Publications by authors named "Chris Shaw"

275 Publications

Generation of truncated derivatives through enzymatic digest of peptide GV30 target MRSA both and .

Comput Struct Biotechnol J 2021 29;19:4984-4996. Epub 2021 Aug 29.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

Methicillin-resistant (MRSA) causing serious hospital-acquired infections and skin infections has become a "superbug" in clinical treatment. Although the clinical treatment of MRSA is continuously improving, due to its unceasing global spread, MRSA has produced much heated discussion and focused study, therefore suggesting an urgent task to find new antibacterial drugs to combat this issue. Antimicrobial peptides (AMPs) are used as the last-resort drugs for treating multidrug-resistant bacterial infections, but their utilisation is still limited due to their low stability and often strong toxicity. Here, we evaluated the structure and the bioactivity of an AMP, GV30, derived from the frog skin secretions of and designed seven truncated derivatives based on the presence of cleavage sites for trypsin using an online proteomic bioinformatic resource PeptideCutter tool. We investigated the anti-MRSA effect, toxicity and salt- and serum-resistance of these peptides. Interestingly, the structure-activity relationship revealed that removing "Rana box" loop could significantly improve the bactericidal speed on MRSA. Among these derivatives, GV21 (GVIFNALKGVAKTVAAQLLKK-NH), because of its faster antibacterial effect, lower toxicity, and retains the good antibacterial activity and stability of the parent peptide, is considered to become a new potential antibacterial candidate against MRSA.
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http://dx.doi.org/10.1016/j.csbj.2021.08.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441110PMC
August 2021

Modification Strategy of D-leucine Residue Addition on a Novel Peptide from , with Enhanced Bioactivity and In Vivo Efficacy.

Toxins (Basel) 2021 Aug 31;13(9). Epub 2021 Aug 31.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

Brevinins are a well-characterised, frog-skin-derived, antimicrobial peptide (AMP) family, but their applications are limited by high cytotoxicity. In this study, a wild-type des-Leu2 brevinin peptide, named brevinin-1OS (B1OS), was identified from . To explore the significant role of the leucine residue at the second position, two variants, B1OS-L and B1OS-D-L, were designed by adding L-leucine and D-leucine residues at this site, respectively. The antibacterial and anticancer activities of B1OS-L and B1OS-D-L were around ten times stronger than the parent peptide. The activity of B1OS against the growth of Gram-positive bacteria was markedly enhanced after modification. Moreover, the leucine-modified products exerted in vivo therapeutic potential in an methicillin-resistant (MRSA)-infected waxworm model. Notably, the single substitution of D-leucine significantly increased the killing speed on lung cancer cells, where no viable H838 cells survived after 2 h of treatment with B1OS-D-L at 10 μM with low cytotoxicity on normal cells. Overall, our study suggested that the conserved leucine residue at the second position from the N-terminus is vital for optimising the dual antibacterial and anticancer activities of B1OS and proposed B1OS-D-L as an appealing therapeutic candidate for development.
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http://dx.doi.org/10.3390/toxins13090611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473181PMC
August 2021

Evaluation of antimicrobial and anticancer activities of three peptides identified from the skin secretion of Hylarana latouchii.

Acta Biochim Biophys Sin (Shanghai) 2021 Sep 11. Epub 2021 Sep 11.

Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, UK.

The skins of frogs of the family Ranidae are particularly rich sources of biologically active peptides, among which antimicrobial peptides (AMPs) constitute the major portion. Some of these have attracted the interest of researchers because they possess both antimicrobial and anticancer activities. In this study, with 'shotgun' cloning and MS/MS fragmentation, three AMPs, homologues of family brevinin-1 (brevinin-1HL), and temporin (temporin-HLa and temporin-HLb), were discovered from the skin secretion of the broad-folded frog, Hylarana latouchii. They exhibited various degrees of antimicrobial and antibiofilm activities against test microorganisms and hemolysis on horse erythrocytes. It was found that they could induce bacteria death through disrupting cell membranes and binding to bacterial DNA. In addition, they also showed different potencies towards human cancer cell lines. The secondary structure and physicochemical properties of each peptide were investigated to preliminarily reveal their structure-activity relationships. Circular dichroism spectrometry showed that they all adopted a canonical α-helical conformation in membrane-mimetic solvents. Notably, the prepropeptide of brevinin-1HL from H. latouchii was highly identical to that of brevinin-1GHd from Hylarana guentheri, indicating a close relationship between these two species. Accordingly, this study provides candidates for the design of novel anti-infective and antineoplastic agents to fight multidrug-resistant bacteria and malignant tumors and also offers additional clues for the taxonomy of ranid frogs.
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http://dx.doi.org/10.1093/abbs/gmab126DOI Listing
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 09 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Recent Advances and Challenges in Nanodelivery Systems for Antimicrobial Peptides (AMPs).

Antibiotics (Basel) 2021 Aug 16;10(8). Epub 2021 Aug 16.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.

Antimicrobial peptides (AMPs) can be used as alternative therapeutic agents to traditional antibiotics. These peptides have abundant natural template sources and can be isolated from animals, plants, and microorganisms. They are amphiphilic and mostly net positively charged, and they have a broad-spectrum inhibitory effect on bacteria, fungi, and viruses. AMPs possess significant rapid killing effects and do not interact with specific receptors on bacterial surfaces. As a result, drug resistance is rarely observed with treatments. AMPs, however, have some operational problems, such as a susceptibility to enzymatic (protease) degradation, toxicity in vivo, and unclear pharmacokinetics. However, nanodelivery systems loaded with AMPs provide a safe mechanism of packaging such peptides before they exert their antimicrobial actions, facilitate targeted delivery to the sites of infection, and control the release rate of peptides and reduce their toxic side effects. However, nanodelivery systems using AMPs are at an early stage of development and are still in the laboratory phase of development. There are also some challenges in incorporating AMPs into nanodelivery systems. Herein, an insight into the nanotechnology challenges in delivering AMPs, current advances, and remaining technological challenges are discussed in depth.
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http://dx.doi.org/10.3390/antibiotics10080990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388958PMC
August 2021

Study on the Structure-Activity Relationship of an Antimicrobial Peptide, Brevinin-2GUb, from the Skin Secretion of .

