bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of detectable short-term effects of a single dose of ivermectin on the human immune system
Authors: Wilson Natalie E. , Reaves Barbara J. , Wolstenholme Adrian J. 
Published: June 2021

Abstract
Background
Ivermectin is widely used in human and animal medicine to treat and prevent parasite nematode infections. It has been suggested that its mode of action requires the host immune system, as it is difficult to reproduce its clinical efficacy in vitro. We therefore studied the effects of a single dose of ivermectin (Stromectol®—0.15 mg/kg) on cytokine levels and immune cell gene expression in human volunteers. This dose reduces bloodstream microfilariae rapidly and for several months when given in mass drug administration programmes.

Methods
Healthy volunteers with no travel history to endemic regions were given 3–4 tablets, depending on their weight, of either ivermectin or a placebo. Blood samples were drawn immediately prior to administration, 4 h and 24 h afterwards, and complete blood counts performed. Serum levels of 41 cytokines and chemokines were measured using Luminex® and expression levels of 770 myeloid-cell-related genes determined using the NanoString nCounter®. Cytokine levels at 4 h and 24 h post-treatment were compared to the levels pre-treatment using simple t tests to determine if any individual results required further investigation, taking p =  < 0.05 as the level of significance. NanoString data were analysed on the proprietary software, nSolver™.

Results
No significant differences were observed in complete blood counts or cytokine levels at either time point between people given ivermectin versus placebo. Only three genes showed a significant change in expression in peripheral blood mononuclear cells 4 h after ivermectin was given; there were no significant changes 24 h after drug administration or in polymorphonuclear cells at either time point. Leukocytes isolated from those participants given ivermectin showed no difference in their ability to kill Brugia malayi microfilariae in vitro.

Conclusions
Overall, our data do not support a direct effect of ivermectin, when given at the dose used in current filarial elimination programmes, on the human immune system.
Trial registration ClinicalTrials.gov NCT03459794 Registered 9th March 2018, Retrospectively registered https://clinicaltrials.gov/ct2/show/NCT03459794?term=NCT03459794&draw=2&rank=1.

Graphical Abstract
Pain-Track: a time-series approach for the description and analysis of the burden of pain
Authors: Alonso Wladimir J. , Schuck-Paim Cynthia 
Published: June 2021

AbstractObjectiveTo present the Pain-Track, a novel framework for the description and analysis of the pain experience based on its temporal evolution, around which intensity and other attributes of pain (texture, anatomy), interventions and clinical symptoms can be registered. This time-series approach can provide valuable insight on the expected evolution of the pain typically associated with different medical conditions and on time-varying (risk) factors associated with the temporal dynamics of pain.ResultsWe illustrate the use of the framework to explore hypotheses on the temporal profile of the pain associated with an acute injury (bone fracture), and the magnitude of the pain burden it represents. We also show that, by focusing on the critical dimensions of the pain experience (intensity and time), the approach can help map different conditions to a common scale directly relating to the experiences of those who endure them (time in pain), providing the basis for the quantification of the burden of pain inflicted upon individuals or populations. An electronic version for data entry and interpretation is also presented.
Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance
Authors: Gallon John , Loomis Erick , Curry Edward , Martin Nicholas , Brody Leigh , Garner Ian , Brown Robert , Flanagan James M. 
Published: June 2021

AbstractBackgroundResistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.ResultsResistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions.ConclusionsChromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.
Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy
Authors: Choi Chloe , Finlay David K. 
Published: June 2021

AbstractImmunotherapy has ushered in an exciting new era for cancer treatment. The recent discovery and success of immune checkpoint blockade and chimeric antigen receptor (CAR) T cell adoptive cell transfer has raised interest in using other immune cells, including Natural Killer (NK) cells, which might overcome some limitations with CAR T cell therapy. In this review article, we discuss the evidence that cellular metabolism is crucial for NK cell effector function. Additionally, potential strategies to optimise the metabolism of therapeutic NK cells for improved function within the metabolically adverse tumour microenvironment will be explored.
Bone marrow mesenchymal stem cells and their derived exosomes resolve doxorubicin-induced chemobrain: critical role of their miRNA cargo
Authors: El-Derany Marwa O. , Noureldein Mohamed H. 
Published: June 2021

