Benedek G et al. (2020) PLoS Negl Trop Dis "Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove."

Benedek G, Edvardson S, Alon SA, Galun E, Lako R, Rivkin M, Riek LP, Ramadhan Lasu AA, Levite M, Miller K, Abed El Latif M

[PLoS Negl Trop Dis, 2020]

Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an 'Autoimmune Epilepsy' since: 1. ~50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently-published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B-peptide autoimmune-antibodies that bind, induce Reactive-Oxygen-Species, and kill both neural cells and T cells. Furthermore, NS patient's IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not.

Matencio A et al. (2020) Int J Pharm "Lifespan extension in caenorhabditis elegans by oxyresveratrol supplementation in hyper-branched cyclodextrin-based nanosponges."

Cecone C, Caldera F, Matencio A, Manuel Lopez-Nicolas J, Trotta F, Alejandra Guerrero-Rubio M, Garcia-Carmona F

[Int J Pharm, 2020]

In this work, the increase of the Caenorhabditis elegans (C.elegans) lifespan extension using hyper-branched cyclodextrin-based nanosponges (CD-NS) complexing oxyresveratrol (OXY), and the possible inhibition of C.elegans phosphodiesterase type 4 (PDE4) were evaluated. The titration displacement of fluorescein was used to calculate the apparent complexation constant (K_F) between CD-NS and OXY. Moreover, PDE4 was expressed in E.coli, purified and refolded in presence of cyclodextrins (CDs) to study its possible inhibition as pharmacological target of OXY. The apparent activity was characterized and the inhibitory effect of OXY on PDE4 displayed a competitive in vitro inhibition corroborated in silico. A maximum increase of the in vivo life expectancy of about 9.6% of using OXY/CD-NS complexes in comparison with the control was obtained, in contrast to the 6.5 % obtained with free OXY. No effect on lifespan or toxicity with CD-NS alone was found. These results as a whole represent new opportunities to use OXY and CD-NS in lifespan products.

Lagoro DK et al. (2017) Pan Afr Med J "Nodding syndrome (NS) and Onchocerca Volvulus (OV) in Northern Uganda."

Arony DA, Lagoro DK

[Pan Afr Med J, 2017]

Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction, wasting and stunted growth. There are recent published information suggesting associations between Nodding Syndrome (NS) with cerebrospinal fluid (CSF) VGKC antibodies and serum leiomidin-1 antibody cross reacting with Onchocerca Volvulus (OV). These findings suggest a neuro-inflammatory cause of NS and they are important findings in the search for the cause of Nodding Syndrome. These observations perhaps provide further, the unique explanation for the association between Nodding Syndrome and Onchocerca Volvulus. Many clinical and epidemiological studies had shown a significant correlation between NS and infestation with a nematode, Onchocerca volvulus which causes a disease, Onchocerciasis, some of which when left untreated can develop visual defect ("River Blindness"). While these studies conducted in Northern Uganda and Southern Sudan indicate a statistically significant association with (OV infection (using positive skin snips), we observe that (OV is generally endemic in many parts of Sub Saharan Africa and Latin America and that to date, no NS cases have been recorded in those regions. This letter to the Editor is to provide additional information on the current view about the relationship between Nodding Syndrome and Onchocerca Volvulus as seen in Northern Uganda.

Campion R et al. (2023) Int J Pharm "Zein-based nanospheres and nanocapsules for the encapsulation and oral delivery of quercetin."

