bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach
Authors: Bekaddour Nassima , Smith Nikaïa , Beitz Benoit , Llibre Alba , Dott Tom , Baudry Anne , Korganow Anne-Sophie , Nisole Sébastien , Mouy Richard , Breton Sylvain , Bader-Meunier Brigitte , Duffy Darragh , Terrier Benjamin , Schneider Benoit , Quartier Pierre , Rodero Mathieu P , Herbeuval Jean-Philippe 
Published: October 2021

ABSTRACTAmong immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-α, IL-6 and IL-1β. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.
On the use of facial and neck cooling to improve indoor occupant thermal comfort in warm conditions
Authors: Yang Bin , Lei Tze-Huan , Wang Faming , Yang Pengfei 
Published: October 2021

AbstractFace and neck cooling has been found effective to improve thermal comfort during exercise in the heat despite the surface area of human face and neck regions accounts for only 5.5% of the entire body. Presently, very limited work in the literature has been reported on face and neck cooling to improve indoor thermal comfort. In this work, two energy-efficient wearable face and neck cooling fans were used to enhance occupants’ thermal comfort in two warm indoor conditions (30 & 32 °C). Local skin temperatures and perceptual responses while using those two wearable cooling fans were examined and compared. Results showed that both cooling fans could largely reduce local skin temperatures at the forehead, face and neck regions up to 2.1 °C. Local thermal sensation votes at the face and neck were decreased by 0.82-1.21 scale unit at two studied temperatures. Overall TSVs dropped by 1.03-1.14 and 1.34-1.66 scale unit at 30 and 32 °C temperatures, respectively. Both cooling fans could extend the acceptable HVAC temperature setpoint to 32.0 °C, resulting in an average energy saving of 45.7% as compared to the baseline HVAC setpoint of 24.5 °C. Further, the free-control cooling mode is recommended to occupants for further improving thermal comfort while using those two types of wearable cooling fans indoors. Lastly, it is concluded that those two wearable cooling fans could greatly improve thermal comfort and save HVAC energy despite some issues on dry eyes and dry lips associated with those wearable cooling fans were noted.
Single injection of very mild dose BOTOX in the vastus lateralis improves testicular spermatogenesis and sperm motility in ageing experimental mice
Authors: Radhakrishnan Risna Kanjirassery , Ravichandran Sowbarnika , Sukesh Aishwarya , Kadalmani Balamuthu , Kandasamy Mahesh 
Published: October 2021

AbstractAcetylcholine (ACh), a key neurochemical messenger that plays key roles in neuroplasticity and muscle contraction. While ACh is important for the physiological function of the testis, abnormal levels of ACh cause testicular atrophy and male infertility. BOTOX is a therapeutic form of the botulinum neurotoxin that blocks the excessive release of ACh at the neuromuscular junction. Previously, repeated intracremasteric injections and slight overdose of BOTOX have been reported to induce adverse effects in the testicular parameter of experimental rodents. However, a mild dose of BOTOX is highly beneficial against skin ageing, neurological deficits, overactive urinary bladder problems, testicular pain and erectile dysfunctions. Considering the facts, the possible therapeutic benefit of BOTOX on the testis might be achieved via its minimal dose and indirect mode of action rather than repeated high quantity in the local supply. Therefore, we revisited the effect of BOTOX but with a trace amount injected into the vastus lateralis of the thigh muscle, and analyzed histological parameters of testis and quality of semen in ageing experimental mice. Experimental animals injected with 1 U/kg bodyweight of BOTOX showed enhanced spermatogenesis in associations with increased activities of key antioxidants in the testis, leading to increased total sperm count and motility. This study signifies that a mild intramuscular dose of BOTOX can be considered as a potential treatment strategy to manage and prevent male infertility.
Zebrafish airinemes optimize their shape between ballistic and diffusive search
Authors: Park Sohyeon , Kim Hyunjoong , Wang Yi , Eom Dae Seok , Allard Jun 
Published: October 2021