Abstract
Background
Doxorubicin (DOX), a widely used chemotherapeutic agent, can cause neurodegeneration in the brain, which leads to a condition known as chemobrain. In fact, chemobrain is a deteriorating condition which adversely affects the lives of cancer survivors. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) and their derived exosomes (BMSCs-Exo) in DOX-induced chemobrain in rat models.

Methods
Chemobrain was induced by exposing rats to DOX (2 mg/kg, i.p) once weekly for 4 consecutive weeks. After 48 h of the last DOX dose, a subset of rats was supplied with either an intravenous injection of BMSCs (1 × 106) or a single dose of 150 μg of BMSCs-Exo. Behavioral tests were conducted 7 days post injection. Rats were sacrificed after 14 days from BMSCs or BMSCs-Exo injection.

Results
BMSCs and BMSCs-Exo successfully restored DOX-induced cognitive and behavioral distortion. These actions were mediated via decreasing hippocampal neurodegeneration and neural demyelination through upregulating neural myelination factors (myelin%, Olig2, Opalin expression), neurotropic growth factors (BDNF, FGF-2), synaptic factors (synaptophysin), and fractalkine receptor expression (Cx3cr1). Halting neurodegeneration in DOX-induced chemobrain was achieved through epigenetic induction of key factors in Wnt/β-catenin and hedgehog signaling pathways mediated primarily by the most abundant secreted exosomal miRNAs (miR-21-5p, miR-125b-5p, miR-199a-3p, miR-24-3p, let-7a-5p). Moreover, BMSCs and BMSCs-Exo significantly abrogate the inflammatory state (IL-6, TNF-α), apoptotic state (BAX/Bcl2), astrocyte, and microglia activation (GFAP, IBA-1) in DOX-induced chemobrain with a significant increase in the antioxidant mediators (GSH, GPx, SOD activity).

Conclusions
BMSCs and their derived exosomes offer neuroprotection against DOX-induced chemobrain via genetic and epigenetic abrogation of hippocampal neurodegeneration through modulating Wnt/β-catenin and hedgehog signaling pathways and through reducing inflammatory, apoptotic, and oxidative stress state.

Graphical abstract
Proposed mechanisms of the protective effects of bone marrow stem cells (BMSCs) and their exosomes (BMSCs-Exo) in doxorubicin (DOX)-induced chemobrain. Blue arrows: induce. Red arrows: inhibit.
IL-1β pre-stimulation enhances the therapeutic effects of endometrial regenerative cells on experimental colitis
Authors: Yu Dingding , Zhao Yiming , Wang Hongda , Kong Dejun , Jin Wang , Hu Yonghao , Qin Yafei , Zhang Baoren , Li Xiang , Hao Jingpeng , Li Guangming , Wang Hao 
Published: June 2021

Abstract
Background
Ulcerative colitis (UC) is a chronic, relapsing, and non-specific inflammatory bowel disease, and the current treatment strategies were mainly used to relieve symptoms or for maintenance. Endometrial regenerative cells (ERCs) are mesenchymal-like stromal cells and have been demonstrated to alleviate multiple immune-dysregulation diseases. Pro-inflammatory stimuli were reported to enhance the immunosuppressive functions of ERCs, but the mechanism underlined is not fully understood. Here, we have designed this study to investigate the therapeutic effects of IL-1β-primed ERCs in the attenuation of experimental colitis.

