Wu LF et al. (2002) Nat Genet "Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters."

Stoughton R, Altschuler SJ, Hughes TR, Davierwala AP, Robinson MD, Wu LF

[Nat Genet, 2002]

Genome sequencing has led to the discovery of tens of thousands of potential new genes. Six years after the sequencing of the well-studied yeast Saccharomyces cerevisiae and the discovery that its genome encodes approximately 6,000 predicted proteins, more than 2,000 have not yet been characterized experimentally, and determining their functions seems far from a trivial task. One crucial constraint is the generation of useful hypotheses about protein function. Using a new approach to interpret microarray data, we assign likely cellular functions with confidence values to these new yeast proteins. We perform extensive genome-wide validations of our predictions and offer visualization methods for exploration of the large numbers of functional predictions. We identify potential new members of many existing functional categories including 285 candidate proteins involved in transcription, processing and transport of non-coding RNA molecules. We present experimental validation confirming the involvement of several of these proteins in ribosomal RNA processing. Our methodology can be applied to a variety of genomics data types and organisms.

(2011) MMWR Morb Mortal Wkly Rep "Progress toward elimination of lymphatic filariasis--Togo, 2000--2009."

[MMWR Morb Mortal Wkly Rep, 2011]

Lymphatic filariasis (LF) is a disabling, mosquito-borne disease of humans caused by the parasitic filarial nematodes Wuchereria bancrofti, Brugia malayi, and Brugia timori. In 2000, the Global Program to Eliminate LF (GPELF) was established with the objective of eliminating LF as a public health problem by 2020. At that time, 80 countries had ongoing transmission, with an estimated 1.34 billion persons at risk for infection and 120 million infected. This report describes the LF elimination program in Togo, one of the 39 LF-endemic countries in the World Health Organization (WHO) African Region. Togo's approach to interrupt LF transmission included screening for infection to identify LF-endemic districts and mass drug administration (MDA) of ivermectin and albendazole in LF-endemic districts. MDA coverage and the impact of MDAs on the prevalence of infection were monitored throughout the program. In 2000, seven of 35 districts were LF-endemic, with baseline prevalence rates ranging from 1% to 22%. By 2009, MDAs had been conducted at least six times in each LF-endemic district. At that time, the decision was made to stop MDAs because reported drug coverage in LF-endemic districts exceeded 80% and no microfilaremia was detected in persons tested to monitor impact of MDAs. Togo is the first sub-Saharan country to have stopped MDAs after prevalence data suggested that LF transmission had been interrupted. Post-MDA surveillance is continuing nationally; the next step will be to certify elimination. The successful Togo program demonstrates that LF elimination can be achieved in countries with limited resources.

Chen B et al. (2007) Curr Biol "UNC-1 regulates gap junctions important to locomotion in C. elegans."

Ge Q, Chen B, Liu Q, Wang ZW, Xie J

[Curr Biol, 2007]

In C. elegans, loss-of-function (lf) mutations of the stomatin-like protein (SLP) UNC-1 and the innexin UNC-9 inhibit locomotion [1, 2] and modulate sensitivity to volatile anesthetics [3, 4]. It was unknown why unc-1(lf) and unc-9(lf) mutants have similar phenotypes. We tested the hypothesis that UNC-1 is a regulator of gap junctions formed by UNC-9. Analyses of junctional currents between body-wall muscle cells showed that electrical coupling was inhibited to a similar degree in unc-1(lf), unc-9(lf), and unc-1(lf);unc-9(lf) double mutants, suggesting that UNC-1 and UNC-9 function together. Expression of Punc-1::DsRED2 and Punc-9::GFP transcriptional fusions suggests that unc-1 and unc-9 are coexpressed in neurons and body-wall muscle cells. Immunohistochemistry showed that UNC-1 and UNC-9 colocalized at intercellular junctions and that unc-1(lf) did not alter UNC-9 expression or subcellular localization. Bimolecular fluorescence complementation (BiFC) assays suggest that UNC-1 and UNC-9 are physically very close at intercellular junctions. Targeted rescue experiments suggest that UNC-9 and UNC-1 function predominantly in neurons to control locomotion. Thus, in addition to the recently reported function of regulating mechanosensitive ion channels [5, 6], SLPs might have a novel function of regulating gap junctions.

Castillo-Quan JI et al. (2016) Cell "Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging."

Castillo-Quan JI, Blackwell TK

[Cell, 2016]

In this issue of Cell, Wu etal. employed C.elegans and human cell experiments to identify a pathway through which metformin increases lifespan and inhibits growth. A key transcriptional target, ACAD10, is activated when metformin induces nuclear exclusion of the GTPase RagC, thereby inhibiting mTORC1 through an unexpected mechanism.