Antibiotics (Basel) 2021 Jul 22;10(8). Epub 2021 Jul 22.

School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.

Antimicrobial peptides (AMPs) are considered potential alternatives to antibiotics due to their advantages in solving antibiotic resistance. Brevinin-2GUb, which was extracted from the skin secretion of , is a peptide with modest antimicrobial activity. Several analogues were designed to explore the structure-activity relationship and enhance its activity. In general, the Rana box is not an indispensable motif for the bioactivity of Brevinin-2GUb, and the first to the 19th amino acids at the N-terminal end are active fragments, such that shortening the peptide while maintaining its bioactivity is a promising strategy for the optimisation of peptides. Keeping a complete hydrophobic face and increasing the net charges are key factors for antimicrobial activity. With the increase of cationic charges, α-helical proportion, and amphipathicity, the activity of t-Brevinin-2GUb-6K (tB2U-6K), in combatting bacteria, drastically improved, especially against Gram-negative bacteria, and the peptide attained the capacity to kill clinical isolates and fungi as well, which made it possible to address some aspects of antibiotic resistance. Thus, peptide tB2U-6K, with potent antimicrobial activity against antibiotic-resistant bacteria, the capacity to inhibit the growth of biofilm, and low toxicity against normal cells, is of value to be further developed into an antimicrobial agent.
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http://dx.doi.org/10.3390/antibiotics10080895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388802PMC
July 2021

First-recruited motor units adopt a faster phenotype in amyotrophic lateral sclerosis.

J Physiol 2021 Sep 9;599(17):4117-4130. Epub 2021 Aug 9.

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Key Points: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder of motor neurons, carrying a short survival. High-density motor unit recordings permit analysis of motor unit size (amplitude) and firing behaviour (afterhyperpolarization duration and muscle fibre conduction velocity). Serial recordings from biceps brachii indicated that motor units fired faster and with greater amplitude as disease progressed. First-recruited motor units in the latter stages of ALS developed characteristics akin to fast-twitch motor units, possibly as a compensatory mechanism for the selective loss of this motor unit subset. This process may become maladaptive, highlighting a novel therapeutic target to reduce motor unit vulnerability.

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a median survival of 3 years. We employed serial high-density surface electromyography (HDSEMG) to characterize voluntary and ectopic patterns of motor unit (MU) firing at different stages of disease. By distinguishing MU subtypes with variable vulnerability to disease, we aimed to evaluate compensatory neuronal adaptations that accompany disease progression. Twenty patients with ALS and five patients with benign fasciculation syndrome (BFS) underwent 1-7 assessments each. HDSEMG measurements comprised 30 min of resting muscle and 1 min of light voluntary activity from biceps brachii bilaterally. MU decomposition was performed by the progressive FastICA peel-off technique. Inter-spike interval, firing pattern, MU potential area, afterhyperpolarization duration and muscle fibre conduction velocity were determined. In total, 373 MUs (ALS = 287; BFS = 86) were identified from 182 recordings. Weak ALS muscles demonstrated a lower mean inter-spike interval (82.7 ms) than strong ALS muscles (96.0 ms; P = 0.00919) and BFS muscles (95.3 ms; P = 0.0039). Mean MU potential area (area under the curve: 487.5 vs. 98.7 μV ms; P < 0.0001) and muscle fibre conduction velocity (6.2 vs. 5.1 m/s; P = 0.0292) were greater in weak ALS muscles than in BFS muscles. Purely fasciculating MUs had a greater mean MU potential area than MUs also under voluntary command (area under the curve: 679.6 vs. 232.4 μV ms; P = 0.00144). These results suggest that first-recruited MUs develop a faster phenotype in the latter stages of ALS, likely driven by the preferential loss of vulnerable fast-twitch MUs. Inhibition of this potentially maladaptive phenotypic drift may protect the longevity of the MU pool, stimulating a novel therapeutic avenue.
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http://dx.doi.org/10.1113/JP281310DOI Listing
September 2021

A novel bioengineered fragment peptide of Vasostatin-1 exerts smooth muscle pharmacological activities and anti-angiogenic effects via blocking VEGFR signalling pathway.

Comput Struct Biotechnol J 2021 3;19:2664-2675. Epub 2021 May 3.

Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.

Chromogranin A (CgA) is a hydrophilic glycoprotein released by post-ganglionic sympathetic neurons. CgA consists of a single peptide chain containing numerous paired basic residues, which are typical cleavage sites in prohormones to generate bioactive peptides. It is recognized as a diagnostic and prognostic serum marker for neuroendocrine tumours. Vasostatin-1 is one of the most conserved regions of CgA and has diverse inhibitory biological activities. In this study, a novel peptide fragment that contains three typical functional structures of Vasostatin-1 was synthesized. This unique bioengineered Vasostatin-1 Derived Peptide (named V1DP) includes a highly conserved domain between vertebrate species in its N-terminal region, comprising a disulphide bridge formed by two cysteine residues at amino acid positions 17 and 38, respectively. Besides, V1DP contains two significant tripeptide recognition sequences: the amino acid triplets, RGD and KGD. Our data demonstrated that V1DP could induce a dose-dependent relaxation of rat arterial smooth muscle and also increase the contraction activity of rat uterus smooth muscle. More importantly, we found that V1DP inhibits cancer cell proliferation, modulate the HUVEC cell migration, and exhibit anti-angiogenesis effect both in and in We further investigated the actual mechanism of V1DP, and our results confirmed that V1DP involves inhibiting the vascular endothelial growth factor receptor (VEGFR) signalling. We docked V1DP to the apo structures of VEGFR2 and examined the stability of the peptide in the protein pockets. Our simulation and free energy calculations results indicated that V1DP can bind to the catalytic domain and regulatory domain pockets, depending on whether the conformational state of the protein is JM-in or JM-out. Taken together, our data suggested that V1DP plays a role as the regulator of endothelial cell function and smooth muscle pharmacological homeostasis. V1DP is a water-soluble and biologically stable peptide and could further develop as an anti-angiogenic drug for cancer treatment.
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http://dx.doi.org/10.1016/j.csbj.2021.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131715PMC
May 2021