Irache JM, Campion R, Cristina Martinez-Oharriz M, Luisa Martnez Lopez A, Collantes M, Gonzalez-Navarro CJ, Saiz-Abajo MJ, Matias C, Penuelas I

[Int J Pharm, 2023]

In this study, the ability of zein nanospheres (NS) and zein nanocapsules containing wheat germ oil (NC) to enhance the bioavailability and efficacy of quercetin was evaluated. Both types of nanocarriers had similar physico-chemical properties, including size (between 230 and 250 nm), spherical shape, negative zeta potential, and surface hydrophobicity. However, NS displayed a higher ability than NC to interact with the intestinal epithelium, as evidenced by an oral biodistribution study in rats. Moreover, both types of nanocarriers offered similar loading efficiencies and release profiles in simulated fluids. In C. elegans, the encapsulation of quercetin in nanospheres (Q-NS) was found to be two twice more effective than the free form of quercetin in reducing lipid accumulation. For nanocapsules, the presence of wheat germ oil significantly increased the storage of lipids in C. elegans; although the incorporation of quercetin (Q-NC) significantly counteracted the presence of the oil. Finally, nanoparticles improved the oral absorption of quercetin in Wistar rats, offering a relative oral bioavailability of 26% and 57% for Q-NS and Q-NC, respectively, compared to a 5% for the control formulation. Overall, the study suggests that zein nanocarriers, particularly nanospheres, could be useful in improving the bioavailability and efficacy of quercetin.

Aleshin VV et al. (1998) FEBS Lett "Secondary structure of some elements of 18S rRNA suggests that strongylid and a part of rhabditid nematodes are monophyletic."

Aleshin VV, Kedrova OS, Petrov NB, Milyutina IA, Vladychenskaya NS

[FEBS Lett, 1998]

Analysis of the secondary structure of 18S rRNA molecules in nematodes revealed some new traits in the secondary structure peculiar to their hairpin 17. Some of them are characteristic of all the nematodes, whereas others are characteristic exclusively of the order Rhabditida. The loss of a nucleotide pair in the highly conservative region of hairpin 17 distinguishes 18S rRNA of the Strongylida and some species of the Rhabditida from other nematodes and, moreover, from all other organisms. Hence, it is possible to regard the Strongylida and a part of the Rhabditida including Caenorhabditis elegans as a new monophyletic taxon.

Rao GN et al. (2008) Opt Express "In vivo nanosecond laser axotomy: cavitation dynamics and vesicle transport."

Kulkarni SS, Rao GN, Rau KR, Koushika SP

[Opt Express, 2008]

Nanosecond laser pulses (lambda = 355 nm) were used to cut mechanosensory neurons in Caenorhabditis elegans and motorneurons in Drosophila melanogaster larvae. A pulse energy range of 0.8-1.2 microJ and < 20 pulses in single shot mode were sufficient to generate axonal cuts. Viability post-surgery was >95% for C. elegans and 60% for Drosophila. Cavitation bubble dynamics generated due to laser-induced plasma formation were observed in vivo by time-resolved imaging in both organisms. Bubble oscillations were severely damped in vivo and cavitation dynamics were complete within 100 ns in C. elegans and 800 ns in Drosophila. We report the use of this system to study axonal transport for the first time and discuss advantages of nanosecond lasers compared to femtosecond sources for such procedures.

Schollen E et al. (2003) Eur J Hum Genet "PTPN11 mutation in a large family with Noonan syndrome and dizygous twinning."

Matthijs G, Gewillig M, Schollen E, Legius E, Fryns JP

[Eur J Hum Genet, 2003]

Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans.European Journal of Human Genetics (2002) 11, 85-88. doi:10.1038/sj.ejhg.5200915

Eijkelkamp BA et al. (2013) Infect Immun "H-NS plays a role in expression of Acinetobacter baumannii virulence features."

Brown MH, Eijkelkamp BA, Elbourne LD, Stroeher UH, Hassan KA, Paulsen IT

[Infect Immun, 2013]

Acinetobacter baumannii has become a major problem in the clinical setting with the prevalence of infections caused by multidrug-resistant strains on the increase. Nevertheless, only a limited number of molecular mechanisms involved in the success of A. baumannii as a human pathogen have been described. In this study, we examined the virulence features of a hypermotile derivative of A. baumannii strain ATCC 17978, which was found to display enhanced adherence to human pneumocytes and elevated levels of lethality toward Caenorhabditis elegans nematodes. Analysis of cellular lipids revealed modifications to the fatty acid composition, providing a possible explanation for the observed changes in hydrophobicity and subsequent alteration in adherence and motility. Comparison of the genome sequences of the hypermotile variant and parental strain revealed that an insertion sequence had disrupted an hns-like gene in the variant. This gene encodes a homologue of the histone-like nucleoid structuring (H-NS) protein, a known global transcriptional repressor. Transcriptome analysis identified the global effects of this mutation on gene expression, with major changes seen in the autotransporter Ata, a type VI secretion system, and a type I pilus cluster. Interestingly, isolation and analysis of a second independent hypermotile ATCC 17978 variant revealed a mutation to a residue within the DNA binding region of H-NS. Taken together, these mutants indicate that the phenotypic and transcriptomic differences seen are due to loss of regulatory control effected by H-NS.

Sangaletti R et al. (2014) Am J Physiol Cell Physiol "Mechanosensitive unpaired innexin channels in C. elegans touch neurons."

Sangaletti R, Bianchi L, Dahl G

[Am J Physiol Cell Physiol, 2014]

Invertebrate innexin proteins share sequence homology with vertebrate pannexins and general membrane topology with both pannexins and connexins. While connexins form gap junctions that mediate intercellular communication, pannexins are thought to function exclusively as plasma membrane channels permeable to both ions and small molecules. Undoubtedly, certain innexins function as gap junction proteins. However, due to sequence similarity to pannexins, it was postulated that innexins also function as plasma membrane channels. Indeed, some of the leech innexins were found to mediate ATP release as unpaired membrane channels with shared pharmacology to pannexin channels. We show here that Caenorhabditis elegans touch-sensing neurons express a mechanically gated innexin channel with a conductance of 1 nS and voltage-dependent and K(+)-selective subconductance state. We also show that C. elegans touch neurons take up ethidium bromide through a mechanism that is activated and blocked by innexin activating stimuli and inhibitors, respectively. Finally, we present evidence that touch neurons' innexins are required for cell death induced by chemical ischemia. Our work demonstrates that innexins function as plasma membrane channels in native C. elegans neurons, where they may play a role in pathological cell death.

Miller KG et al. (1999) Neuron "Goalpha and diacylglycerol kinase negatively regulate the Gqalpha pathway in C. elegans."

Emerson MD, Rand JB, Miller KG

[Neuron, 1999]

We investigated the EGL-30 (Gqalpha) pathway in C. elegans by using genetic screens to identify genes that confer phenotypes similar to egl-30 mutants. One such gene, egl-8, encodes a phospholipase Cbeta that is present throughout the nervous system and near intestinal cell junctions. EGL-30 and EGL-8 appear to positively regulate synaptic transmission because reducing their function results in strong aldicarb resistance and slow locomotion rates. In contrast, GOA-1 (Goalpha) and DGK-1 (diacylglycerol kinase) appear to negatively regulate synaptic transmission, because reducing their function results in strong aldicarb hypersensitivity and hyperactive locomotion. A genetic analysis suggests that GOA-1 negatively regulates the EGL-30 pathway and that DGK-1 antagonizes the EGL-30 pathway.AD - Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, Oklahoma City 73104, USA.FAU - Miller, K GAU - Miller KGFAU - Emerson, M DAU - Emerson MDFAU - Rand, J BAU - Rand JBLA - engSI - GENBANK/AF179426ID - NS33187/NS/NINDSPT - Journal ArticleCY - UNITED STATESTA - NeuronJID - 8809320RN - 0 (Helminth Proteins)RN - 0 (Isoenzymes)RN - 0 (guanine nucleotide-binding protein Go)RN - EC 2.7.1.107 (Diacylglycerol Kinase)RN - EC 3.1.4.- (phospholipase C beta)RN - EC 3.1.4.3 (Phospholipase C)RN - EC 3.6.1.- (Heterotrimeric GTP-Binding Proteins)SB - IM