biological processes and immune functions necessary for host defense. The acquisition and transmission of HIV, hepatitis, and other communicable diseases are possible serious infectious consequences of METH use. METH also accumulates extensively in major organs. Despite METH being a major public health and safety problem globally, there are limited studies addressing the impact of this popular recreational psychostimulant on tissue adaptive immune responses after exposure to T cell dependent [ovalbumin (OVA)] and independent [lipopolysaccharide (LPS)] antigens. We hypothesized that METH administration causes pulmonary and splenic tissue alterations and reduces T cell responses to OVA and LPS in vivo, suggesting the increased susceptibility of users to infection. Using a murine model of METH administration, we showed that METH causes tissue injury, apoptosis, and alters helper and cytotoxic T cell recruitment in antigen challenged mice. METH also reduces the expression and distribution of CD3 and CD28 molecules on the surface of human Jurkat T cells. In addition, METH decreases the production of IL-2 in these T-like cells, suggesting a negative impact on T lymphocyte activation and proliferation. Our findings demonstrate the pleotropic effects of METH on cell-mediated immunity. These alterations have notable implications on tissue homeostasis and the capacity of the host to respond to infection.
Impact of idiopathic pulmonary fibrosis on clinical outcomes of lung cancer patients
Authors: Kim Ho Cheol , Lee Seonjeong , Song Jin Woo
Published: April 2021

The clinical characteristics of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) differ from those of lung cancer in patients without IPF. Thus, we aimed to evaluate the impact of IPF on the clinical course of patients with lung cancer. Clinical data of IPF patients with lung cancer (n = 122) were compared with those of patients with lung cancer without IPF (n = 488) matched by age, sex, histopathology, stage, and date of diagnosis of lung cancer. The median follow-up period after diagnosis of lung cancer was 16 months. Among patients with IPF, the mean age was 68 years, 95.9% were male, 93.2% were ever-smokers, and squamous cell carcinoma was the most common cancer type (48.4%). The IPF group had poorer lung function and lower lobe predominance of lung cancer than the no-IPF group. The IPF group showed a poorer prognosis than the no-IPF group (5-year survival rate: 14.5% vs. 30.1%, respectively; P < 0.001), even after adjusting for lung function and regardless of the treatment method. Among patients with IPF, 16.8% experienced acute exacerbation within 1 month after treatment of lung cancer. The treatment outcome of patients with lung cancer and IPF was generally unfavorable, and acute exacerbation triggered by treatment frequently occurred.
Investigation of type I interferon responses in ANCA-associated vasculitis
Authors: Batten Isabella , Robinson Mark W. , White Arthur , Walsh Cathal , Fazekas Barbara , Wyse Jason , Buettner Antonia , D’Arcy Suzanne , Greenan Emily , Murphy Conor C. , Wigston Zoe , Gabhann-Dromgoole Joan Ní , Vital Edward M. , Little Mark A. , Bourke Nollaig M.
Published: April 2021

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44LandIFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.
Cooperation among unrelated ant queens provides persistent growth and survival benefits during colony ontogeny
Authors: Ostwald Madeleine M. , Guo Xiaohui , Wong Tyler , Malaekeh Armon , Harrison Jon F. , Fewell Jennifer H.
Published: April 2021

The fitness consequences of cooperation can vary across an organism’s lifespan. For non-kin groups, especially, social advantages must balance intrinsic costs of cooperating with non-relatives. In this study, we asked how challenging life history stages can promote stable, long-term alliances among unrelated ant queens. We reared single- and multi-queen colonies of the primary polygynous harvester ant,Pogonomyrmex californicus, from founding through the first ten months of colony growth, when groups face high mortality risks. We found that colonies founded by multiple, unrelated queens experienced significant survival and growth advantages that outlasted the colony founding period. Multi-queen colonies experienced lower mortality than single-queen colonies, and queens in groups experienced lower mortality than solitary queens. Further, multi-queen colonies produced workers at a faster rate than did single-queen colonies, even while experiencing lower per-queen worker production costs. Additionally, we characterized ontogenetic changes in the organization of labor, and observed increasing and decreasing task performance diversity by workers and queens, respectively, as colonies grew. This dynamic task allocation likely reflects a response to the changing role of queens as they are increasingly able to delegate risky and costly tasks to an expanding workforce. Faster worker production in multi-queen colonies may beneficially accelerate this behavioral transition from a vulnerable parent–offspring group to a stable, growing colony. These combined benefits of cooperation may facilitate the retention of multiple unrelated queens in mature colonies despite direct fitness costs, providing insight into the evolutionary drivers of stable associations between unrelated individuals.
3D printed aluminum flat heat pipes with micro grooves for efficient thermal management of high power LEDs
Authors: Chang Chao , Han Zhaoyang , He Xiaoyu , Wang Zongyu , Ji Yulong
Published: April 2021

