• C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

      Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis; Campanero, Miguel R.; et al. (American Society for Microbiology, 2015-09-04)
      Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease.
    • A calibrated measure to compare fluctuations of different entities across timescales

      Chołoniewski, Jan; Sienkiewicz, Julian; Dretnik, Naum; Leban, Gregor; Thelwall, Mike; Hołyst, Janusz A (Springer Science and Business Media LLC, 2020-11-26)
      A common way to learn about a system’s properties is to analyze temporal fluctuations in associated variables. However, conclusions based on fluctuations from a single entity can be misleading when used without proper reference to other comparable entities or when examined only on one timescale. Here we introduce a method that uses predictions from a fluctuation scaling law as a benchmark for the observed standard deviations. Differences from the benchmark (residuals) are aggregated across multiple timescales using Principal Component Analysis to reduce data dimensionality. The first component score is a calibrated measure of fluctuations—the <jats:italic>reactivity</jats:italic><jats:italic>RA</jats:italic> of a given entity. We apply our method to activity records from the media industry using data from the Event Registry news aggregator—over 32M articles on selected topics published by over 8000 news outlets. Our approach distinguishes between different news outlet reporting styles: high reactivity points to activity fluctuations larger than expected, reflecting a bursty reporting style, whereas low reactivity suggests a relatively stable reporting style. Combining our method with the political bias detector Media Bias/Fact Check we quantify the relative reporting styles for different topics of mainly US media sources grouped by political orientation. The results suggest that news outlets with a liberal bias tended to be the least reactive while conservative news outlets were the most reactive.
    • Calprotectin and lactoferrin faecal levels in patients with Clostridium difficile infection (CDI): a prospective cohort study

      Swale, Andrew; Miyajima, Fabio; Roberts, Paul; Hall, Amanda; Little, Margaret; Beadsworth, Mike BJ; Beeching, Nick J; Kolamunnage-Dona, Ruwanthi; Parry, Chris M; Pirmohamed, Munir (Public Library of Science (PLoS), 2014-08-29)
      Measurement of both calprotectin and lactoferrin in faeces has successfully been used to discriminate between functional and inflammatory bowel conditions, but evidence is limited for Clostridium difficile infection (CDI). We prospectively recruited a cohort of 164 CDI cases and 52 controls with antibiotic-associated diarrhoea (AAD). Information on disease severity, duration of symptoms, 30-day mortality and 90-day recurrence as markers of complicated CDI were recorded. Specimens were subject to microbiological culture and PCR-ribotyping. Levels of faecal calprotectin (FC) and lactoferrin (FL) were measured by ELISA. Statistical analysis was conducted using percentile categorisation. ROC curve analysis was employed to determine optimal cut-off values. Both markers were highly correlated with each other (r2 = 0.74) and elevated in cases compared to controls (p<0.0001; ROC>0.85), although we observed a large amount of variability across both groups. The optimal case-control cut-off point was 148 mg/kg for FC and 8.1 ng/µl for FL. Median values for FL in CDI cases were significantly greater in patients suffering from severe disease compared to non-severe disease (104.6 vs. 40.1 ng/µl, p = 0.02), but were not significant for FC (969.3 vs. 512.7 mg/kg, p = 0.09). Neither marker was associated with 90-day recurrence, prolonged CDI symptoms, positive culture results and colonisation by ribotype 027. Both FC and FL distinguished between CDI cases and AAD controls. Although FL was associated with disease severity in CDI patients, this showed high inter-individual variability and was an isolated finding. Thus, FC and FL are unlikely to be useful as biomarkers of complicated CDI disease.
    • Can Microsoft Academic help to assess the citation impact of academic books?