AbstractIn addition to diffusive signals, cells in tissue also communicate via long, thin cellular protrusions, such as airinemes in zebrafish. Before establishing communication, cellular protrusions must find their target cell. Here we demonstrate that the shape of airinemes in zebrafish are consistent with a finite persistent random walk model. The probability of contacting the target cell is maximized for a balance between ballistic search (straight) and diffusive search (highly curved, random). We find that the curvature of airinemes in zebrafish, extracted from live cell microscopy, is approximately the same value as the optimum in the simple persistent random walk model. We also explore the ability of the target cell to infer direction of the airineme’s source, finding that there is a theoretical trade-off between search optimality and directional information. This provides a framework to characterize the shape, and performance objectives, of non-canonical cellular protrusions in general.
Effect of OTR4120 on pulmonary fibrosis
Authors: Charef Said , Charef Najat Mejdoubi , Chiappini Franck , Papy-Garcia Dulce , Barritault Denis 
Published: October 2021

AbstractBackgroundAcute respiratory distress syndrome (ARDS) can be related to airway remodeling caused by pulmonary fibrosis and systemic inflammation. Etiologies of ARDS are multifaceted such as idiopathic pulmonary fibrosis or as recently the SARS-CoV-2 infection. Antifibrotic drugs may be a better approach to slow the fibrotic process but they often have poor efficacy in patients, and the mortality rate remains high, up to 40% within 5 years of diagnosis.Here, we tested the antifibrotic effect of a ReGeneTaring Agents named OTR4120 in a bleomycin-induced mouse model of pulmonary fibrosis.MethodsSwiss mice were randomly divided into four experimental groups: saline-treated control group, an OTR4120 group, a bleomycin-induced fibrosis group without OTR4120, and a bleomycin-induced fibrosis groups with OTR4120 (intravenous injections every 3 days starting at day 11 post bleomycin I.P. injection). Lungs were compared using the lung/body weight index, and the extend of interstitial injury area was graded using histopathological assessment of haematoxylin & eosin-stained lung tissue sections. Lung tissue Collagen I and Collagen III levels, and blood cytokine levels were measured using a Collagen colorimetric kit and a Cytokine colorimetric kit, respectively.ResultsThe group treated by OTR4120 alone were used as a control. The clincal signs in all animals resoved gradually on day 17 after bleomycin injections and 6 days after OTR4120 treatment, and disappeared almost completetly at day 24 after bleomycin injections and day 13 after OTR4120 treatment. Lung/body weight index values were significantly lower in the bleomycin-OTR4120 treated group versus the bleomycin group (7.31, 9.97 and 7.63 mg/g, p-value< 0.01; respectively). Histopathological analyses suggest that OTR4120 treatment ameliorated the increased inflammatory cell infiltration, and attenuated the reduction in interstitial thickening, associated with bleomycin-induced fibrosis. Collagen III and cytokine levels were decreased in the OTR4120 group versus the fibrotic (bleomycin only) group. OTR4120-treated animals were less affected in their behavior, did not loose weight nor appetite, and recovered overall activities within 6 days of OTR4120 treatment, while none of the vehicle-treated animals recovered to normal.ConclusionOTR4120 is a potential candidate to reduce lung fibrosis.
The preoperative abundance of Prevotella associates with anastomotic healing after colorectal surgery
Authors: Zafeiropoulou Konstantina , Peters Emmeline G. , Brinkman Daan J. , Li Yim Andrew Y.F. , Smeets Boudewijn J.J. , Hakvoort Theodorus B.M. , Levin Evgeni , Davids Mark , Luyer Misha D.P. , de Jonge Wouter J. , Derikx Joep P.M. 
Published: October 2021

SummaryAnastomotic leakage (AL) is a frequent and potentially life-threatening postoperative complication in patients undergoing colorectal surgery with a multifactorial yet unknown pathophysiology. In the present study, we aimed to unravel AL etiology and intestinal anastomotic healing (AH) physiology focusing on both host epithelial and gut microbial components. We make use of patients-related samples and two high throughput next generation sequencing analysis approaches, including anastomotic tissue-associated bulk RNA sequencing and preoperative fecal 16S rRNA gene sequencing. We find that in the absence of host epithelial gene expression differences, the preoperative fecal microbiota of patients who undergo colorectal resection with successful AH differs in the group of patients who develop AL in the abundance of Prevotella and suggests a potential beneficial role of Prevotella that may prove useful as predictive biomarker for AH.
REcovery and SURvival of patients with moderate to severe acute REspiratory distress syndrome (ARDS) due to COVID-19: a multicentre, single-arm, Phase IV Itolizumab Trial: RESURRECT
Authors: Raveendra KR , Rathod Chirag , Darnule Rahul , Loganathan Subramanian , Deodhar Sarika , Radhika A , Marwah Ashwani , Chaudhari Nitin M , Thakur Binay K , Vaidyanathan Sivakumar , Athalye Sandeep Nilkanth 
Published: October 2021