Non-invasive measurement of fasciculation frequency demonstrates diagnostic accuracy in amyotrophic lateral sclerosis.

Brain Commun 2020 7;2(2):fcaa141. Epub 2020 Sep 7.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Delayed diagnosis of amyotrophic lateral sclerosis prevents early entry into clinical trials at a time when neuroprotective therapies would be most effective. Fasciculations are an early hallmark of amyotrophic lateral sclerosis, preceding muscle weakness and atrophy. To assess the potential diagnostic utility of fasciculations measured by high-density surface electromyography, we carried out 30-min biceps brachii recordings in 39 patients with amyotrophic lateral sclerosis, 7 patients with benign fasciculation syndrome, 1 patient with multifocal motor neuropathy and 17 healthy individuals. We employed the surface potential quantification engine to compute fasciculation frequency, fasciculation amplitude and inter-fasciculation interval. Inter-group comparison was assessed by Welch's analysis of variance. Logistic regression, receiver operating characteristic curves and decision trees discerned the diagnostic performance of these measures. Fasciculation frequency, median fasciculation amplitude and proportion of inter-fasciculation intervals <100 ms showed significant differences between the groups. In the best-fit regression model, increasing fasciculation frequency and median fasciculation amplitude were independently associated with the diagnosis of amyotrophic lateral sclerosis. Fasciculation frequency was the single best measure predictive of the disease, with an area under the curve of 0.89 (95% confidence interval 0.81-0.98). The cut-off of more than 14 fasciculation potentials per minute achieved 80% sensitivity (95% confidence interval 63-90%) and 96% specificity (95% confidence interval 78-100%). In conclusion, non-invasive measurement of fasciculation frequency at a single time-point reliably distinguished amyotrophic lateral sclerosis from its mimicking conditions and healthy individuals, warranting further research into its diagnostic applications.
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http://dx.doi.org/10.1093/braincomms/fcaa141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850269PMC
September 2020

Accurate interpretation of fasciculation frequency in amyotrophic lateral sclerosis hinges on both muscle type and stage of disease.

Brain Commun 2020 11;2(2):fcaa189. Epub 2020 Dec 11.

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

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http://dx.doi.org/10.1093/braincomms/fcaa189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784041PMC
December 2020

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

Ann Neurol 2021 04 15;89(4):686-697. Epub 2021 Jan 15.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Objective: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

Methods: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

Results: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

Interpretation: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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http://dx.doi.org/10.1002/ana.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048961PMC
April 2021

Fasciculation analysis reveals a novel parameter that correlates with predicted survival in amyotrophic lateral sclerosis.

Muscle Nerve 2021 03 29;63(3):392-396. Epub 2020 Dec 29.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK Dementia Research Institute, London, UK.

Introduction: Prognostic uncertainty in amyotrophic lateral sclerosis (ALS) confounds clinical management planning, patient counseling, and trial stratification. Fasciculations are an early clinical hallmark of disease and can be quantified noninvasively. Using an innovative analytical method, we correlated novel fasciculation parameters with a predictive survival model.

Methods: Using high-density surface electromyography, we collected biceps recordings from ALS patients on their first research visit. By accessing an online survival prediction tool, we provided eight clinical and genetic parameters to estimate individual patient survival. Fasciculation analysis was performed using an automated algorithm (Surface Potential Quantification Engine), with a Cox proportional hazards model to calculate hazard ratios.

Results: The median predicted survival for 31 patients was 41 (interquartile range, 31.5-57) months. Univariate hazard ratios were 1.09 (95% confidence interval [CI], 1.03-1.16) for the rate of change of fasciculation frequency (RoCoFF) and 1.10 (95% CI, 1.01-1.19) for the amplitude dispersion rate. Only the RoCoFF remained significant (P = .04) in a multivariate model.

Discussion: Noninvasive measurement of fasciculations at a single time-point could enhance prognostic models in ALS, where higher RoCoFF values indicate shorter survival.
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http://dx.doi.org/10.1002/mus.27139DOI Listing
March 2021

Identification of a new myotropic decapeptide from the skin secretion of the red-eyed leaf frog, Agalychnis callidryas.

PLoS One 2020 3;15(12):e0243326. Epub 2020 Dec 3.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Bradykinin-related peptides (BRPs) family is one of the most significant myotropic peptide families derived from frog skin secretions. Here, a novel BRP callitide was isolated and identified from the red-eyed leaf frog, Agalychnis callidryas, with atypical primary structure FRPAILVRPK-NH2. The mature peptide was cleaved N-terminally at a classic propeptide convertase cleavage site (-KR-) and at the C-terminus an unusual -GKGKGK sequence was removed using the first G residue as an amide donor for the C-terminally-located K residue. Thereafter, the synthetic replicates of callitide were assessed the myotropic activity and showed a significant contraction of balder, with the 0.63 nM EC50 value, more potent than most discovered myotropic peptides. The binding mode was further speculated by molecular docking and stimulation. The result indicated that the C-terminal of callitide might selectively bind to bradykinin receptor B2 (BKRB2). Further investigation of the callitide needs to be done in the future to be exploited as potential future drug leads.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714090PMC
January 2021

A Novel Amphibian Antimicrobial Peptide, Phylloseptin-PV1, Exhibits Effective Anti- Activity Without Inducing Either Hepatic or Renal Toxicity in Mice.