      Kousha, Kayvan; Thelwall, Mike (Elsevier, 2018-08-15)
      Despite recent evidence that Microsoft Academic is an extensive source of citation counts for journal articles, it is not known if the same is true for academic books. This paper fills this gap by comparing citations to 16,463 books from 2013 to 2016 in the Book Citation Index (BKCI) against automatically extracted citations from Microsoft Academic and Google Books in 17 fields. About 60% of the BKCI books had records in Microsoft Academic, varying by year and field. Citation counts from Microsoft Academic were 1.5 to 3.6 times higher than from BKCI in nine subject areas across all years for books indexed by both. Microsoft Academic found more citations than BKCI because it indexes more scholarly publications and combines citations to different editions and chapters. In contrast, BKCI only found more citations than Microsoft Academic for books in three fields from 2013-2014. Microsoft Academic also found more citations than Google Books in six fields for all years. Thus, Microsoft Academic may be a useful source for the impact assessment of books when comprehensive coverage is not essential.
    • Can RNAi-mediated hsp90α knockdown in combination with 17-AAG be a therapy for glioma?

      Mehta, A; Shervington, A; Howl, J; Jones, S; Shervington, L; Brain Tumour North West (BTNW), Faculty of Science and Technology, University of Central Lancashire (UCLan), Preston PR1 2HE, UK. (Wiley, 2013-06-20)
      Heat shock protein 90 promotes tumor progression and survival and has emerged as a vital therapeutic target. Previously we reported that the combinatorial treatment of 17AAG/sihsp90α significantly downregulated Hsp90α mRNA and protein levels in Glioblastoma Multiforme (GBM). Here we investigated the ability of cell penetrating peptide (Tat48-60 CPP)-mediated siRNA-induced hsp90α knockdown as a single agent and in combination with 17-allylamino-17-demethoxygeldanamycin (17-AAG) to induce tumor growth inhibition in GBM and whether it possessed therapeutic implications. GBM and non-tumorigenic cells exposed to siRNA and/or 17-AAG were subsequently assessed by qRT-PCR, immunofluorescence, FACS analysis, quantitative Akt, LDH leakage and cell viability assays. PAGE was performed for serum stability assessment. A combination of siRNA/17-AAG treatment significantly induced Hsp90α gene and protein knockdown by 95% and 98%, respectively, concomitant to 84% Akt kinase activity attenuation, induced cell cycle arrest and tumor-specific cytotoxicity by 88%. Efficient complex formation between CPP and siRNA exhibited improved serum stability of the siRNA with minimal intrinsic toxicity in vitro. The preliminary in vivo results showed that combination therapy induced hsp90α knockdown and attenuated Akt kinase activity in intracranial glioblastoma mouse models. The results imply that RNAi-mediated hsp90α knockdown increases 17-AAG treatment efficacy in GBM. In addition, the cytotoxic response observed was the consequence of downregulation of hsp90α gene expression, reduced Akt kinase activity and S-G2/M cell cycle arrest. These results are novel and highlight the ability of Tat to efficiently deliver siRNA in GBM and suggest that the dual inhibition of Hsp90 has therapeutic potentials. © 2013 The Authors.
    • Can the impact of grey literature be assessed? An investigation of UK government publications cited by articles and books

      Bickley, Matthew; Kousha, Kayvan; Thelwall, Michael (International Society for Scientometrics and Informetrics, 2019-08-06)
      Grey literature encompasses a range of relatively informal textual outputs that are not indexed in citation databases. Although they are usually ignored in research evaluations, it is important to develop methods to assess their impact so that their contributions can be recognised, and successful types of grey literature can be encouraged. This article investigates the extent to which 97,150 UK government publications were cited by Scopus articles and Google Books during 2013-2017 in eleven broad subject areas. A method was used to semi-automatically extract citations to the UK government publications from articles and books with high recall and precision. The results showed that Scopus citations are more common than Google Books citations to UK government publications, especially for older documents, and for those in Healthcare, Education and Science. Since the difference is not huge, both may provide useful grey literature impact data.
    • Can Twitter give insights into international differences in Covid-19 vaccination? Eight countries’ English tweets to 21 March 2021