Goncalves J et al. (2022) iScience "Stearoyl-CoA desaturases sustain cholinergic excitation and copulatory robustness in metabolically aging C.elegans males."

Goncalves J, Garcia LR, Wan Y

[iScience, 2022]

Regulated metabolism is required for behaviors as adults age. To understand how lipid usage affects motor coordination, we studied male Caenorhabditis elegans copulation as a model of energy-intensive behavior. Copulation performance drops after 48 h of adulthood. We found that 12-24 h before behavioral decline, males prioritize exploring and copulation behavior over feeding, suggesting that catabolizing stored metabolites, such as lipids, occurs during this period. Because fat-6/7-encoded stearoyl-CoA desaturases are essential for converting the ingested fatty acids to lipid storage, we examined the copulation behavior and neural calcium transients of fat-6(lf); fat-7(lf) mutants. In wild-type males, intestinal and epithelial fat-6/7 expression increases during the first 48 h of adulthood. The fat-6(lf); fat-7(lf) behavioral and metabolic defects indicate that in aging wild-type males, the increased expression of stearoyl-CoA desaturases in the epidermis may indirectly modulate the levels of EAG-family K+ channels in the reproductive cholinergic neurons and muscles.

Chen B et al. (2011) J Neurosci "Dystrobrevin controls neurotransmitter release and muscle Ca(2+) transients by localizing BK channels in Caenorhabditis elegans."

Liu P, Wang ZW, Zhan H, Chen B

[J Neurosci, 2011]

Dystrobrevin is a major component of a dystrophin-associated protein complex. It is widely expressed in mammalian tissues, including the nervous system, in which it is localized to the presynaptic nerve terminal with unknown function. In a genetic screen for suppressors of a lethargic phenotype caused by a gain-of-function isoform of SLO-1 in Caenorhabditis elegans, we isolated multiple loss-of-function (lf) mutants of the dystrobrevin gene dyb-1.dyb-1(lf) phenocopied slo-1(lf), causing increased neurotransmitter release at the neuromuscular junction, increased frequency of Ca(2+) transients in body-wall muscle, and abnormal locomotion behavior. Neuron- and muscle-specific rescue experiments suggest that DYB-1 is required for SLO-1 function in both neurons and muscle cells. DYB-1 colocalized with SLO-1 at presynaptic sites in neurons and dense body regions in muscle cells, and dyb-1(lf) caused SLO-1 mislocalization in both types of cells without altering SLO-1 protein level. The neuronal phenotypes of dyb-1(lf) were partially rescued by mouse -dystrobrevin-1. These observations revealed novel functions of the BK channel in regulating muscle Ca(2+) transients and of dystrobrevin in controlling neurotransmitter release and muscle Ca(2+) transients by localizing the BK channel.

Brissette B et al. (2019) Neuron "Insulin-like Peptides as Agents of Social Change."

Ringstad N, Brissette B

[Neuron, 2019]

Many behaviors promote reproduction or food finding. These critical functions of behavior can conflict; successful reproductive strategies can grow populations to the point where food is depleted. In this issue of Neuron, Wu etal. (2019) show how the nematode C.elegans detects crowding to change feeding behavior by coupling pheromone sensing to signaling via insulin-like peptides.

Liu Q et al. (2007) J Neurosci "Presynaptic Ca2+/calmodulin-dependent protein kinase II modulates neurotransmitter release by activating BK channels at Caenorhabditis elegans neuromuscular junction."

Chen B, Ge Q, Liu Q, Wang ZW

[J Neurosci, 2007]

Although Ca2+/calmodulin-dependent protein kinase II (CaMKII) is enriched at the presynaptic nerve terminal, its role in neurotransmitter release is poorly defined. We assessed the function of presynaptic CaMKII in neurotransmitter release and tested the hypothesis that BK channel is a mediator of presynaptic CaMKII function by analyzing miniature and evoked postsynaptic currents at the Caenorhabditis elegans neuromuscular junction. Both loss-of-function (lf) and gain-of-function (gf) of unc-43, the gene encoding CaMKII, inhibited neurotransmitter release. The inhibitory effect of unc-43(gf) was reversed by mutation or blockade of the BK channel SLO-1. SLO-1 expressed in Xenopus oocytes could be activated by recombinant rat alpha-CaMKII, and this effect of CaMKII was abolished by mutating a threonine residue (T425) at a consensus CaMKII phosphorylation site in the first RCK (regulator of conductance for K+) domain of the channel. Expression of slo-1(T425A) in neurons antagonized the inhibitory effect of unc-43(gf) on neurotransmitter release as slo-1(lf) did. The inhibitory effect of unc-43(gf) was not reversed by unc-103(lf), dgk-1(lf), or eat-16(lf), which reportedly suppress behavioral phenotypes of unc-43(gf). These observations suggest that presynaptic CaMKII is a bidirectional modulator of neurotransmitter release, presumably by phosphorylating different molecular targets, and that its negative modulatory effect on the release is mainly mediated by SLO-1 activation.

O'Hern PJ et al. (2017) Elife "Decreased microRNA levels lead to deleterious increases in neuronal M2 muscarinic receptors in Spinal Muscular Atrophy models."

Kye MJ, Brecht J, Lipscombe D, Hart AC, do Carmo G Goncalves I, Simon J, Chapkis N, O'Hern PJ, Lopez Soto EJ

[Elife, 2017]

Spinal Muscular Atrophy (SMA) is caused by diminished Survival of Motor Neuron (SMN) protein, leading to neuromuscular junction (NMJ) dysfunction and spinal motor neuron (MN) loss. Here, we report that reduced SMN function impacts the action of a pertinent microRNA and its mRNA target in MNs. Loss of the C. elegans SMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of the C. elegans Gemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function in smn-1(lf) animals. We determined that miR-2 regulates expression of the C. elegans M2 muscarinic receptor (m2R) ortholog, GAR-2. GAR-2 loss ameliorated smn-1(lf) and mel-46(lf) synaptic defects. In an SMA mouse model, m2R levels were increased and pharmacological inhibition of m2R rescued MN process defects. Collectively, these results suggest decreased SMN leads to defective microRNA function via MEL-46 misregulation, followed by increased m2R expression, and neuronal dysfunction in SMA.

Dolo H et al. (2019) PLoS Negl Trop Dis "Integrated seroprevalence-based assessment of Wuchereria bancrofti and Onchocerca volvulus in two lymphatic filariasis evaluation units of Mali with the SD Bioline Onchocerciasis/LF IgG4 Rapid Test."

Traore MO, Diallo AA, Dolo M, Diarra D, Dicko I, Zhang Y, Dolo H, Nutman TB, Coulibaly YI, Dembele B, Coulibaly SY, Coulibaly ME, Colebunders R, Dembele M, Soumaoro L, Doumbia SS, Goita S, Guindo B

[PLoS Negl Trop Dis, 2019]

BACKGROUND: Mali has become increasingly interested in the evaluation of transmission of both Wuchereria bancrofti and Onchocerca volvulus as prevalences of both infections move toward their respective elimination targets. The SD Bioline Onchocerciasis/LF IgG4 Rapid Test was used in 2 evaluation units (EU) to assess its performance as an integrated surveillance tool for elimination of lymphatic filariasis (LF) and onchocericiasis. METHODOLOGY/PRINCIPAL FINDINGS: A cross sectional survey with SD Bioline Onchocerciasis/LF IgG4 Rapid Test was piggy-backed onto a transmission assessment survey (TAS) (using the immunochromatographic card test (ICT) Binax Filariasis Now test for filarial adult circulating antigen (CFA) detection) for LF in Mali among 6-7 year old children in 2016 as part of the TAS in two EUs namely Kadiolo-Kolondieba in the region of Sikasso and Bafoulabe -Kita-Oussoubidiagna-Yelimane in the region of Kayes. In the EU of Kadiolo- Kolondieba, of the 1,625 children tested, the overall prevalence of W. bancrofti CFA was 0.62% (10/1,625) [CI = 0.31-1.09]; while that of IgG4 to Wb123 was 0.19% (3/1,600) [CI = 0.04-0.50]. The number of positives tested with the two tests were statistically comparable (p = 0.09). In the EU of Bafoulabe-Kita-Oussoubidiagna-Yelimane, an overall prevalence of W. bancrofti CFA was 0% (0/1,700) and that of Wb123 IgG4 antibody was 0.06% (1/1,700), with no statistically significant difference between the two rates (p = 0.99). In the EU of Kadiolo- Kolondieba, the prevalence of Ov16-specific IgG4 was 0.19% (3/1,600) [CI = 0.04-0.50]. All 3 positives were in the previously O. volvulus-hyperendemic district of Kolondieba. In the EU of Bafoulabe-Kita-Oussoubidiagna-Yelimane, an overall prevalence of Ov16-specific IgG4 was 0.18% (3/1,700) [CI = 0.04-0.47]. These 3 Ov16 IgG4 positives were from previously O.volvulus-mesoendemic district of Kita. CONCLUSIONS/SIGNIFICANCE: The SD Bioline Onchocerciasis/LF IgG4 Rapid test appears to be a good tool for integrated exposure measures of LF and onchocerciasis in co-endemic areas.