Front Microbiol 2020 26;11:565158. Epub 2020 Oct 26.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom.

In order to part address the problem of drug-resistant pathogens, antimicrobial peptides (AMPs) have been proposed as alternatives to traditional antibiotics. Herein, a novel phylloseptin peptide, named phylloseptin-PV1 (PPV1), is described from the defensive skin secretion of the Neotropical white-lined leaf frog, . The peptide was synthesized by solid phase peptide synthesis (SPPS) and purified by RP-HPLC, prior to assessment of its biological activities. PPV1 not only demonstrated potent antimicrobial activity against planktonic ESKAPE microorganisms and the yeast, , but also inhibited and eradicated and MRSA biofilms. The antimicrobial mechanism was shown to include permeabilization of target cell membranes. The antimicrobial activity of the peptide was then evaluated using mice. PPV1 also exhibited antiproliferative activity against the cancer cell lines, H157, MCF-7, and U251MG, but had a lower potency against the normal cell line, HMEC-1. Although, the peptide possessed a moderate hemolytic action on mammalian red blood cells , it did not induce significant hepatic or renal toxicity in injected infected mice. These studies have thus found PPV1 to be a potent phylloseptin group AMP, which can effectively inhibit staphylococci, both and , without eliciting toxicity. These data thus provide support for further evaluation of PPV1 as a novel antimicrobial agent with therapeutic potential.
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http://dx.doi.org/10.3389/fmicb.2020.565158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649123PMC
October 2020

The rise and fall of fasciculations in amyotrophic lateral sclerosis.

Brain Commun 2020 20;2(1):fcaa018. Epub 2020 Feb 20.

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a median survival of 3 years from symptom onset. Accessible and reliable biomarkers of motor neuron decline are urgently needed to quicken the pace of drug discovery. Fasciculations represent an early pathophysiological hallmark of amyotrophic lateral sclerosis and can be reliably detected by high-density surface electromyography. We set out to quantify fasciculation potentials prospectively over 14 months, seeking comparisons with established markers of disease progression. Twenty patients with amyotrophic lateral sclerosis and five patients with benign fasciculation syndrome underwent up to seven assessments each. At each assessment, we performed the amyotrophic lateral sclerosis-functional rating scale, sum power score, slow vital capacity, 30-min high-density surface electromyography recordings from biceps and gastrocnemius and the motor unit number index. We employed the Surface Potential Quantification Engine, which is an automated analytical tool to detect and characterize fasciculations. Linear mixed-effect models were employed to account for the pseudoreplication of serial measurements. The amyotrophic lateral sclerosis-functional rating scale declined by 0.65 points per month ( < 0.0001), 35% slower than average. A total of 526 recordings were analysed. Compared with benign fasciculation syndrome, biceps fasciculation frequency in amyotrophic lateral sclerosis was 10 times greater in strong muscles and 40 times greater in weak muscles. This was coupled with a decline in fasciculation frequency among weak muscles of -7.6/min per month ( = 0.003), demonstrating the rise and fall of fasciculation frequency in biceps muscles. Gastrocnemius behaved differently, whereby strong muscles in amyotrophic lateral sclerosis had fasciculation frequencies five times greater than patients with benign fasciculation syndrome while weak muscles were increased by only 1.5 times. Gastrocnemius demonstrated a significant decline in fasciculation frequency in strong muscles (2.4/min per month, < 0.0001), which levelled off in weak muscles. Fasciculation amplitude, an easily quantifiable surrogate of the reinnervation process, was highest in the biceps muscles that transitioned from strong to weak during the study. Pooled analysis of >900 000 fasciculations revealed inter-fasciculation intervals <100 ms in the biceps of patients with amyotrophic lateral sclerosis, particularly in strong muscles, consistent with the occurrence of doublets. We hereby present the most comprehensive longitudinal quantification of fasciculation parameters in amyotrophic lateral sclerosis, proposing a unifying model of the interactions between motor unit loss, muscle power and fasciculation frequency. The latter showed promise as a disease biomarker with linear rates of decline in strong gastrocnemius and weak biceps muscles, reflecting the motor unit loss that drives clinical progression.
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http://dx.doi.org/10.1093/braincomms/fcaa018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425399PMC
February 2020

Characterisation of a novel peptide, Brevinin-1H, from the skin secretion of Amolops hainanensis and rational design of several analogues.

Chem Biol Drug Des 2021 02 7;97(2):273-282. Epub 2020 Sep 7.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast, UK.

As drug-resistant bacteria have become a serious health problem and have caused thousands of deaths, finding new antibiotics has become an urgent research priority. A novel antimicrobial peptide, named Brevinin-1H, was identified in the skin secretion of Amolops hainanensis through 'shotgun' cloning. It has broad-spectrum antimicrobial activity against tested micro-organisms and has anticancer cell activity. To improve its bioactivity and decrease its cytotoxicity, two structural analogues-Brevinin-1Ha and Brevinin-1HY-were designed based on the secondary structure of the natural peptide. Brevinin-1HY, in which tyrosine substituted Pro , had similar activity to the natural peptide against Gram-negative bacteria and cancer cells, but showed a dramatic increase in haemolytic activity and cytotoxicity at its minimum inhibitory concentration. Brevinin-1Ha, which transferred the Rana-box from the C-terminal to a central position, had significantly decreased haemolytic activity, but also in antimicrobial and anticancer activity. The present data suggest that increasing the proportion of α-helix structure in an AMP can increase its target micro-organism bioactivity to some extent.
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http://dx.doi.org/10.1111/cbdd.13779DOI Listing
February 2021

Enhanced Antimicrobial Activity of N-Terminal Derivatives of a Novel Brevinin-1 Peptide from The Skin Secretion of .

