Actions of Novel Hybrid Peptides on Hyperglycaemia and Immunomodulation in Experimental Diabetes

Type 2 diabetes (T2D) represents one of the major disease challenges worldwide, with epidemic proportions of more than 400 million affected across the globe. Therapeutic agents for disease management are often met by challenges such as the inability to restore long-term glucose homeostasis; highlighting the need for novel agents with increased potency or better therapeutic efficacy. The discovery of exendin-4, a compound isolated from venom of the Gila monster lizard (Heloderma suspectum) and developed into a potent anti-diabetic drug, further motivated interests in the search animal sources for novel therapeutic agents. Over the last decade, much attention has been drawn towards amphibian skin peptides, which have uncovered their previously unexplored anti-diabetic actions. Among many other peptides, tigerinin-1R (isolated from Hoplobatracus rugulosus) and magainin-AM2 (isolated from Xenopus amieti) have been extensively characterised for their anti-diabetic actions both in vitro and in vivo, showing promise for further investigations. In the context of T2D, a recently explored approach yielding pre-clinical success is based on the creation of hybrid peptides with established anti-diabetic components into a single molecular entity. The rationale for this concept is the generation of hybrids presenting features of their individual components, while introducing additional beneficial effects. This study characterised the in vitro potential of novel hybrid peptides, designed by combining established anti-diabetic agents, exendin-4 and d-Ala2-GIP, with the amphibian peptides tigerinin-1R and magainin-AM2. After assessing their insulinotropic actions in the clonal pancreatic cells, BRIN-BD11, and in isolated primary islets, specific modulators of insulin secretion were employed to elucidate the mechanism of action of the peptides. This screening revealed that combining magainin-AM2 with exendin-4 produced the best augmented and non-toxic actions on insulin secretion from BRIN-BD11 cells and isolated islets through the activation of the ATP-dependent pathway of insulin secretion. Metabolomic analysis under hyperglycaemic conditions, using 1H-NMR and GC-MS, along with gene expression studies further highlighted the anti-diabetic actions of these peptides. A reduction in lipid abundance as well as an increase in glucose metabolism were observed. Gene expression studies revealed increase in the genes encoding for insulin and beta-cell proliferation, further expanding on the anti-diabetic potential of these compounds. Finally, by considering the inflammatory component associated with T2D, characterisation of the peptides’ actions on bone-marrow derived dendritic cells (BM-DCs) revealed, for the first time in this model, reduction of perpetuating inflammatory signals, in favour of an anti-inflammatory environment. Taken together, these studies revealed that combining the selected amphibian skin peptides with exendin-4 significantly enhanced the therapeutic promise of these peptides and encourage further analysis of their in vivo actions as well as further development into a clinically available therapy for type 2 diabetes

Essential Amino Acid Quality Profile in Neglected and Underutilized Legumes (NULs)

A large number of consumers use plant-based products instead of animal-based products for their nourishment. This calls for a thorough investigation of the capacity of NULs to supply nutrients such as amino acids. Five different NULs protein extracts were profiled to ascertain the presence of the essential amino acids. In order to evaluate the quality, the essential amino acids from each of the NULs were matched against the standard FAO/WHO dietary indispensable amino acids for infants, children and adults. It was found that two of the NULs; Vigna sp. and Phaseolus sp. were the most promising, out of the five studied. Vigna sp. could supply adequate quantities of histidine (26.2 mg/g) for all the three age groups. However, isoleucine (35.9 mg/g) and the aromatic amino acid (phenylalanine + tyrosine) (94 mg/g) can supply adequate quantities for only children and adults. Lysine (53.6 mg/g) and threonine (44 mg/g) on the other hand, could be adequately supplied by Phaseolus sp. for at least, the adults’ requirement. If the digestibilities of the two NULs proteins were evaluated to ascertain the levels of the post-prandial amino acids, and the two NULs were complimented with cereals, the NULs flour could eventually supply the essential amino acids for consumers who use them as food. Keywords: Essential amino acids, Quality, Neglected legumes

What it takes to make it: profile and characteristics of DIY bio laboratory founders