Methods
BALB/c mice were given 3% dextran sodium sulfate (DSS) for 7 consecutive days and free tap water for 3 days sequentially to induce experimental colitis. PBS (200 μL), ERCs, and IL-1β-primed ERCs (10ng/mL, 48 h) were injected (1 million/mouse/day, i.v.) on day 2, 5, and 8, respectively. Colonic and splenic samples were harvested on day 10 after DSS induction.

Results
It was found that IL-1β-primed ERC treatment markedly attenuated colonic damage, body weight loss, and colon length shortening in colitis mice. Compared with other treatments, cell populations of CD4+IL-4+Th2 cells, CD4+CD25+FOXP3+ regulatory T cells (Tregs), and CD68+CD206+ macrophages in spleens were also significantly upregulated in the IL-1β-primed ERC-treated group (p < 0.05). In addition, lower expression of pro-inflammatory (IFN-γ, IL-17, TNF-α, and IL-6), but higher levels of anti-inflammatory cytokines (IL-4 and IL-10) were detected in colons in the IL-1β-primed ERC-treated group (p < 0.05 vs. other groups). Importantly, we also found that different generations of ERCs had an overall lower secretion of Dickkopf-1 (DKK1) by IL-1β pre-stimulation (p < 0.05) and a higher expression of β-catenin in colonic and splenic tissues after the administration of IL-1β-primed ERCs.

Conclusions
This study has demonstrated that IL-1β pre-stimulation effectively downregulated DKK1 expression in ERCs, which in turn promoted the wnt/β-catenin pathway activation in colonic and splenic tissues. Consequently, IL-1β-primed ERCs exhibited an enhanced therapeutic effect in the attenuation of DSS-induced colitis.
Methylsulfonylmethane enhances MSC chondrogenic commitment and promotes pre-osteoblasts formation
Authors: Dalle Carbonare Luca , Bertacco Jessica , Marchetto Giulia , Cheri Samuele , Deiana Michela , Minoia Arianna , Tiso Natascia , Mottes Monica , Valenti Maria Teresa 
Published: June 2021

Abstract
Background
Methylsulfonylmethane (MSM) is a nutraceutical compound which has been indicated to counteract osteoarthritis, a cartilage degenerative disorder. In addition, MSM has also been shown to increase osteoblast differentiation. So far, few studies have investigated MSM role in the differentiation of mesenchymal stem cells (MSCs), and no study has been performed to evaluate its overall effects on both osteogenic and chondrogenic differentiation. These two mutually regulated processes share the same progenitor cells.

Methods
Therefore, with the aim to evaluate the effects of MSM on chondrogenesis and osteogenesis, we analyzed the expression of SOX9, RUNX2, and SP7 transcription factors in vitro (mesenchymal stem cells and chondrocytes cell lines) and in vivo (zebrafish model). Real-time PCR as well Western blotting, immunofluorescence, and specific in vitro and in vivo staining have been performed. Student’s paired t test was used to compare the variation between the groups.

Results
Our data demonstrated that MSM modulates the expression of differentiation-related genes both in vitro and in vivo. The increased SOX9 expression suggests that MSM promotes chondrogenesis in treated samples. In addition, RUNX2 expression was not particularly affected by MSM while SP7 expression increased in all MSM samples/model analyzed. As SP7 is required for the final commitment of progenitors to preosteoblasts, our data suggest a role of MSM in promoting preosteoblast formation. In addition, we observed a reduced expression of the osteoclast-surface receptor RANK in larvae and in scales as well as a reduced pERK/ERK ratio in fin and scale of MSM treated zebrafish.

Conclusions
In conclusion, our study provides new insights into MSM mode of action and suggests that MSM is a useful tool to counteract skeletal degenerative diseases by targeting MSC commitment and differentiation.
BMSC-derived extracellular vesicles intervened the pathogenic changes of scleroderma in mice through miRNAs
Authors: Jin Jiahui , Ou Qingjian , Wang Zhe , Tian Haibin , Xu Jing-Ying , Gao Furong , Hu Shuqin , Chen Jie , Wang Juan , Zhang Jieping , Lu Lixia , Jin Caixia , Xu Guo-Tong , Zhao Jingjun 
Published: June 2021

Abstract
Background
Systemic sclerosis (SSc) is a disease that features severe fibrosis of the skin and lacks effective therapy. Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) are potential stem cell-based tools for the treatment of SSc.