Toxins (Basel) 2020 07 30;12(8). Epub 2020 Jul 30.

Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast BT9 7BL, Northern Ireland, UK.

Antimicrobial peptides (AMPs) are promising therapeutic alternatives compared to conventional antibiotics for the treatment of drug-resistant bacterial infections. However, the application of the overwhelming majority of AMPs is limited because of the high toxicity and high manufacturing costs. Amphibian skin secretion has been proven to be a promising source for the discovery and development of novel AMPs. Herein, we discovered a novel AMP from the skin secretion of , and designed the analogues by altering the key factors, including conformation, net charge and amphipathicity, to generate short AMPs with enhanced therapeutic efficacy. All the peptides were chemically synthesised, followed by evaluating their biological activity, stability and cytotoxicity. OSd, OSe and OSf exhibited broad-spectrum antibacterial effects, especially OSf, which presented the highest therapeutic index for the tested bacteria. Moreover, these peptides displayed good stability. The results from scanning electron microscopy and transmission electron microscopy studies, indicated that brevinin-OS, OSd, OSe and OSf possessed rapid bactericidal ability by disturbing membrane permeability and causing the release of cytoplasmic contents. In addition, OSd, OSe and OSf dramatically decreased the mortality of waxworms acutely infected with MRSA. Taken together, these data suggested that a balance between positive charge, degrees of α-helicity and hydrophobicity, is necessary for maintaining antimicrobial activity, and these data successfully contributed to the design of short AMPs with significant bactericidal activity and cell selectivity.
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http://dx.doi.org/10.3390/toxins12080484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472354PMC
July 2020

Pharmacological Effects of a Novel Bradykinin-Related Peptide (RR-18) from the Skin Secretion of the Hejiang Frog () on Smooth Muscle.

Biomedicines 2020 Jul 17;8(7). Epub 2020 Jul 17.

Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau.

Bradykinin (BK) and bradykinin-related peptides (BRPs), which were identified from a diversity of amphibian skin secretions, exerted contractile and relaxing effects on non-vascular and vascular smooth muscle, respectively. Here, we report a novel bradykinin-related peptide with a molecular mass of 1890.2 Da, RVAGPDKPARISGLSPLR, which was isolated and identified from skin secretions, followed by a C-terminal extension sequence VAPQIV. The biosynthetic precursor-encoding cDNA was cloned by the "shotgun" cloning method, and the novel RR-18 was identified and structurally confirmed by high-performance liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS). Subsequently, the myotropic activity of the synthetic replicate of RR-18 was investigated on the rat bladder, uterus, tail artery and ileum smooth muscle. The peptide was named RR-18 in accordance (R = N-terminal arginine, R = C-terminal arginine, 18 = number of residues). In this study, the synthetic replicates of RR-18 showed no agonist/antagonism of BK-induced rat bladder and uterus smooth muscle contraction. However, it displayed an antagonism of bradykinin-induced rat ileum contraction and arterial smooth muscle relaxation. The EC values of BK for ileum and artery, were 214.7 nM and 18.3 nM, respectively. When the tissue was pretreated with the novel peptide, RR-18, at the maximally effective concentration of bradykinin (1 × 10 M), bradykinin-induced contraction of the ileum and relaxation of the arterial smooth muscle was reduced by 50-60% and 30-40%, respectively. In conclusion, RR-18 represents novel bradykinin antagonising peptide from amphibian skin secretions. It may provide new insight into possible treatment options for chronic pain and chronic inflammation.
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http://dx.doi.org/10.3390/biomedicines8070225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400415PMC
July 2020

Ranacyclin-NF, a Novel Bowman-Birk Type Protease Inhibitor from the Skin Secretion of the East Asian Frog, .

Biology (Basel) 2020 Jul 2;9(7). Epub 2020 Jul 2.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.

Serine protease inhibitors are found in plants, animals and microorganisms, where they play important roles in many physiological and pathological processes. Inhibitor scaffolds based on natural proteins and peptides have gradually become the focus of current research as they tend to bind to their targets with greater specificity than small molecules. In this report, a novel Bowman-Birk type inhibitor, named ranacyclin-NF (RNF), is described and was identified in the skin secretion of the East Asian frog, . A synthetic replicate of the peptide was subjected to a series of functional assays. It displayed trypsin inhibitory activity with an inhibitory constant, Ki, of 447 nM and had negligible direct cytotoxicity. No observable direct antimicrobial activity was found but RNF improved the therapeutic potency of Gentamicin against Methicillin-resistant (MRSA). RNF shared significant sequence similarity to previously reported and related inhibitors from (ORB) and (ranacyclin-T), both of which were found to be multi-functional. Two analogues of RNF, named ranacyclin-NF1 (RNF1) and ranacyclin-NF3L (RNF3L), were designed based on some features of ORB and ranacyclin-T to study structure-activity relationships. Structure-activity studies demonstrated that residues outside of the trypsin inhibitory loop (TIL) may be related to the efficacy of trypsin inhibitory activity.
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http://dx.doi.org/10.3390/biology9070149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407945PMC
July 2020

A Novel Antimicrobial Peptide (Kassinatuerin-3) Isolated from the Skin Secretion of the African Frog, .