As the electronic technology becomes increasingly integrated and miniaturized, thermal management has become a major challenge for electronic device applications. A heat pipe is a highly efficient two-phase heat transfer device. Due to its simple structure, high thermal conductivity and good temperature uniformity, it has been used in many different industrial fields. A novel aluminum flat heat pipe, with micro-grooves, has in the present work been designed and fabricated by using a 3D printing technology. Aluminum powder was used as a raw material, which was selectively melted and solidified to form the shape of the heat pipe. The sintered aluminum powder increased the roughness of the inner surface of the heat pipe, and the designed micro-grooves further enhanced the capillary forces induced by the wick structure. The wettability, for the working fluid (acetone), was excellent and the capillary forces were sufficient for the working fluid to flow back in the pipe. The effects of working fluid filling ratio, on the heat transfer performance of the heat pipe, was also investigated. It was shown that a filling ratio of 10% gave the best heat transfer performance with the lowest thermal resistance. The 3D-printed flat heat pipe was, therefore, also tested for the thermal management of a LED. The temperature of the LED could be kept within 40 °C and its service life became prolonged.
Integrin αvβ5 heterodimer is a specific marker of human pancreatic beta cells
Authors: Schiesser Jacqueline V. , Loudovaris Thomas , Thomas Helen E. , Elefanty Andrew G. , Stanley Edouard G.
Published: April 2021

The identification of cell surface markers specific to pancreatic beta cells is important for both the study of islet biology and for investigating the pathophysiology of diseases in which this cell type is lost or damaged. Following analysis of publicly available RNAseq data, we identified specific integrin subunits, integrin αv and integrin β5, that were expressed in beta cells. This finding was further elaborated using immunofluorescence analysis of histological sections derived from donor human pancreas. Despite the broad expression of specific integrin subunits, we found that expression of integrin αvβ5 heterodimers was restricted to beta cells and that this complex persisted in islet remnants of some type 1 diabetic individuals from which insulin expression had been lost. This study identifies αvβ5 heterodimers as a novel cell surface marker of human pancreatic beta cells, a finding that will aid in the identification and characterisation of this important cell type.
Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition
Authors: Wang Ming , Yoon Gwangho , Song Juhyun , Jo Jihoon
Published: April 2021

Metabolic syndrome, which increases the risk of obesity and type 2 diabetes has emerged as a significant issue worldwide. Recent studies have highlighted the relationship between metabolic imbalance and neurological pathologies such as memory loss. Glucagon-like peptide 1 (GLP-1) secreted from gut L-cells and specific brain nuclei plays multiple roles including regulation of insulin sensitivity, inflammation and synaptic plasticity. Although GLP-1 and GLP-1 receptor agonists appear to have neuroprotective function, the specific mechanism of their action in brain remains unclear. We investigated whether exendin-4, as a GLP-1RA, improves cognitive function and brain insulin resistance in metabolic-imbalanced mice fed a high-fat diet. Considering the result of electrophysiological experiments, exendin-4 inhibits the reduction of long term potentiation (LTP) in high fat diet mouse brain. Further, we identified the neuroprotective effect of exendin-4 in primary cultured hippocampal and cortical neurons in in vitro metabolic imbalanced condition. Our results showed the improvement of IRS-1 phosphorylation, neuronal complexity, and the mature of dendritic spine shape by exendin-4 treatment in metabolic imbalanced in vitro condition. Here, we provides significant evidences on the effect of exendin-4 on synaptic plasticity, long-term potentiation, and neural structure. We suggest that GLP-1 is important to treat neuropathology caused by metabolic syndrome.
4-Methylumbelliferone administration enhances radiosensitivity of human fibrosarcoma by intercellular communication
Authors: Saga Ryo , Matsuya Yusuke , Takahashi Rei , Hasegawa Kazuki , Date Hiroyuki , Hosokawa Yoichiro
Published: April 2021

Hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) is a candidate of radiosensitizers which enables both anti-tumour and anti-metastasis effects in X-ray therapy. The curative effects under such 4-MU administration have been investigated in vitro; however, the radiosensitizing mechanisms remain unclear. Here, we investigated the radiosensitizing effects under 4-MU treatment from cell experiments and model estimations. We generated experimental surviving fractions of human fibrosarcoma cells (HT1080) after 4-MU treatment combined with X-ray irradiation. Meanwhilst, we also modelled the pharmacological effects of 4-MU treatment and theoretically analyzed the synergetic effects between 4-MU treatment and X-ray irradiation. The results show that the enhancement of cell killing by 4-MU treatment is the greatest in the intermediate dose range of around 4 Gy, which can be reproduced by considering intercellular communication (so called non-targeted effects) through the model analysis. As supposed to be the involvement of intercellular communication in radiosensitization, the oxidative stress level associated with reactive oxygen species (ROS), which leads to DNA damage induction, is significantly higher by the combination of 4-MU treatment and irradiation than only by X-ray irradiation, and the radiosensitization by 4-MU can be suppressed by the ROS inhibitors. These findings suggest that the synergetic effects between 4-MU treatment and irradiation are predominantly attributed to intercellular communication and provide more efficient tumour control than conventional X-ray therapy.
Extracellular vesicles from dHL-60 cells as delivery vehicles for diverse therapeutics
Authors: Kim Jun-Kyu , Youn Young-Jin , Lee Yu-Bin , Kim Sun-Hwa , Song Dong-Keun , Shin Minsang , Jin Hee Kyung , Bae Jae-sung , Shrestha Sanjeeb , Hong Chang-Won
Published: April 2021

Extracellular vesicles (EVs) are membrane-derived heterogeneous vesicles that mediate intercellular communications. They have recently been considered as ideal vehicles for drug-delivery systems, and immune cells are suggested as a potential source for drug-loaded EVs. In this study, we investigated the possibility of neutrophils as a source for drug-loaded EVs. Neutrophil-like differentiated human promyelocytic leukemia cells (dHL-60) produced massive amounts of EVs within 1 h. The dHL-60 cells are also easily loaded with various cargoes such as antibiotics (penicillin), anticancer drug (paclitaxel), chemoattractant (MCP-1), miRNA, and Cas9. The EVs derived from the dHL-60 cells showed efficient incorporation of these cargoes and significant effector functions, such as bactericidal activity, monocyte chemotaxis, and macrophage polarization. Our results suggest that neutrophils or neutrophil-like promyelocytic cells could be an attractive source for drug-delivery EVs.
The effects of type 2 diabetes mellitus on the corneal endothelium and central corneal thickness
Authors: Kim Yoo Jin , Kim Tae Gi
Published: April 2021

Aim of this study is to evaluate the differences in corneal endothelial cell morphology and corneal thickness in patients with and without type 2 diabetes related to age, disease duration, and HbA1c percentage. This retrospective cross-sectional study included 511 (1022 eyes) type 2 diabetes patients and 900 (1799 eyes) non-diabetic patients. The endothelial cell density (ECD), variation in endothelial cell size (CV), percentage of hexagonal cells, and central corneal thickness (CCT) were analyzed using a noncontact specular microscope and a Pentacam Scheimpflug camera. We also examined the correlation between the corneal parameters and the duration of diabetes. For total ages, the subjects with type 2 diabetes showed significantly lower ECD, hexagonality, higher CV, and thicker CCT than the control group. This difference was more pronounced in patients with long-standing DM (≥ 10 years) and high HbA1c (≥ 7%). When stratified by age group, from the 60 s group, corneal endothelial cell parameters showed a statistically significant difference between DM and control groups. The duration of diabetes was inversely correlated with ECD (r =  − 0.167;p = 0.000). These findings suggest that diabetes affects corneal endothelial cell in older age and those with long-standing DM and higher HbA1c. Regular corneal endothelial examinations are required in diabetic patients.
Temporal trends in incidence of time-loss injuries in four male professional North American sports over 13 seasons
Authors: Bullock Garrett S. , Murray Elizabeth , Vaughan Jake , Kluzek Stefan
Published: April 2021