© 2021 The Author(s). As important antecedents of the emerging DIY laboratory movement, the aspects of profiles and characteristics of those pioneers who establish DIY laboratories have remained under-researched in extant literature. In order to address this issue and explore common profiles and characteristics of DIY laboratory founders, by employing content analysis, this paper analyses secondary data on 23 founders/co-founders of eight DIY bio laboratories that are publicly available (DIYbio.org). The results reveal that a common profile of a DIY bio laboratory founder is someone most likely to be highly educated (often times PhD), with experience and expertise in the field of science and has strong ideological beliefs. Additionally, the founders/co-founders have characteristics of entrepreneurship, research, ideology and community that strongly advocate for open source sharing of scientific information and for the democratisation of science

Dietary acrylamide-linked burden of cancers in four sub-sahara African countries:A review and data synthesis

Acrylamide (AA) is a food processing byproduct that forms at high temperatures and is classified as a probable human carcinogen. Previous studies have linked AA to kidney, uterus, and ovary cancer burdens, but its study in African countries remains underexplored. This study systematically used six recent articles on dietary AA concentration data from scholarly databases using specific search terms. We also collected health metrics secondary data from the Institute of Health Metrics and Evaluation and other sources for the period 2015-2019. We used a Monte-Carlo simulation to integrate the dietary AA exposure, risks, and health metrics to estimate the cancer burdens. The results showed that the modal healthy life years lost ranged from 0.00488 (Ghana) to 0.218 (Ethiopia) per 100,000 population. The median statistic indicated 1.2 and 26.10 healthy life years lost for Ghana and Ethiopia, respectively, due to the three cancer types. The four-country study areas' total disability-adjusted life years (DALYs) were 63.7 healthy life-year losses. Despite the limitations of the non-standardized age-related food consumption data and the few inclusive articles, the probabilistic approach may account for the uncertainties and provide valid conclusions

Dietary acrylamide-linked burden of cancers in four sub-sahara African countries:A review and data synthesis

Acrylamide (AA) is a food processing byproduct that forms at high temperatures and is classified as a probable human carcinogen. Previous studies have linked AA to kidney, uterus, and ovary cancer burdens, but its study in African countries remains underexplored. This study systematically used six recent articles on dietary AA concentration data from scholarly databases using specific search terms. We also collected health metrics secondary data from the Institute of Health Metrics and Evaluation and other sources for the period 2015-2019. We used a Monte-Carlo simulation to integrate the dietary AA exposure, risks, and health metrics to estimate the cancer burdens. The results showed that the modal healthy life years lost ranged from 0.00488 (Ghana) to 0.218 (Ethiopia) per 100,000 population. The median statistic indicated 1.2 and 26.10 healthy life years lost for Ghana and Ethiopia, respectively, due to the three cancer types. The four-country study areas' total disability-adjusted life years (DALYs) were 63.7 healthy life-year losses. Despite the limitations of the non-standardized age-related food consumption data and the few inclusive articles, the probabilistic approach may account for the uncertainties and provide valid conclusions

Trends and risk factors associated with stillbirths: a case study of the Navrongo War Memorial Hospital in Northern Ghana

Maternal and Child health remains at the core of global health priorities transcending the Millennium Development Goals into the current era of Sustainable Development Goals. Most low and middle-income countries including Ghana are yet to achieve the required levels of reduction in child and maternal mortality. This paper analysed the trends and the associated risk factors of stillbirths in a district hospital located in an impoverished and remote region of Ghana.; Retrospective hospital maternal records on all deliveries conducted in the Navrongo War Memorial hospital from 2003-2013 were retrieved and analysed. Descriptive and inferential statistics were used to summarise trends in stillbirths while the generalized linear estimation logistic regression is used to determine socio-demographic, maternal and neonatal factors associated with stillbirths.; A total of 16,670 deliveries were analysed over the study period. Stillbirth rate was 3.4% of all births. There was an overall decline in stillbirth rate over the study period as stillbirths declined from 4.2% in 2003 to 2.1% in 2013. Female neonates were less likely to be stillborn (Adjusted Odds ratio = 0.62 and 95%CI [0.46, 0.84]; p = 0.002) compared to male neonates; neonates with low birth weight (4.02 [2.92, 5.53]) and extreme low birth weight (18.9 [10.9, 32.4]) were at a higher risk of still birth (p<0.001). Mothers who had undergone Female Genital Mutilation had 47% (1.47 [1.04, 2.09]) increase odds of having a stillbirth compared to non FGM mothers (p = 0.031). Mothers giving birth for the first time also had a 40% increase odds of having a stillbirth compared to those who had more than one previous births (p = 0.037).; Despite the modest reduction in stillbirth rates over the study period, it is evident from the results that stillbirth rate is still relatively high. Primiparous women and preterm deliveries leading to low birth weight are identified factors that result in increased stillbirths. Efforts aimed at impacting on stillbirths should include the elimination of outmoded cultural practices such as FGM