Biology (Basel) 2020 Jul 2;9(7). Epub 2020 Jul 2.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

Amphibian skin secretions are remarkable sources of novel bioactive peptides. Among these, antimicrobial peptides have demonstrated an outstanding efficacy in killing microorganisms via a general membranolytic mechanism, which may offer the prospect of solving specific target-driven antibiotic resistance. Here, the discovery of a novel defensive peptide is described from the skin secretion of the African frog, Named kassinatuerin-3, it was identified through a combination of "shot-gun" cloning and MS/MS fragmentation sequencing. Subsequently, a synthetic replicate was subjected to biofunctional evaluation. The results indicated that kassinatuerin-3 possessed antimicrobial activity against Gram-positive bacteria but no effect against Gram-negative bacteria. Additionally, it was active in biofilm eradication on and MRSA and in the antiproliferation of selected cancer cell lines. Moreover, it had a very mild hemolytic effect, which demonstrated a high therapeutic index for kassinatuerin-3. Collectively, although kassinatuerin-3 did not demonstrate remarkable bioactivities compared with other natural or synthetic antimicrobial peptides (AMPs), it offered a new insight into the design of antimicrobial derivatives.
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http://dx.doi.org/10.3390/biology9070148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408539PMC
July 2020

Association of with Declining Vegetation in an Urban Forest Environment.

Microorganisms 2020 Jun 29;8(7). Epub 2020 Jun 29.

Phytophthora Science and Management, Centre for Climate Impacted Terrestrial Ecosystems, Harry Butler Institute, Murdoch University, Murdoch 6150, Australia.

Urban forests consist of various environments from intensely managed spaces to conservation areas and are often reservoirs of a diverse range of invasive pathogens due to their introduction through the nursery trade. Pathogens are likely to persist because the urban forest contains a mixture of native and exotic plant species, and the environmental conditions are often less than ideal for the trees. To test the impact of different land management approaches on the community, 236 discrete soil and root samples were collected from declining trees in 91 parks and nature reserves in Joondalup, Western Australia (WA). Sampling targeted an extensive variety of declining native trees and shrubs, from families known to be susceptible to . A sub-sample was set aside and DNA extracted for metabarcoding using -specific primers; the remaining soil and root sample was baited for the isolation of We considered the effect on the community of park class and area, soil family, and the change in canopy cover or health as determined through sequential measurements using remote sensing. Of the 236 samples, baiting techniques detected species from 24 samples (18 parks), while metabarcoding detected from 168 samples (64 parks). Overall, forty-four phylotypes were detected. Considering only sampling sites where was detected, species richness averaged 5.82 (range 1-21) for samples and 9.23 (range 2-24) for parks. was the most frequently found species followed by , and While park area and canopy cover had a significant effect on community the R values were very low, indicating they have had little effect in shaping the community. and the two most invasive species, often co-occurring (61% of samples); however, the communities with were more common than those with , reflecting observations over the past decade of the increasing importance of as a pathogen in the urban environment.
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http://dx.doi.org/10.3390/microorganisms8070973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409110PMC
June 2020

Identification and Rational Design of a Novel Antibacterial Peptide Dermaseptin-AC from the Skin Secretion of the Red-Eyed Tree Frog .

Antibiotics (Basel) 2020 May 10;9(5). Epub 2020 May 10.

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, UK.

Antibiotic resistance represents a tremendous contemporary clinical challenge. Given this challenge, antimicrobial peptides (AMPs) are regarded as one of the most promising new options for next-generation lead antibiotics. Here, we describe the antibacterial activities of a cationic peptide named DRP-AC4, obtained from frog skin secretion using shotgun cloning. Two modified peptides were derived by substituting the sequence of amino acids to complete the hydrophobic face (DRP-AC4b) and increase net charge (DRP-AC4a), respectively. The activity and cytotoxicity of these two peptides were compared. DRP-AC4a displayed significantly increased potency against bacteria compared to the natural peptide. It should be noted, however, that both analogue peptides demonstrated higher lytic ability than the natural peptide against the membranes of mammalian erythrocytes. At the same time, all three peptides displayed lower hemolytic activity compared to their antibacterial activity. Here, we demonstrate that AMPs have more complex activity mechanisms and faster bactericidal rates than traditional antibiotics, which may be one of the reasons why bacteria do not develop resistance to them. These discoveries provide interesting insights into the discovery and development of novel drugs from natural sources.
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http://dx.doi.org/10.3390/antibiotics9050243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277532PMC
May 2020

Brevinin-1GHd: a novel Hylarana guentheri skin secretion-derived Brevinin-1 type peptide with antimicrobial and anticancer therapeutic potential.

Biosci Rep 2020 05;40(5)

Natural Drug Discovery Group, School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, Northern Ireland, U.K.

Host-defense antimicrobial peptides (AMPs) from amphibians are usually considered as one of the most promising next-generation antibiotics because of their excellent antimicrobial properties and low cytotoxicity. In the present study, one novel Brevinin-1 type peptide, Brevinin-1GHd, was isolated and characterized from the skin secretion of the frog, Hylarana guentheri. Brevinin-1GHd was found to possess a wide range of antimicrobial activity through penetrating the bacterial membrane within a short time while showing low hemolysis at bactericidal concentrations, even against the resistant strains. It also inhibited and eradicated biofilms that are thought to be closely related to the rise in resistance. Meanwhile, Brevinin-1GHd exhibited wide-spectrum anti-proliferation activity toward human cancer lines. Taken together, these results indicate that Brevinin-1GHd with its excellent antimicrobial and anticancer activities is a promising candidate for a novel antibiotic agent, and study of its structure-activity relationships also provided a rational template for further research and peptide analog design.
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http://dx.doi.org/10.1042/BSR20200019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225409PMC
May 2020

UK case control study of smoking and risk of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 17;21(3-4):222-227. Epub 2020 Apr 17.

School of Psychological Science, University of Bristol, Bristol, United Kingdom.

: Susceptibility to amyotrophic lateral sclerosis (ALS) is associated with smoking in some studies, but it is not clear which aspect of smoking behavior is related. Using detailed records of lifetime smoking we investigated the relationship between smoking and ALS in a UK population. : In this retrospective case-control study, smoking status was collected using environmental questionnaires from people diagnosed with ALS between 2008 and 2013 and from age, sex and geographically matched controls. Categorical measures of smoking behavior were: smoking at the time of survey and smoking initiation; continuous measures were intensity (cigarettes per day), duration (years from starting to stopping or time of survey), cigarette pack years, and comprehensive smoking index (CSI), a measure of lifetime smoking. We used logistic regression to assess the risk of ALS with different combinations of smoking variables adjusted for age at survey, gender, level of education, smoking status and alcohol initiation, selecting the best model using the Akaike Information Criterion. : There were 388 records with full smoking history. The best-fitting model used CSI and smoking status at the time of survey. We found a weak association between current smoking and risk of ALS, OR 3.63 (95% CI 1.02-13.9) value 0.05. Increase in CSI score did not increase risk of ALS: OR 0.81 (95% CI 0.58-1.11) value 0.2.: There is weak evidence of a positive effect of current smoking on the risk of ALS which does not show dose-dependence with higher levels of lifetime smoking and maybe a false positive result.
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http://dx.doi.org/10.1080/21678421.2019.1706580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261396PMC
May 2020

Efficacy of a Physical Activity Counseling Program With Use of a Wearable Tracker in People With Inflammatory Arthritis: A Randomized Controlled Trial.

Arthritis Care Res (Hoboken) 2020 12;72(12):1755-1765

University of British Columbia, Vancouver, and Arthritis Research Canada, Richmond, British Columbia, Canada.

Objective: To assess the efficacy of a multifaceted counseling intervention at improving physical activity participation and patient outcomes.

Methods: We recruited people with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). In weeks 1-8, the immediate group received education and counseling by a physical therapist, used a Fitbit and a web application to obtain feedback about their physical activity, and received 4 follow-up calls from the physical therapist. The delay group received the same intervention in weeks 10-17. Participants were assessed at baseline and at weeks 9, 18, and 27. The primary outcome was time spent in moderate/vigorous physical activity (MVPA; in bouts of ≥10 minutes) measured with a SenseWear device. Secondary outcomes included step count, time in sedentary behavior, pain, fatigue, mood, self-management capacity, and habitual behaviors.

Results: A total of 118 participants enrolled. The adjusted mean difference in MVPA was 9.4 minutes/day (95% confidence interval [95% CI] -0.5, 19.3, P = 0.06). A significant effect was found in pain (-2.45 [95% CI -4.78, -0.13], P = 0.04), and perceived walking habit (0.54 [95% CI 0.08, 0.99], P = 0.02). The remaining secondary outcomes improved, but were not statistically significant. Post hoc analysis revealed a significant effect in MVPA (14.3 minutes/day [95% CI 2.3, 26.3]) and pain (-4.05 [95% CI -6.73, -1.36]) in participants with RA, but not in those with SLE.

Conclusion: Counseling by a physical therapist has the potential to improve physical activity in people with inflammatory arthritis, but further study is needed to understand the intervention effect on different diseases. We found a significant improvement in pain, suggesting that the intervention might have a positive effect on symptom management.
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http://dx.doi.org/10.1002/acr.24199DOI Listing
December 2020

Fasciculations demonstrate daytime consistency in amyotrophic lateral sclerosis.

Muscle Nerve 2020 06 7;61(6):745-750. Epub 2020 Apr 7.

UK Dementia Research Institute, Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, UK.

Introduction: Fasciculations represent early neuronal hyperexcitability in amyotrophic lateral sclerosis (ALS). To aid calibration as a disease biomarker, we set out to characterize the daytime variability of fasciculation firing.

Methods: Fasciculation awareness scores were compiled from 19 ALS patients. In addition, 10 ALS patients prospectively underwent high-density surface electromyographic (HDSEMG) recordings from biceps and gastrocnemius at three time-points during a single day.

Results: Daytime fasciculation awareness scores were low (mean: 0.28 muscle groups), demonstrating significant variability (coefficient of variation: 303%). Biceps HDSEMG recordings were highly consistent for fasciculation potential frequency (intraclass correlation coefficient [ICC] = 95%, n = 19) and the interquartile range of fasciculation potential amplitude (ICC = 95%, n = 19). These parameters exhibited robustness to observed fluctuations in data quality parameters. Gastrocnemius demonstrated more modest levels of consistency overall (44% to 62%, n = 20).

Discussion: There was remarkable daytime consistency of fasciculation firing in the biceps of ALS patients, despite sparse and intermittent awareness among patients' accounts.
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http://dx.doi.org/10.1002/mus.26864DOI Listing
June 2020

and MD Simulation Study to Explore Physicochemical Parameters for Antibacterial Peptide to Become Potent Anticancer Peptide.

Mol Ther Oncolytics 2020 Mar 10;16:7-19. Epub 2019 Dec 10.

Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, China.

Although the physicochemical properties of antimicrobial peptides (AMPs) and anticancer peptides (ACPs) are very similar, it remains unclear which specific parameter(s) of ACPs confer the major anticancer activity. By answering how to construct a short AMP/ACP that could easily be synthesized in the most cost effective way plus conferring a maximum anticancer effect is a very important scientific breakthrough in the development of protein/peptide drugs. In this study, an 18-amino-acids antimicrobial peptide, AcrAP1 (named AP1-Z1), was used as a template. Bioinformatics algorithms were then performed to design its six mutants (AP1-Z3a, AP1-Z3b, AP1-Z5a, AP1-Z5b, AP1-Z7, and AP1-Z9). After a series of experiments plus intensive computational analysis, the data demonstrated that AP1-Z5a and AP1-Z5b induced both apoptosis and anti-angiogenic effects to achieve the maximum anticancer activity. Specifically, the most effective mutant, AP1-Z5b, exhibited high selectivity for the charged membrane in molecular dynamics simulations. These findings clearly demonstrated that both charge and hydrophobicity play an important role and are necessary to reach an optimum equilibrium for optimizing the anticancer activity of AMPs. Overall, the present study provides a very crucial theoretical basis and important scientific evidence on the key physicochemical parameters of ACP drugs development.
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http://dx.doi.org/10.1016/j.omto.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940675PMC
March 2020

Effectiveness of an online self-management tool, OPERAS (an On-demand Program to EmpoweR Active Self-management), for people with rheumatoid arthritis: a research protocol.

Trials 2019 Dec 11;20(1):712. Epub 2019 Dec 11.

Arthritis Research Canada, Milan Ilich Arthritis Research Centre, 5591 No. 3 Road, Richmond, BC, V6X 2C7, Canada.

Background: Active self-management is a process where patients are fully engaged in managing their health in daily life by having access to contextualized health data and tailored guidance to support a healthy lifestyle. This study aims to determine whether an e-health intervention that incorporates symptom/disease activity monitoring and physical activity counselling can improve self-management ability in patients with rheumatoid arthritis (RA).

Methods: The 'Empowering active self-management of arthritis: Raising the bar with OPERAS (an On-demand Program to EmpoweR Active Self-management)' project is a randomized controlled trial that uses a delayed control design. One hundred thirty-four participants with RA will be randomly assigned to start the intervention either immediately (immediate group) or 6 months later (delayed group). The intervention involves (1) use of a Fitbit-compatible web app to record and monitor their RA disease activity, symptoms, and time spent on physical activity and a Fitbit; (2) group education and individual counselling by a physiotherapist (PT); and (3) six phone calls with a PT. The primary outcome measure is self-management ability measured by the Patient Activation Measure. Secondary outcome measures include disease status, fatigue, pain, depressive symptoms, and characteristics of habitual behavior and also time spent in physical activity and sedentary activity with a wearable multi-sensor device (SenseWear Mini). After the 6-month intervention, we will interview a sample of participants to examine their experiences with the intervention.

Discussion: The results of this study will help to determine whether this technology-enhanced self-management intervention improves self-management ability and health outcomes for people living with RA. A limitation of this study is that participants will need to self-report their symptoms, disease status, and treatment use through questionnaires on the OPERAS web app. The user-friendly interface, reminder emails from the research staff, and tailored guidance from PTs will encourage participants to actively engage with the app.

Trial Registration: Date of last update in ClinicalTrials.gov: January 2, 2019. ClinicalTrials.gov Identifier: NCT03404245.
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http://dx.doi.org/10.1186/s13063-019-3851-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907135PMC
December 2019

Use of Routine Environmental Monitoring Data to Establish a Dose-based Compliance System for a Low-level Radioactive Waste Disposal Site.

Health Phys 2020 01;118(1):1-17

Risk Assessment Corporation, Neeses SC.

A dose-based compliance methodology was developed for Waste Control Specialists, LLC, low-level radioactive waste facility in Andrews, Texas, that allows routine environmental measurement data to be evaluated not only at the end of a year to determine regulatory compliance, but also throughout the year as new data become available, providing a continuous assessment of the facility. The first step in the methodology is a screening step to determine the potential presence of site emissions in the environment, and screening levels are established for each environmental media sampled. The screening accounts for spatial variations observed in background for soil and temporal fluctuations observed in background for air. For groundwater, the natural activity concentrations in groundwater wells at the facility are highly variable, and therefore the methodology uses ratios for screening levels. The methodology compares the ratio of gross alpha to U + U to identify potentially abnormal alpha activity and the ratio of U to U to identify the potential presence of depleted uranium. Compliance evaluation is conducted for any samples that fail the screening step. Compliance evaluation uses the radionuclide-specific measurements to first determine (1) if the dose exceeds the background dose and if so, (2) the dose consequences, so that the appropriate investigation or action occurs. The compliance evaluation is applied to all environmental samples throughout the year and on an annual basis to determine regulatory compliance. The methodology is implemented in a cloud-based software application that is also made accessible to the regulator. The benefits of the methodology over the existing system are presented.
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http://dx.doi.org/10.1097/HP.0000000000001116DOI Listing
January 2020

Unravelling the Skin Secretion Peptides of the Gliding Leaf Frog, (Hylidae).

Biomolecules 2019 10 30;9(11). Epub 2019 Oct 30.

Natural Drug Discovery Group, School of Pharmacy, Queen's University, Belfast 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.

Frog skin secretions contain medically-valuable molecules, which are useful for the discovery of new biopharmaceuticals. The peptide profile of the skin secretion of has not been investigated; therefore, the structural and biological characterization of its compounds signify an inestimable opportunity to acquire new biologically-active chemical scaffolds. In this work, skin secretion from this amphibian was analysed by molecular cloning and tandem mass spectrometry. Although the extent of this work was not exhaustive, eleven skin secretion peptides belonging to five peptide families were identified. Among these, we report the occurrence of two phyllokinins, and one medusin-SP which were previously reported in other related species. In addition, eight novel peptides were identified, including four dermaseptins, DRS-SP2 to DRS-SP5, one phylloseptin-SP1, and three orphan peptides. Phylloseptin-SP1 and dermaseptins-SP2 were identified in HPLC fractions based on their molecular masses determined by MALDI-TOF MS. Among the antimicrobial peptides, dermaseptin-SP2 was the most potent, inhibiting , and ORSA with a minimum inhibitory concentration (MIC) of 2.68 μM, and with an MIC of 10.71 μM, without haemolytic effects. The peptides described in this study represent but a superficial glance at the considerable structural diversity of bioactive peptides produced in the skin secretion of .
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http://dx.doi.org/10.3390/biom9110667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920962PMC
October 2019
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