Sports-related injuries increase healthcare cost burden, and in some instances have harmful long term physical and psychological implications. There is currently a lack of comprehensive data on temporal injury trends across professional North American sports. The purpose of this study was to compare temporal trends, according to incidence and time-loss injuries, by body part in professional baseball, basketball, football, and ice hockey. Public injury data from Major League Baseball, National Basketball Association, National Football League, and National Hockey League from 2007 to December 2019 were extracted and used. A mean of 62.49 injuries per 100 players per season was recorded for all professional sports. The groin/hip/thigh reported the greatest season proportional injury incidence for baseball, football, and ice hockey, with the groin/hip/thigh as the third highest injury incidence in basketball. When stratifying by more specific body part groupings, the knee demonstrated the greatest injury proportional incidence for basketball, football, and ice hockey, with the knee as the third highest proportional injury incidence for baseball. There was an increased in basketball ankle injuries following 2011–2012 season. Football and ice hockey reported the greatest concussion proportion incidence, with football demonstrating an increase in concussions over time, and a substantial increase in concussions from the 2014 to 2015 season. These publicly extracted data and findings can be used as a shared resource for professional baseball, basketball, football, and ice hockey for future individual and across sport collaborations concerning resource allocation and decision making in order to improve player health.
The development of an endoplasmic reticulum-targeting fluorescent probe for the imaging of 1,4-dithiothreitol (DTT) in living cells
Authors: Mehmood Abdul Hadi , Dong Baoli , Lu Yaru , Song Wenhui , Sun Yaru , Lin Weiying
Published: April 2021

An effective turn-on ER-targeting fluorescent probe ER-DTT was designed to image DTT of endoplasmic reticulum for the first time.
Beneficial effects ofDendrobium officinaleon metabolic hypertensive rats by triggering the enteric-origin SCFA-GPCR43/41 pathway
Authors: Li Bo , He Xinglishang , Jin Hai-Ying , Wang Hui-Ying , Zhou Fu-Chen , Zhang Ning-Yu , Jie Dong-Ying , Li Lin-Zi , Su Jie , Zheng Xiang , Luo Rong , Lv Gui-Yuan , Jiang Ning-Hua , Yu Qiao-Xian , Chen Su-Hong
Published: April 2021

DOFP enhances the production of SCFAs and absorption from the intestines and then activates the SCFA-GPCR43/41 pathway, resulting in improvements in vascular endothelial function and reduction in blood pressure of the ACHSFD-induced MH rats.
Characterization and structure–activity relationship of novel umami peptides isolated from Thai fish sauce
Authors: Bu Ying , Liu Yingnan , Luan Hongwei , Zhu Wenhui , Li Xuepeng , Li Jianrong
Published: April 2021

Fish sauce has a prominent umami flavor.
A fully bio-based wood adhesive valorising hemicellulose-rich sidestreams from the pulp industry
Authors: Todorovic Tijana , Norström Emelie , Khabbaz Farideh , Brücher Jörg , Malmström Eva , Fogelström Linda
Published: April 2021

The current study demonstrates how hemicelluloses in sidestreams from the pulp industry can be valorised to substitute fossil-based materials in wood-adhesive applications in the quest for a more sustainable society.
Synthesis of heteroleptic phosphine–copper(i) complexes: fluorescence sensing and catalytic properties
Authors: Luo Chen-Lin , Hu Chu-Xing , Shang Ping , Wen Guan-Zhao , Zhu Jia-Jun , Xuan Ya-Hui , Xia Bang-Lian , Liu Yu-Chen , Jiang Zi-Hao , Dong Geng , Zhang Wei , Gui Liu-Cheng , Jiang Xuan-Feng
Published: April 2021

A series of heteroleptic Cu(i) complexes were precisely synthesized using different bipyridine and diphosphine ligands. These complexes exhibited fluorescence sensing towards silver ions and high catalytic activity towards the CuAAC reaction.
The detection of fipronil residue in egg on layered gold nanorod–graphene oxide-based 3D SERS substrate
Authors: Lai Hung Lin , Ghosh Sandip , Chattopadhyay Surojit
Published: April 2021

Fipronil and fipronil sulfone have been detected by SERS in spiked eggs using gold nanorod and graphene oxide based substrates. The limit of detection was ~4.4 ppb, and an error of ~15 % was found for blind detection.
Anodic near-infrared electrochemiluminescence from Cu-doped CdTe quantum dots for tetracycline detection
Authors: Li Zhen-Zhen , Wu Mei-Xia , Ding Shou-Nian
Published: April 2021

In this paper, the NECL properties of Cu-doped CdTe QDs were explored for the first time, and the NECL immunosensor was constructed using QDs as a label signal to sensitively detect tetracycline.
Catalytic asymmetric coupling of vinylogous species via deconjugated butenolide addition to vinylogous imines in situ generated from arylsulfonyl indoles
Authors: Yuan Shu-Pei , Zhang Xia-Yan , Jia Yun-Qing , Wang Zhen-Hua , Zhao Jian-Qiang , You Yong , Zhou Ming-Qiang , Yuan Wei-Cheng
Published: April 2021

An efficient catalytic asymmetric coupling of vinylogous species was developed for the synthesis of enantioenriched sec-alkyl-3-substituted indoles containing adjacent quaternary-tertiary stereocenters in synthetically viable results.
Autonomous optimisation of a nanoparticle catalysed reduction reaction in continuous flow
Authors: Hall Brendan L. , Taylor Connor J. , Labes Ricardo , Massey Alexander F. , Menzel Robert , Bourne Richard A. , Chamberlain Thomas W.
Published: April 2021

An automated continuous flow reactor system for the optimisation of nanoparticle catalysed reactions, demonstrated through the optimisation of a gold nanoparticle catalysed nitrophenol reduction reaction.
Redox tuning in Pt(bpy)-viologen catalyst-acceptor dyads enabling photocatalytic hydrogen evolution from water
Authors: Yatsuzuka Koichi , Yamauchi Kosei , Sakai Ken
Published: April 2021

A Pt(ii)-based molecular photocatalyst tethered to redox-tuned viologen acceptors was synthesized to reveal its improved activity in photoreduction of water.
Wireless electrochemiluminescence at functionalised gold microparticles using 3D titanium electrode arrays
Authors: Douman Samantha F. , Collins David , Cumba Loanda R. , Beirne Stephen , Wallace Gordon G. , Yue Zhilian , Iwuoha Emmanuel I. , Melinato Federica , Pellegrin Yann , Forster Robert J.
Published: April 2021

Wireless electrochemiluminescence is generated from functionalised gold microparticles using interdigitated, 3D printed, titanium arrays as feeder electrodes. Active transport and intense electric fields leads to bright electrochemiluminescence.
Transition metal-free approach to azafluoranthene scaffolds by aldol condensation/[1+2+3] annulation tandem reaction of isocyanoacetates with 8-(alkynyl)-1-naphthaldehydes
Authors: Dong Penghui , Majeed Kashif , Wang Lingna , Guo Zijian , Zhou Fengtao , Zhang Qiuyu
Published: April 2021

A transition metal-free aldol condensation/[1+2+3] annulation reaction for access to acenaphtho[1,2-c]pyridines, chromeno[4,3-c]pyridines and benzo[c][2,6]naphthy-ridines.
Mechanochromic properties in a mononuclear Cu(i) complex without cuprophilic interactions
Authors: Yu Xiao , Li Xiaoyue , Cai Zelun , Sun Lingzhi , Wang Chengbo , Rao Haixia , Wei Chen , Bian Zuqiang , Jin Qionghua , Liu Zhiwei
Published: April 2021

A mononuclear Cu(i) complex with a pore structure was found to show evident mechanochromic luminescent (MCL) properties.
Recent developments in selective N-arylation of azoles
Authors: Halder Pallabi , Roy Tanumay , Das Parthasarathi
Published: April 2021

The feature article focuses on recent advances in chemoselective/regioselective N-arylation either on one N-centre or the exocyclic N-site present in the azole ring of azole-containing frameworks.