      Thelwall, Mike (Ediciones Profesionales de la Informacion SL, 2021-05-30)
      Vaccination programs may help the world to reduce or eliminate Covid-19. Information about them may help countries to design theirs more effectively, with important benefits for public health. This article investigates whether it is possible to get insights into national vaccination programmes from a quick international comparison of public comments on Twitter. For this, word association thematic analysis (WATA) was applied to English-language vaccine-related tweets from eight countries gathered between 5 December 2020 and 21 March 2021. The method was able to quickly identify multiple international differences. Whilst some were irrelevant, potentially non-trivial differences include differing extents to which non-government scientific experts are important to national vaccination discussions. For example, Ireland seemed to be the only country in which university presidents were widely tweeted about in vaccine discussions. India’s vaccine kindness term #VaccineMaitri was another interesting difference, highlighting the need for international sharing.
    • Cangrelor vs. Ticagrelor in Patients Treated with Primary Percutaneous Coronary Intervention: Impact on Platelet Activity, Myocardial Microvascular Function and Infarct Size: A randomized controlled trial

      Ubaid, Salahaddin; Ford, Thomas J; Berry, Colin; Murray, Heather M; Wrigley, Benjamin; Khan, Nazish; Thomas, Mark R; Armesilla, Angel L; Townend, Jon N; Khogali, Saib S; et al. (Thieme Publishing, 2019-05-26)
      Background Oral P2Y12 inhibitors take more than 2 hours to achieve full effect in healthy subjects and this action is further delayed in patients with acute myocardial infarction. Intravenous P2Y12 inhibition might lead to more timely and potent anti-platelet effect in the context of emergency primary angioplasty, improving myocardial recovery. Objectives This article compares the efficacy of intravenous cangrelor versus ticagrelor in a ST-elevation myocardial infarction (STEMI) population treated with primary percutaneous coronary intervention (PPCI). Materials and Methods In an open-label, prospective, randomized controlled trial, 100 subjects with STEMI were assigned 1:1 to intravenous cangrelor or oral ticagrelor. The co-primary endpoints were platelet P2Y12 inhibition at infarct vessel balloon inflation time, 4 and 24 hours. Secondary endpoints included indices of coronary microcirculatory function: index of microvascular resistance (IMR), initial infarct size (troponin at 24 hours) and final infarct size at 12 weeks (cardiac magnetic resonance). Secondary endpoints included indices of coronary microcirculatory function (index of microvascular resistance [IMR]), initial infarct size (troponin at 24 hours), final infarct size at 12 weeks (cardiac magnetic resonance), corrected thrombolysis in myocardial infarction (TIMI) frame count, TIMI flow grade, myocardial perfusion grade, and ST-segment resolution (ClinicalTrials.gov NCT02733341). Results P2Y12 inhibition at first balloon inflation time was significantly greater in cangrelor-treated patients (cangrelor P2Y12 reaction unit [PRU] 145.2 ± 50.6 vs. ticagrelor 248.3 ± 55.1). There was no difference in mean PRU at 4 and 24 to 36 hours post-dosing. IMR, final infarct size, angiographic and electrocardiographic measures of reperfusion were all similar between groups. Conclusion Cangrelor produces more potent P2Y12 inhibition at the time of first coronary balloon inflation time compared with ticagrelor. Despite this enhanced P2Y12 inhibition, coronary microvascular function and final infarct size did not differ between groups.
    • Carbon sequestration and relationship between carbon addition and storage under rainfed soybean–wheat rotation in a sandy loam soil of the Indian Himalayas