Presence and distribution of progerin in HGPS cells is ameliorated by drugs that impact on the mevalonate and mTOR pathways

© The Author(s) 2019. Hutchinson–Gilford progeria syndrome (HGPS) is a rare, premature ageing syndrome in children. HGPS is normally caused by a mutation in the LMNA gene, encoding nuclear lamin A. The classical mutation in HGPS leads to the production of a toxic truncated version of lamin A, progerin, which retains a farnesyl group. Farnesyltransferase inhibitors (FTI), pravastatin and zoledronic acid have been used in clinical trials to target the mevalonate pathway in HGPS patients to inhibit farnesylation of progerin, in order to reduce its toxicity. Some other compounds that have been suggested as treatments include rapamycin, IGF1 and N-acetyl cysteine (NAC). We have analysed the distribution of prelamin A, lamin A, lamin A/C, progerin, lamin B1 and B2 in nuclei of HGPS cells before and after treatments with these drugs, an FTI and a geranylgeranyltransferase inhi- bitor (GGTI) and FTI with pravastatin and zoledronic acid in combination. Confirming other studies pre- lamin A, lamin A, progerin and lamin B2 staining was different between control and HGPS fibroblasts. The drugs that reduced progerin staining were FTI, pravastatin, zoledronic acid and rapamycin. However, drugs affecting the mevalonate pathway increased prelamin A, with only FTI reducing internal prelamin A foci. The distribution of lamin A in HGPS cells was improved with treatments of FTI, pravastatin and FTI ? GGTI. All treatments reduced the number of cells displaying internal speckles of lamin A/C and lamin B2. Drugs targeting the mevalonate pathway worked best for progerin reduction, with zoledronic acid removing internal progerin speckles. Rapamycin and NAC, which impact on the MTOR pathway, both reduced both pools of progerin without increasing prelamin A in HGPS cell nuclei.SPARKS Children’s Medical Research projec

Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients.

Naturally acquired blood-stage infections of the malaria parasite Plasmodium falciparum typically harbour multiple haploid clones. The apparent number of clones observed in any single infection depends on the diversity of the polymorphic markers used for the analysis, and the relative abundance of rare clones, which frequently fail to be detected among PCR products derived from numerically dominant clones. However, minority clones are of clinical interest as they may harbour genes conferring drug resistance, leading to enhanced survival after treatment and the possibility of subsequent therapeutic failure. We deployed new generation sequencing to derive genome data for five non-propagated parasite isolates taken directly from 4 different patients treated for clinical malaria in a UK hospital. Analysis of depth of coverage and length of sequence intervals between paired reads identified both previously described and novel gene deletions and amplifications. Full-length sequence data was extracted for 6 loci considered to be under selection by antimalarial drugs, and both known and previously unknown amino acid substitutions were identified. Full mitochondrial genomes were extracted from the sequencing data for each isolate, and these are compared against a panel of polymorphic sites derived from published or unpublished but publicly available data. Finally, genome-wide analysis of clone multiplicity was performed, and the number of infecting parasite clones estimated for each isolate. Each patient harboured at least 3 clones of P. falciparum by this analysis, consistent with results obtained with conventional PCR analysis of polymorphic merozoite antigen loci. We conclude that genome sequencing of peripheral blood P. falciparum taken directly from malaria patients provides high quality data useful for drug resistance studies, genomic structural analyses and population genetics, and also robustly represents clonal multiplicity

Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

Objective:RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals\u27 proprietary Adjuvant Systems AS02A or AS01B. A recent trial of the RTS,S/AS02A and RTS,S/AS01B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02A and RTS,S/AS01B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.Design:The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.Setting:The study was conducted in Kombewa District, western Kenya.Participants:Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections.Outcome:Parasite isolates used for determining MOI and divergence of csp T cell&ndash;epitopes were 191 at baseline and 87 from break-through infections.Results:Grouping recipients of RTS,S/AS01A and RTS,S/AS02B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01B group, but not the RTS,S/AS02A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.Conclusions:It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct