Consultative engagement of stakeholders toward a roadmap for African language technologies.

There has been a rise in natural language processing (NLP) communities across the African continent (Masakhane, AfricaNLP workshops). With this momentum noted, and given the existing power asymmetries that plague the African continent, there is an urgent need to ensure that these technologies move toward shared goals between organizations and stakeholders, not only to improve the representation of African languages in cutting-edge NLP research but also to ensure that NLP research enables technological advances toward human dignity, well-being, and equity for those who speak African languages. This study investigates the motivations, focus, and challenges faced by various stakeholders who are at the core of the NLP process. We perform structured stakeholder identification to identify core stakeholders in the NLP process. Interviews with representatives of these stakeholder groups are performed and are collated into relevant themes. Finally, a set of recommendations are proposed for use by policy and artificial intelligence (AI) researchers.

A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report.

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant inherited disease characterized by age-related cerebellar degeneration and ataxia caused by mutations in the Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) gene. The ELOVL4 enzyme catalyzes the biosynthesis of both very long chain saturated fatty acids (VLC-SFA) and very long chain polyunsaturated fatty acids (VLC-PUFA) that are important for neuronal, reproductive, and skin function. Several variants in ELOVL4 have been shown to cause different tissue-specific disorders including SCA34 with or without Erythrokeratodermia Variabilis (EKV), a skin condition characterized by dry, scaly skin, Autosomal Dominant Stargardt-Like Macular Dystrophy (STGD3), and seizures associated with neuro-ichthyotic disorders. What is puzzling is how different mutations in the same gene seem to cause different tissue-specific disorders. To date, no SCA34 patients have presented with both SCA34 and STGD3 pathology that is caused by ELOVL4 variants that cause truncation of ELOVL4. Here, we report a novel case of an early childhood onset and rapidly progressive cerebellar degeneration and retinal dysfunction in a Belgian-Italian girl who developed severe dysarthria and gait problems starting at about 3.5 years of age and progressed to immobility by 4.5 years of age. Brain magnetic resonance imaging (MRI) revealed progressive vermian, cerebellar, cortical atrophy, progressive corpus callosum slimming, and hot cross bun sign visible on the MRI. Ophthalmological examinations also revealed progressive macular dysfunction as measured by electroretinography. Using exome sequencing, we identified a novel heterozygous ELOVL4 variant, c.503 T > C (p. L168S) in the patient. To understand the enzymatic function of this novel ELOVL4 variant and how it alters the levels of VLC-PUFA and VLC-SFA biosynthesis to contribute to cerebellar and retinal dysfunction, we expressed wild-type ELOVL4 or the L168S ELOVL4 variant in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. We showed that the L168S ELOVL4 variant is deficient in the biosynthesis of VLC-SFA and VLC-PUFA. Our work suggests that differential depletion of these fatty acids may be a contributing factor to the pathogenic mechanism of SCA34 with or without EKV. Further studies will help further define how the different ELOVL4 variants cause different tissue-specific disorders with variable ages of onset.

The Aqueous Stem Bark Extract of Alstonia boonei Exhibits Anticataract Activity in Sprague Dawley Rat.

In Africa, Alstonia boonei is used folklorically for the management of the multitude of conditions including cataract, which accounts for 50% of cases of blindness in the region. The current study set out to probe the traditional use of the aqueous extract of Alstonia boonei stem bark (ABE) as an anticataract remedy using Sprague Dawley rat models. We investigated the probable phytochemical constituents in the extract, in vitro antioxidant potential, and its in vitro aldose reductase inhibition. For the anticataract investigations, diabetic cataract was induced using galactose in 3-week-old Sprague Dawley rats, and age-related cataract was induced by the administration of sodium selenite to 10-day-old rat pups. Cataract scores in both models were determined after treatment with 30, 100, and 300 mgkg-1 doses of ABE and 10 mlkg-1 of distilled water. Lens glutathione, total lens protein, soluble lens proteins (alpha-A) crystallin, and aquaporin 0 levels in the enucleated lens homogenates were determined. Changes in lens to body weight were also determined with histopathological analysis done on the lenses in the selenite-induced cataract model. The presence of alkaloids, tannins, flavonoids, glycosides, and triterpenoids was identified in the extract. The extract inhibited aldose reductase activity with IC50 of 92.30 µgml-1. The 30, 100, and 300 mgkg-1ABE-treated rats recorded significantly (p < 0.05) reduced cataract scores indicating a delay in cataractogenesis in galactose-induced cataract and in selenite-induced cataractogenesis as well. Markers of lens transparency such as AQP0, alpha-A crystallin, and total lens proteins and lens glutathione levels were significantly (p < 0.05) preserved. In conclusion, this study establishes the anticataract potential of the aqueous stem bark extract of Alstonia boonei in Sprague Dawley rat models.

Anticataract Effect of the Aqueous Extract of the Flowers of Aspilia africana in Murine Model of Diabetic and Age-Related Cataracts.