      Kundu, S.; Bhattacharyya, Ranjan; Prakash, Ved; Ghosh, B.N.; Gupta, H.S. (Elsevier, 2007)
      Soil organic matter (SOM) contributes to the productivity and physical properties of soils. Although crop productivity is sustained mainly through the application of organic manure in the Indian Himalayas, no information is available on the effects of long-term manure addition along with mineral fertilizers on C sequestration and the contribution of total C input towards soil organic C (SOC) storage. We analyzed results of a long-term experiment, initiated in 1973 on a sandy loam soil under rainfed conditions to determine the influence of different combinations of NPK fertilizer and fertilizer + farmyard manure (FYM) at 10 Mg ha−1 on SOC content and its changes in the 0–45 cm soil depth. Concentration of SOC increased 40 and 70% in the NPK + FYM-treated plots as compared to NPK (43.1 Mg C ha−1) and unfertilized control plots (35.5 Mg C ha−1), respectively. Average annual contribution of C input from soybean (Glycine max (L.) Merr.) was 29% and that from wheat (Triticum aestivum L. Emend. Flori and Paol) was 24% of the harvestable above-ground biomass yield. Annual gross C input and annual rate of total SOC enrichment were 4852 and 900 kg C ha−1, respectively, for the plots under NPK + FYM. It was estimated that 19% of the gross C input contributed towards the increase in SOC content. C loss from native SOM during 30 years averaged 61 kg C ha−1 yr−1. The estimated quantity of biomass C required to maintain equilibrium SOM content was 321 kg ha−1 yr−1. The total annual C input by the soybean–wheat rotation in the plots under unfertilized control was 890 kg ha−1 yr−1. Thus, increase in SOC concentration under long-term (30 years) rainfed soybean–wheat cropping was due to the fact that annual C input by the system was higher than the required amount to maintaining equilibrium SOM content.
    • Carbon sources for polyhydroxyalkanoates and an integrated biorefinery

      Jiang, Guozhan; Hill, David; Kowalczuk, Marek; Johnston, Brian; Adamus, Grazyna; Irorere, Victor; Radecka, Iza (MDPI, 2016-07-19)
      Polyhydroxyalkanoates (PHAs) are a group of bioplastics that have a wide range of applications. Extensive progress has been made in our understanding of PHAs’ biosynthesis, and currently, it is possible to engineer bacterial strains to produce PHAs with desired properties. The substrates for the fermentative production of PHAs are primarily derived from food-based carbon sources, raising concerns over the sustainability of their production in terms of their impact on food prices. This paper gives an overview of the current carbon sources used for PHA production and the methods used to transform these sources into fermentable forms. This allows us to identify the opportunities and restraints linked to future sustainable PHA production. Hemicellulose hydrolysates and crude glycerol are identified as two promising carbon sources for a sustainable production of PHAs. Hemicellulose hydrolysates and crude glycerol can be produced on a large scale during various second generation biofuels’ production. An integration of PHA production within a modern biorefinery is therefore proposed to produce biofuels and bioplastics simultaneously. This will create the potential to offset the production cost of biofuels and reduce the overall production cost of PHAs.
    • Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

      Martínez-Martínez, Sara; Lozano-Vidal, Noelia; López-Maderuelo, María Dolores; Jiménez-Borreguero, Luis Jesús; Armesilla, Ángel Luis; Redondo, Juan Miguel (Wiley, 2018-12-29)
      Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy. In these studies, loss-of-function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of cardiac hypertrophy in adults. Here, we exploited a mouse model of cardiac hypertrophy based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in cardiac hypertrophy in adulthood. AngII-induced cardiac hypertrophy in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII-induced cardiac hypertrophy. Surprisingly, cardiac-specific delection of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of pro-fibrotic genes revealed that AngII-induced expression of Tgfβ-family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac-specific calcineurin deletion. These results show that AngII induces a direct, calcineurin-dependent pro-hypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.
    • Carefully examining Bornean Stegonotus (Serpentes, Colubridae): the montane groundsnake population in Sabah is a new and distinct species

      Kaiser, Christine; Lapin, Jack; O'Shea, Mark; Kaiser, Hinrich (Magnolia Press, 2020-12-08)
      During a taxonomic revision of species in the genus Stegonotus Duméril et al., 1854, we re-examined over 90% of all known museum specimens from this taxon. Of the five specimens available to us from the island of Borneo, three are clearly distinct from the other two. The latter are from the lowland rainforest in Sarawak, Malaysia, which includes the type locality of S. borneensis, and therefore these specimens retain that name. We here describe the other three, which include the paratype of S. borneensis, as a new species from Sabah, Malaysia. The new species can be differentiated from S. borneensis and all other species of Stegonotus by the combination of a high number of ventrals (&gt; 210) combined with a low number of subcaudals (&lt; 70), a short tail (indicated by a low subcaudal ratio of &lt; 0.25), 17-17-15 dorsal scale rows, a snout-scale ratio of 1/4–1/3, the “gull wing +” condition of the rostral, the number of supralabials touching the eye, and a dorsal color pattern featuring a dark gray-brown head offset from a lighter-brown rest of the body. The number of subcaudals in the holotype of the new species is only 21% of the number of ventrals, the lowest proportion in the genus. The new species is found at elevations above 1000 m in the cool, montane habitats of the Crocker Range and around the foot of Mt. Kinabalu, Southeast Asia’s tallest mountain, from where it has been known but taxonomically unrecognized since at least the 1880s. 
    • Cariprazine: pharmacology and clinical management of psychiatric disorders

      Antoun Reyad, Ayman; Mishriky, Raafat (Healio, 2019-03-11)
      Cariprazine is a new atypical antipsychotic for schizophrenia and bipolar disorders 2 management. In this article, the role of cariprazine, a partial D2 and D3 receptors 3 agonist with a higher D3 affinity, in the management of psychiatric conditions is 4 illustrated. Cariprazine caused significant improvements in psychiatric scales such 5 as Positive and Negative Syndrome scale (PANSS), clinical global impressions 6 (CGI) and young mania rating scales (YMRS) and was associated with side effects 7 such as akathisia, restlessness and insomnia. These findings will guide psychiatrists 8 and pharmacists in their clinical role for supporting psychiatric patients care.
    • Cathepsin B-sensitive and biocompatible dendritic polyHPMA-gemcitabine prodrug-based nanoscale system markedly enhances the antitumor activity

      Dai, Yan; Ma, Xuelei; Zhang, Yanhong; Chen, Kai; Tang, James Zhenggui; Gong, Qiyong; Luo, Kui (The Royal Society of Chemistry, 2018-09)
      To improve therapeutic indexes of gemcitabine (GEM), a stimuli-responsive dendritic polyHPMA copolymer conjugated with gemcitabine (Dendritic polyHPMA-GEM) prodrug was designed and synthesized via one-pot synthesis of RAFT polymerization. The prodrug with dendritic architectures is able to aggregate and form stable nanoscale system with a size of 46 nm. The dendritic prodrug with high molecular weight (HMW) of 168 kDa can biodegrade to low molecular weight (LMW, 29 kDa) segments for excretion. The prodrug demonstrates enzyme-responsive drug release features, and over 95% GEM was released from the carrier with the Cathepsin B within 3 h. The cellular mechanism of the dendritic prodrug was studied, suggesting the cytotoxicity is associated with the cell uptake and cell apoptosis. The prodrug shows good hemocompatibility and in vivo biosafety. Of interest, the dendritic polymer prodrug displays high accumulation within tumors, and markedly improves the in vivo antitumor activity against 4T1 murine breast cancer model compared to the free GEM. These in vivo antitumor activities are characterized as with markedly suppressed tumor volumes, indicating as the much higher tumor growth inhibition (TGI 83%) than that in GEM treatment (TGI, 36%), moreover some tumors are eliminated. The tumor xenograft immunohistochemistry study clearly indicates that the tumor apoptosis is through antiangiogenic effects. These results suggest that the stimuli-responsive dendritic polymer-gemcitabine has great potential as an efficient anticancer agent
    • CD8 epitope escape and reversion in acute HCV infection