Methods
BMSCs were isolated from the bone marrow of mice and identified with surface markers according to multilineage differentiation. EVs were isolated from the BMSC culture medium by ultracentrifugation and identified with a Nanosight NS300 particle size analyzer, transmission electron microscopy (TEM), and western blot. The microRNAs (miRNAs) of BMSC-derived EVs (BMSC-EVs) were studied via miRNA sequencing (miRNA-seq) and bioinformatic analysis. An SSc mouse model was established via subcutaneous bleomycin (BLM) injection, and the mice were treated with BMSCs or BMSC-derived EVs. Skin tissues were dissociated and analyzed with H&E staining, RNA sequencing (RNA-seq), western blot, and immunohistochemical staining.

Results
Evident pathological changes, like fibrosis and inflammation, were induced in the skin of BLM-treated mice. BMSCs and BMSC-EVs effectively intervened such pathological manifestations and disease processes in a very similar way. The effects of the BMSC-EVs were found to be caused by the miRNAs they carried, which were proven to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple EV-related biological processes. Furthermore, TGF-β1-positive cells and α-SMA-positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice but evidently reduced in the scleroderma skin of the EV-treated SSc group. In addition, the numbers of mast cells and infiltrating macrophages and lymphocytes were evidently increased in the skin of BLM-treated mice but significantly reduced by EV treatment. In line with these observations, there were significantly higher mRNA levels of the inflammatory cytokines Il6, Il10, and Tnf-α in SSc mice than in control mice, but the levels decreased following EV treatment. Through bioinformatics analysis, the TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes seen in mouse SSc, and these pathways could be therapeutic targets for treating the disease.

Conclusions
BMSC-derived EVs could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy. The effects of EVs are generated by the miRNAs they carry, which alleviate SSc pathogenic changes by regulating the WNT and TGFβ signaling pathways.
Optimizing similarity factor of in vitro drug release profile for development of early stage formulation of drug using linear regression model
Authors: Sheth Tulsi Sagar , Acharya Falguni 
Published: June 2021

AbstractThe objective of this article is to optimize the similarity factor within immediate release (IR) and modified release (MR) of in vitro drug release profiles. The least square method is used to minimize the difference between empirical and regression curve fitting data of in vitro IR/MR drug release profiles. An estimation of percentage drug release at intermediate timepoints has been done to improve the similarity factor $f_{2}$

f
2

using linear curve fit method. In this study linear regression model is used to analyze the similarity factor $f_{2}$

f
2

for Nitrofurantoin MR Capsules, Venlafaxine HCl MR Tablets and Lurasidone IR Tablets in order to exhibit the significance as well as similarity owing to the consideration of extra intervening timepoints. This linear regression model may help pharmaceutical industries to examine the inside comparison of IR/MR in vitro drug release profile with few modifications in timepoint selection to improve similarity factor $f_{2}$

f
2

.
Synapse-specific Lrp4 mRNA enrichment requires Lrp4/MuSK signaling, muscle activity and Wnt non-canonical pathway
Authors: Jing Hongyang , Chen Peng , Hui Tiankun , Yu Zheng , Zhou Jin , Fei Erkang , Wang Shunqi , Ren Dongyan , Lai Xinsheng , Li Baoming 
Published: June 2021

Abstract
Background
The neuromuscular junction (NMJ) is a peripheral synapse critical to muscle contraction. Like acetylcholine receptors (AChRs), many essential proteins of NMJ are extremely concentrated at the postjunctional membrane. However, the mechanisms of synapse-specific concentration are not well understood; furthermore, it is unclear whether signaling molecules critical to NMJ formation and maintenance are also locally transcribed.

Results
We studied the β-gal activity encoded by a lacZ cassette driven by the promoter of the Lrp4 gene. As reported for Lrp4 mRNA, β-gal was in the central region in embryonic muscles and at the NMJ after its formation. However, β-gal was no longer in the central areas of muscle fibers in Lrp4 or MuSK mutant mice, indicating a requirement of Lrp4/MuSK signaling. This phenotype could be rescued by transgenic expression of LRP4 with a transmembrane domain but not soluble ECD in Lrp4 mutant mice. β-gal and AChR clusters were distributed in a broader region in lacZ/ECD than that of heterozygous lacZ/+ mice, indicating an important role of the transmembrane domain in Lrp4 signaling. Synaptic β-gal activity became diffused after denervation or treatment with µ-conotoxin, despite its mRNA was increased, indicating synaptic Lrp4 mRNA enrichment requires muscle activity. β-gal was also diffused in aged mice but became re-concentrated after muscle stimulation. Finally, Lrp4 mRNA was increased in C2C12 myotubes by Wnt ligands in a manner that could be inhibited by RKI-1447, an inhibitor of ROCK in Wnt non-canonical signaling. Injecting RKI-1447 into muscles of adult mice diminished Lrp4 synaptic expression.

Conclusions
This study demonstrates that synapse-specific enrichment of Lrp4 mRNA requires a coordinated interaction between Lrp4/MuSK signaling, muscle activity, and Wnt non-canonical signaling. Thus, the study provides a new mechanism for Lrp4 mRNA enrichment. It also provides a potential target for the treatment of NMJ aging and other NMJ-related diseases.
Relating environmental variables with aquatic community structure in an agricultural/urban coldwater stream
Authors: Myers Daniel T. L. , Rediske Richard R. , McNair James N. , Parker Aaron D. , Ogilvie E. Wendy 
Published: June 2021

Abstract
Background
Urban areas are often built along large rivers and surrounded by agricultural land. This may lead to small tributary streams that have agricultural headwaters and urbanized lower reaches. Our study objectives assessed are as follows: (1) landscape, geomorphic, and water quality variables that best explained variation in aquatic communities and their integrity in a stream system following this agricultural-to-urban land use gradient; (2) ways this land use gradient caused aquatic communities to differ from what would be expected for an idealized natural stream or other longitudinal gradients; and (3) whether the impacts of this land use gradient on aquatic communities would grow larger in a downstream direction through the agricultural and urban developments. Our study area was an impaired coldwater stream in Michigan, USA.

Results
Many factors structured the biological communities along the agricultural-to-urban land use gradient. Instream woody debris had the strongest relationship with EPT (Ephemeroptera, Plecoptera, and Trichoptera) abundance and richness and were most common in the lower, urbanized watershed. Fine streambed substrate had the strongest relationship with Diptera taxa and surface air breather macroinvertebrates and was dominant in agricultural headwaters. Fish community assemblage was influenced largely by stream flow and temperature regimes, while poor fish community integrity in lower urban reaches could be impacted by geomorphology and episodic urban pollution events. Scraping macroinvertebrates were most abundant in deforested, first-order agricultural headwaters, while EPT macroinvertebrate richness was the highest downstream of agricultural areas within the urban zone that had extensive forest buffers.

Conclusion
Environmental variables and aquatic communities would often not conform with what we would expect from an idealized natural stream. EPT richness improved downstream of agricultural areas. This shows promise for the recovery of aquatic systems using well-planned management in watersheds with this agricultural-to-urban land use pattern. Small patches of forest can be the key to conserving aquatic biodiversity in urbanized landscapes. These findings are valuable to an international audience of researchers and water resource managers who study stream systems following this common agricultural-to-urban land use gradient, the ecological communities of which may not conform with what is generally known about land use impacts to streams.