Background: The use of Aspilia africana in traditional medicine for the management of ocular diseases has been reported in India and some indigenous communities of Africa. The aim of this study was to investigate the aqueous extract of the flowers of A. africana (AAE) as an anticataract remedy using murine models of diabetic and senile cataracts. Methods: Preliminary phytochemical screening of the extract, in vitro antioxidant assays, and in vitro aldose reductase inhibitory activity were performed. For anticataract investigations of the extracts, diabetic cataract was induced by galactose administration in 3-week-old Sprague Dawley rats. The evaluation of experimentally induced age-related cataract was performed by administering sodium selenite to 10-day-old rat pups. Results: The phytochemical analysis revealed the presence of alkaloids, tannins, flavonoids, glycosides, and saponins. In vitro aldose reductase inhibitory property of the extract on rat lenses revealed that the AAE inhibited the enzyme activity with IC50 of 12.12 µg/ml. For the anticataract investigations, 30, 100, and 300 mg·kg-1AAE-treated rats recorded significantly low (p ≤ 0.0001) cataract scores compared to the negative control rats, indicating a delay in cataractogenesis from the second week of treatment in the galactose-induced cataractogenesis. Similarly, the treatment with AAE caused a significant reduction (p ≤ 0.0001) in cataract scores compared to the negative control rats in the selenite-induced cataractogenesis. Markers of lens transparency, such as aquaporin 0, alpha-A crystallin, and total lens proteins and lens glutathione levels, were significantly preserved (p ≤ 0.05-0.0001) in each cataract model after AAE treatment. Conclusion: The study established the anticataract potential of the aqueous extract of flowers of A. africana in murine models, hence giving scientific credence to its folkloric use in the management of cataract.

Acetic acid-induced colitis modulating potential of total crude alkaloidal extract of Picralima nitida seeds in rats.

PURPOSE: The total crude alkaloidal extract of Picralima nitida seeds (PNE) is known to possess anti-inflammatory activity among other therapeutic benefits although its benefits in colitis has not been investigated. The current study therefore seeks to investigate the anti-colitis potential of PNE using acetic acid-induced colitis model in rats. METHODS: Sprague Dawley rats were treated with oral 500 mg/kg sulphasalazine or 30, 100, and 300 mg/kg of PNE daily for 8 days with induction of colitis on the fourth day with acetic acid. Rats were killed 24 h after the last treatment and whole blood was obtained from the jugular vein for hematological analysis and biochemical assays. Colons were extirpated for assessment of macroscopic and histological damage to the colon. RESULTS: Treatment with PNE protected against colonic injury induced with acetic acid by decreasing mucosal ulceration, epithelial erosion, inflammatory cell infiltration, and colonic edema. Thus, PNE preserved mucosal architecture and suppressed goblet cells depletion. Moreover, treatment with PNE was associated with improved hematological parameters and reductions in the expression of serum tumor necrosis factor-alpha, interleukin-1ß, and p38 mitogen-activated protein kinase. Also, PNE treatment exerted antioxidant effects by reducing nitric oxide production and increasing glutathione levels. In addition, PNE inhibited colonic lipid peroxidation by decreasing myeloperoxidase activity and malondialdehyde production. CONCLUSION: It can be concluded that PNE attenuates intestinal oxidative and inflammatory damages following intrarectal acetic acid challenge. Thus, demonstrates potential for use in chronic intestinal inflammatory diseases such as ulcerative colitis.

ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis.

The FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3), other ELOVL4 point mutations, such as L168F and W246G, affect the brain and/or skin, leading to Spinocerebellar Ataxia-34 (SCA34) and Erythrokeratodermia variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the different tissue-specific pathologies are not well understood. To understand how these mutations alter VLC-PUFA and VLC-SFA biosynthesis, we expressed WT-ELOVL4, L168F, and W246G ELOVL4 variants in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. Total lipids were extracted, converted to FA methyl esters, and quantified by gas chromatography. We showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells. However, compared with WT-ELOVL4, both L168F and W246G mutants were deficient in VLC-SFA biosynthesis, especially the W246G protein, which showed negligible VLC-SFA biosynthesis. These results suggest VLC-PUFA biosynthetic capabilities of L168F and W246G in the retina, which may explain the lack of retinal phenotype in SCA34. Defects in VLC-SFA biosynthesis by these variants may be a contributing factor to the pathogenic mechanism of SCA34 and Erythrokeratodermia variabilis.

Inflammation Modulating Activity of the Hydroethanol Stem Bark Extract of Bombax costatum in Murine Models.

Bombax costatum (Bombacaceae) is traditionally used as a decoction of the leaves, stem, and root to treat headaches, fever, and oedema that may be associated with inflammatory conditions. Thus, the aim of this study was to evaluate the effect of 70%v/v ethanolic extract of the stem bark of Bombax costatum on acute and chronic inflammation. The effect of Bombax costatum extract (10, 50, 100 mg kg-1, p.o) was studied in prostaglandin E2-induced paw oedema in Sprague-Dawley rats (n = 5). Subsequently, the effect of the extract on clonidine and haloperidol-induced catalepsy was also investigated in ICR mice (n = 5). Finally, the ability of the extract to inhibit chronic inflammation was studied using a rat adjuvant-induced arthritis model. Pre-emptive and therapeutic administration of the extract at all doses significantly suppressed the formation of oedema following prostaglandin E 2 administration. As a measure of indirect antihistaminic effect, treatment with the extract suppressed clonidine-induced catalepsy but not haloperidol-induced catalepsy. Moreover, Bombax costatum extract significantly inhibited joint inflammation and damage following injection of complete Freund's adjuvant. Treatment with the extract also inhibited the onset of polyarthritis; thus, suppressing the systemic spread of joint inflammation from ipsilateral limbs to contralateral limbs. In conclusion, the hydroethanol extract of the stem bark of Bombax costatum inhibits both acute and chronic inflammation.

A STING-based fluorescent polarization assay for monitoring activities of cyclic dinucleotide metabolizing enzymes.

Cyclic dinucleoties, such as cGAMP, c-di-GMP and c-di-AMP, are fascinating second messengers with diverse roles in both prokaryotes and eukaryotes. Consequently there is a need for simple and inexpensive methods for profiling these compounds in biological media, monitoring their synthesis or degradation by enzymes and for identifying inhibitors of proteins that metabolize or bind to these dinucleotides. Since 2011, when we reported the first simple method to detect c-di-GMP (S. Nakayama, I. Kelsey, J. Wang, K. Roelofs, B. Stefane, Y. Luo, V. T. Lee and H. O. Sintim, J. Am. Chem. Soc., 2011, 133, 4856) or in 2014 when we revealed another surprisingly simple assay to detect c-di-AMP (J. Zhou, D. A. Sayre, Y. Zheng, H. Szmacinski and H. O. Sintim, Anal. Chem., 2014, 86, 2412), there have been efforts to develop assays to detect cyclic dinucleotides by others. However a unified and simple assay, which can be used for all cyclic dinucleotides is lacking. Here, we investigate STING binding by various fluorescein-labeled c-di-GMP, c-di-AMP and cGAMP, using fluorescent polarization (FP). Fluorescein-labeled c-di-GMP (F-c-di-GMP) was found to be the best binder of STING. This probe could be displaced by unlabeled cGAMP, c-di-AMP or c-di-GMP and hence it is a universal probe, which can be used to monitor all three dinucleotides. HPLC analysis was used to validate the new F-c-di-GMP-based FP assay.

Bacterial Cyclic Dinucleotides and the cGAS-cGAMP-STING Pathway: A Role in Periodontitis?

Host cells can recognize cytosolic double-stranded DNAs and endogenous second messengers as cyclic dinucleotides-including c-di-GMP, c-di-AMP, and cGAMP-of invading microbes via the critical and essential innate immune signaling adaptor molecule known as STING. This recognition activates the innate immune system and leads to the production of Type I interferons and proinflammatory cytokines. In this review, we (1) focus on the possible role of bacterial cyclic dinucleotides and the STING/TBK1/IRF3 pathway in the pathogenesis of periodontal disease and the regulation of periodontal immune response, and (2) review and discuss activators and inhibitors of the STING pathway as immune response regulators and their potential utility in the treatment of periodontitis. PubMed/Medline, Scopus, and Web of Science were searched with the terms "STING", "TBK 1", "IRF3", and "cGAS"-alone, or together with "periodontitis". Current studies produced evidence for using STING-pathway-targeting molecules as part of anticancer therapy, and as vaccine adjuvants against microbial infections; however, the role of the STING/TBK1/IRF3 pathway in periodontal disease pathogenesis is still undiscovered. Understanding the stimulation of the innate immune response by cyclic dinucleotides opens a new approach to host modulation therapies in periodontology.

Identification of a Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase Inhibitor.

Immune cells sense bacteria-derived c-di-GMP and c-di-AMP as well as host-derived cGAMP, which is synthesized by cGAS upon binding to the pathogen's DNA, to mount an immunological response (cytokine production) via the STING-TBK1 pathway. Successful pathogens, such as Mycobacterium tuberculosis and group B streptococcus, harbor phosphodiesterases (PDEs) that can cleave bacterial c-di-AMP as well as host-derived cGAMP to blunt the host's response to infection. Selective inhibitors of bacterial cyclic dinucleotide (CDN) PDEs are needed as tool compounds to study the role(s) of CDN PDEs during infection and they could also become bona fide antivirulence compounds, but there is a paucity of such compounds. Using a high-throughput assay, we identified six inhibitors of MTB CDN PDE (CdnP). The most potent inhibitor, C82 with an IC50 of ∼18 µM, did not inhibit the enzymatic activities of three other bacterial CDN PDEs (Yybt, RocR, and GBS-CdnP), a viral CDN PDE (poxin) or mammalian ENPP1.