      Timm, J; Lauer, GM; Kavanagh, DG; Sheridan, I; Kim, AY; Lucas, M; Pillay, T; Ouchi, K; Reyor, LL; Schulze Zur Wiesch, J; et al. (Rockefeller University Press, 2004-12-20)
      In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70-80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8-restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon γ enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8-associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.
    • Cell identity switching regulated by retinoic acid signaling maintains homogeneous segments in the hindbrain

      Addison, M; Xu, Q; Cayuso, J; Wilkinson, DG; Neural Development Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. (Elsevier, 2018-06-04)
      The patterning of tissues to form subdivisions with distinct and homogeneous regional identity is potentially disrupted by cell intermingling. Transplantation studies suggest that homogeneous segmental identity in the hindbrain is maintained by identity switching of cells that intermingle into another segment. We show that switching occurs during normal development and is mediated by feedback between segment identity and the retinoic acid degrading enzymes, cyp26b1 and cyp26c1. egr2, which specifies the segmental identity of rhombomeres r3 and r5, underlies the lower expression level of cyp26b1 and cyp26c1 in r3 and r5 compared with r2, r4, and r6. Consequently, r3 or r5 cells that intermingle into adjacent segments encounter cells with higher cyp26b1/c1 expression, which we find is required for downregulation of egr2b expression. Furthermore, egr2b expression is regulated in r2, r4, and r6 by non-autonomous mechanisms that depend upon the number of neighbors that express egr2b. These findings reveal that a community regulation of retinoid signaling maintains homogeneous segmental identity.
    • Cell mechanotransduction machinery, and signaling defects: small tools and nano-bio interface for influential regenerative remedies

      Kumar, Rajiv; Gulia, Kiran (Longdorm, 2021-05-02)
      Designing nanotools and devices offers a wider platform having high therapeutic claims for the discovery of drug discovery and promoting cellular events including cell motility, signaling pathways, cellular proliferation, cell physiology, apoptosis, and microenvironmental conditions during tissue engineering and regeneration. To enhance cellular environment in a physical and chemical context, the nanotools having remedies to care for the endothelial matrix during various cellular processes and mechanisms (nutrient transport, cell health, cellular interactions, differentiation, and proliferation). The influential regenerative remedies were also transported by drug delivery tools and devices for enhancing biophysical interactions with multiple mechanoresponsive that further support healing. Therefore, the small tools and nano-bio interface were also applied for stimulation and rejuvenation. The role of the Wnt/β-Catenin pathway, growth factor-β (TGF-β) signaling, inflammasome, IL-1β, cytokine, cadherin, and Ca2+dependent cell-cell adhesion proteins in the regeneration were underlined and highlighted. The elucidation of interlinked signaling pathways of cellular events offers a new approach for developing novel therapeutic remedies and emerged as new concepts in tissue regeneration and repair. Cell damage tempted injury leads to apoptosis, autophagy, and necroptosis via different processes.
    • Cell-penetrating peptides, targeting the regulation of store-operated channels, slow decay of the progesterone-induced [Ca 2+ ] i signal in human sperm