AbstractObjectiveTo evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO2/FiO2 ratio (PFR) ≤200 requiring oxygen therapy.DesignA multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days.MethodsHospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200; oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19-specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90.ResultsDay-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO2 without increasing FiO2. Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH, and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS, and respiratory failure. No deaths were attributable to Itolizumab.ConclusionItolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.Trial registry numberCTRI/2020/09/027941
Evaluation of the Nallasamy Formula: A Stacking Ensemble Machine Learning Method for Refraction Prediction in Cataract Surgery
Authors: Li Tingyang , Stein Joshua D. , Nallasamy Nambi 
Published: October 2021

AbstractAimsTo develop a new intraocular lens (IOL) power selection method with improved accuracy for general cataract patients receiving Alcon SN60WF lenses.Methods and AnalysisA total of 5016 patients (6893 eyes) who underwent cataract surgery at University of Michigan’ s Kellogg Eye Center and received the Alcon SN60WF lens were included in the study. A machine learning-based method was developed using a training dataset of 4013 patients (5890 eyes), and evaluated on a testing dataset of 1003 patients (1003 eyes). Each eye had a complete profile of preoperative biometry, the implanted IOL power, and postoperative refraction. The performance of our method was compared to that of Barrett Universal II, Haigis, Hoffer Q, Holladay 1, and SRK/T.ResultsMAE of the Nallasamy formula in the testing dataset was 0.312 Diopters (MedAE = 0.242 D). Performance of existing methods were as follows: Barrett Universal II MAE = 0.328 D (MedAE = 0.256 D), Haigis MAE = 0.363 D (MedAE = 0.289 D), Hoffer Q MAE = 0.404 D (MedAE = 0.331 D), Holladay 1 MAE = 0.371 D (MedAE = 0.298 D) and SRK/T MAE = 0.376 D (MedAE = 0.300 D). The Nallasamy formula performed significantly better than all five existing methods based on the paired Wilcoxon test with Bonferroni correction (p-value < 0.05).ConclusionsNallasamy formula outperformed the five methods studied (including Barrett Universal II) on overall MAE and MedAE, percentage of eyes within 0.5 D of prediction, as well as MAE in short, medium, and long axial length eyes.SYNOPSISNallasamy formula, a novel machine learning-based IOL power calculation formula developed based on a dataset of 6893 eyes, achieved significantly better prediction accuracy than five traditional IOL power formulas including Barrett Universal II.
Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival
Authors: Viswanathan Vignesh , Cao Hongbin , Saiki Julie , Jiang Dadi , Mattingly Aaron , Nambiar Dhanya , Bloomstein Joshua , Li Yang , Jiang Sizun , Chamoli Manish , Sirjani Davud , Kaplan Michael , Christopher Holsinger F , Liang Rachel , Von Eyben Rie , Jiang Haowen , Guan Li , Lagory Edward , Feng Zhiping , Nolan Garry , Ye Jiangbin , Denko Nicholas , Knox Sarah , Rosen Daria-Mochly , Le Quynh-Thu 
Published: October 2021

AbstractAdult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.
Clarifying intercellular signalling in yeast: Saccharomyces cerevisiae does not undergo a quorum sensing-dependent switch to filamentous growth
Authors: Winters Michela , Aru Violetta , Howell Kate , Arneborg Nils 
Published: October 2021

ABSTRACTSaccharomyces cerevisiae can alter its morphology to a filamentous form associated with unipolar budding in response to environmental stressors. Induction of filamentous growth is suggested under nitrogen deficiency in response to alcoholic signalling molecules through a quorum sensing mechanism. To investigate this claim, we analysed the budding pattern of S. cerevisiae cells over time under low nitrogen while concurrently measuring cell density and extracellular metabolite concentration. We found that the proportion of cells displaying unipolar budding increased between local cell densities of 4.8×106 and 5.3×107 cells/ml. However, the observed increase in unipolar budding could not be reproduced when cells were prepared at the critical cell density and in conditioned media. Removing the nutrient restriction by growth under high nitrogen conditions also resulted in an increase in unipolar budding between local cell densities of 5.2×106 and 8.2×107 cells/ml, but there were differences in metabolite concentration compared to the low nitrogen conditions. This suggests that neither cell density, metabolite concentration, nor nitrogen deficiency were necessary or sufficient to increase the proportion of unipolar budding cells. It is therefore unlikely that quorum sensing is the mechanism controlling the switch to filamentous growth in S. cerevisiae. Only a high concentration of the putative signalling molecule, 2-phenylethanol resulted in an increase in unipolar budding, but this concentration was not physiologically relevant. We suggest that the compound 2-phenylethanol acts through a toxicity mechanism, rather than quorum sensing, to induce filamentous growth.IMPORTANCEInvestigating dimorphism in the model organism Saccharomyces cerevisiae has been instrumental in understanding the signalling pathways that control hyphal growth and virulence in human pathogenic fungi. Quorum sensing was proposed to signal morphogenesis in S. cerevisiae populations. This mechanism requires the switch to filamentous growth to occur at a critical quorum sensing molecule concentration corresponding to a critical cell density. However, evidence for this mechanism is sparse and limited by the use of non-physiologically relevant concentrations of signalling metabolites. Our study designed a methodology to address this gap and may be applied to further studies of dimorphism in other types of yeasts. A significant implication of our findings is that morphogenesis does not occur in S. cerevisiae via a quorum sensing mechanism, and this important definition needs to be corrected. Mechanistic studies to understand dimorphism in yeasts, by considering metabolite concentrations, will further shed light onto this important cellular behaviour.
Decoding the transcriptome of denervated muscle at single-nucleus resolution
Authors: Lin Hongchun , Ma Xinxin , Sun Yuxiang , Peng Hui , Wang Yanlin , Thomas Sandhya Sara , Hu Zhaoyong 
Published: October 2021

AbstractBackgroundSkeletal muscle exhibits remarkable plasticity under both physiological and pathological conditions. One major manifestation of this plasticity is muscle atrophy that is an adaptive response to catabolic stimuli. Since the heterogeneous transcriptome responses to catabolism in different types of muscle cells are not fully characterized, we applied single-nucleus RNA sequencing (snRNA-seq) to unveil muscle atrophy related transcriptional changes at single nucleus resolution.MethodsUsing a sciatic denervation mouse model of muscle atrophy, snRNA-seq was performed to generate single-nucleus transcriptional profiles of the gastrocnemius muscle from normal and denervated mice. Various bioinformatics analyses, including unsupervised clustering, functional enrichment analysis, trajectory analysis, regulon inference, metabolic signature characterization and cell-cell communication prediction, were applied to illustrate the transcriptome changes of the individual cell types.ResultsA total of 29,539 muscle nuclei (normalvsdenervation: 15,739vs13, 800) were classified into 13 nuclear types according to the known cell markers. Among these, the type IIb myonuclei were further divided into two subgroups, which we designated as type IIb1 and type IIb2 myonuclei. In response to denervation, the proportion of type IIb2 myonuclei increased sharply (78.12%vs38.45%,p<0.05). Concomitantly, trajectory analysis revealed that denervated type IIb2 myonuclei clearly deviated away from the normal type IIb2 myonuclei, indicating that this subgroup underwent robust transcriptional reprogramming upon denervation. Signature genes in denervated type IIb2 myonuclei includedRunx1,Gadd45a,Igfn1,Robo2,Dlg2, andSh3d19(p<0.001). The gene regulatory network analysis captured a group of atrophy-related regulons (Foxo3, Runx1, Elk4, Bhlhe40) whose activities were enhanced (p<0.01), especially in the type IIb2 myonuclei. The metabolic landscape in the myonuclei showed that most of the metabolic pathways were downregulated by denervation (p<0.001), while some of the metabolic signaling, such as glutathione metabolism, was specifically activated in the denervated type IIb2 myonulei. We also investigated the transcriptomic alterations in the type I myofibers, muscle stem cells, fibro-adipogenic progenitors, macrophages, endothelial cells and pericytes and characterized their signature responses to denervation. By predicting the cell-cell interactions, we observed that the communications between myofibers and muscle resident cells were diminished by denervation.ConclusionOur results define the myonuclear transition, metabolic remodeling and gene regulation networks reprogramming associated with denervation-induced muscle atrophy and illustrate the molecular basis of the heterogeneity and plasticity of muscle cells in response to catabolism. These results provide a useful resource for exploring the molecular mechanism of muscle atrophy.