      Morris, Jennifer; Jones, Sarah; Howl, John; Lukanowska, Monika; Lefievre, Linda; Publicover, Stephen (Oxford University Press on behalf of the European Society of Human Reproduction and Embryology, 2015-04-16)
      Previous work has provided evidence for involvement of store-operated channels (SOCs) in [Ca(2+)]i signalling of human sperm, including a contribution to the transient [Ca(2+)]i elevation that occurs upon activation of CatSper, a sperm-specific cation channel localized to the flagellum, by progesterone. To further investigate the potential involvement of SOCs in the generation of [Ca(2+)]i signals in human sperm, we have used cell-penetrating peptides containing the important basic sequence KIKKK, part of the STIM-Orai activating region/CRAC activating domain (SOAR/CAD) of the regulatory protein stromal interaction molecule 1. SOAR/CAD plays a key role in controlling the opening of SOCs, which occurs upon mobilization of stored Ca(2+). Resting [Ca(2+)]i temporarily decreased upon application of KIKKK peptide (3-4 min), but scrambled KIKKK peptide had a similar effect, indicating that this action was not sequence-specific. However, in cells pretreated with KIKKK, the transient [Ca(2+)]i elevation induced by stimulation with progesterone decayed significantly more slowly than in parallel controls and in cells pretreated with scrambled KIKKK peptide. Examination of single-cell responses showed that this effect was due, at least in part, to an increase in the proportion of cells in which the initial transient was maintained for an extended period, lasting up to 10 min in a subpopulation of cells. We hypothesize that SOCs contribute to the progesterone-induced [Ca(2+)]i transient, and that interference with the regulatory mechanisms of SOC delays their closure, causing a prolongation of the [Ca(2+)]i transient.
    • The cellular pathways and potential therapeutics of polycystic kidney disease

      Richards, T; Modarage, K; Malik, SA; Goggolidou, P; Department of Biomedical Science and Physiology, Faculty of Science and Engineering, University of Wolverhampton, Wulfruna Street, Wolverhampton WV1 1LY, U.K. (Portland Press, 2021-06-22)
      Polycystic Kidney Disease (PKD) refers to a group of disorders, driven by the formation of cysts in renal tubular cells and is currently one of the leading causes of end-stage renal disease. The range of symptoms observed in PKD is due to mutations in cilia-localising genes, resulting in changes in cellular signalling. As such, compounds that are currently in preclinical and clinical trials target some of these signalling pathways that are dysregulated in PKD. In this review, we highlight these pathways including cAMP, EGF and AMPK signalling and drugs that target them and may show promise in lessening the disease burden of PKD patients. At present, tolvaptan is the only approved therapy for ADPKD, however, it carries several adverse side effects whilst comparatively, no pharmacological drug is approved for ARPKD treatment. Aside from this, drugs that have been the subject of multiple clinical trials such as metformin, which targets AMPK signalling and somatostatins, which target cAMP signalling have shown great promise in reducing cyst formation and cellular proliferation. This review also discusses other potential and novel targets that can be used for future interventions, such as β-catenin and TAZ, where research has shown that a reduction in the overexpression of these signalling components results in amelioration of disease phenotype. Thus, it becomes apparent that welldesigned preclinical investigations and future clinical trials into these pathways and other potential signalling targets are crucial in bettering disease prognosis for PKD patients and could lead to personalised therapy approaches.
    • A challenge finding P2X1 and P2X4 ligands

      Beswick, Paul; Wahab, Ben; Honey, Mark A.; Paradowski, Michael; Jiang, Ke; Lochner, Martin; Murrell-Lagnado, Ruth D.; Thompson, Andrew J. (Elsevier, 2019-06-24)
      Identifying novel small-molecule P2X1 and P2X4 ligands with sub-type specificity and high-affinity remains a pharmacological challenge. Here we use computational methods, electrophysiology and fluorescent microplate assays to screen for ligand candidates acting at these receptors. Modelling and docking identified 80 compounds for testing at P2X4 receptors, and 20 of these showed >50% inhibition in fluorescence-based assays, making them appealing for further SAR studies. Confirmation of activity by two-electrode voltage clamp, followed by their elaboration resulted in only minor improvements in potency, with the highest IC50 being 295 μM. Testing on P2X1 receptors, resulted in a series of biguanide compounds that yielded a maximum IC50 of 100 μM, but no consistent SAR could be found. Potencies of established antagonists gave expected results, although the measured potencies varied between techniques and no antagonism could be found for compounds such as paroxetine, carbamazepine, 9(10H)-acridanone, acridinol and phenoxazine-type heterocycles. This study highlights the challenge of identifying P2X4 and P2X1 ligands and suggests that a combination of complimentary approaches is needed if we are to be confident of ligand activities at these receptors.