Association between a common missense variant in LOXL3 gene and the risk of non-syndromic cleft palate

To investigate possible association between functional common variants in the lysyl oxidase like 3 gene and non-syndromic cleft palate we selected a common missense variant p.Ile615Phe (rs17010021), which was predicted to have a probably damaging effect on the lysyl oxidase like 3 enzyme. We genotyped 258 non-syndromic cleft palate case-parent triads of European origin and tested genetic association using the transmission disequilibrium test and log-linear regression analyses of genotypic relative risks and of parent-of-origin effects. The observed genotype frequency in parents was in Hardy-Weinberg equilibrium. Compared with wild-type Ile/Ile homozygotes, the relative risks for Phe/Phe homozygote infants was 6.87 (P value 3.0 × 10-3 ), while that for Ile/Phe heterozygotes was not significant. Assuming an autosomal recessive model, the relative risks for Phe/Phe genotype resulted 10.54 (P value 2.9 × 10-5 ), with a 3.6% population attributable risk. No parent-of-origin effect was observed. The identification in lysyl oxidase like 3 of a missense variant which under a recessive model associates with 10-fold increased risk of non-syndromic cleft palate supports the hypothesis that the genetic etiology of this congenital anomaly includes relatively uncommon recessive variants with moderate penetrance and located in genes which are also involved in syndromes that include cleft palate as part of the phenotype. Our findings require functional validation and replication in a larger independent genetic association study

Assessing The Impact of Cluster Farming Initiatives on Small and Socially Disadvantaged Farmers, Ranchers, and Forestland Owners: A Case of The Southeastern Region of The United States

Farming in clusters is an economically viable practice to sustain small, limited resource, and socially disadvantaged farmers and forestland owners with their agricultural operations. The objectives of the study were to strengthen the capacity of clientele on cluster farming and to lower production and marketing costs by sharing input costs. Clusters were created and interventions were provided by project partners through several activities, including workshops, meetings, field days, loans, and materials/equipment. The results showed that 29 clusters involving 224 farmers, and 14 cooperatives involving 410 farmers were formed and strengthened. The number of farmers participating in workshops, training programs, field days, and meetings were, respectively, 4,921, 3,095, 1,426, and 1,285. The results also revealed that 190 producers received access to farm loans, mobile and stationary cold storage facilities, and marketing materials. Additionally, 930 farmers strengthened their knowledge and skills, and changed their behavior due to the implementation of the cluster farming approach

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

Impaired dopamine- and adenosine-mediated signaling and plasticity in a novel rodent model for DYT25 dystonia

Abstract Dystonia is a neurological movement disorder characterized by sustained or intermittent involuntary muscle contractions. Loss-of-function mutations in the GNAL gene have been identified to be the cause of "isolated" dystonia DYT25. The GNAL gene encodes for the guanine nucleotide-binding protein G(olf) subunit alpha (Gαolf), which is mainly expressed in the olfactory bulb and the striatum and functions as a modulator during neurotransmission coupling with D1R and A2AR. Previously, heterozygous Gαolf -deficient mice (Gnal+/−) have been generated and showed a mild phenotype at basal condition. In contrast, homozygous deletion of Gnal in mice (Gnal−/−) resulted in a significantly reduced survival rate. In this study, using the CRISPR-Cas9 system we generated and characterized heterozygous Gnal knockout rats (Gnal+/−) with a 13 base pair deletion in the first exon of the rat Gnal splicing variant 2, a major isoform in both human and rat striatum. Gnal+/− rats showed early-onset phenotypes associated with impaired dopamine transmission, including reduction in locomotor activity, deficits in rotarod performance and an abnormal motor skill learning ability. At cellular and molecular level, we found down-regulated Arc expression, increased cell surface distribution of AMPA receptors, and the loss of D2R-dependent corticostriatal long-term depression (LTD) in Gnal+/− rats. Based on the evidence that D2R activity is normally inhibited by adenosine A2ARs, co-localized on the same population of striatal neurons, we show that blockade of A2ARs restores physiological LTD. This animal model may be a valuable tool for investigating Gαolf function and finding a suitable treatment for dystonia associated with deficient dopamine transmission

Profiling of ubiquitination pathway genes in peripheral cells from patients with frontotemporal dementia due to C9ORF72 and GRN mutations

We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion

Genome-Wide Identification of Powdery Mildew Resistance in Common Bean (Phaseolus vulgaris L.)

Genome-wide association studies (GWAS) have been utilized to detect genetic variations related to several agronomic traits and disease resistance in common bean. However, its application in the powdery mildew (PM) disease to identify candidate genes and their location in the common bean genome has not been fully addressed. Single-nucleotide polymorphism (SNP) genotyping with a BeadChip containing 5398 SNPs was used to detect genetic variations related to PM disease resistance in a panel of 211 genotypes grown under two field conditions for two consecutive years. Significant SNPs identified on chromosomes Pv04 and Pv10 were repeatable, ensuring the phenotypic data’s reliability and the causal relationship. A cluster of resistance genes was revealed on the Pv04 of the common bean genome, coiled-coil-nucleotide-binding site–leucine-rich repeat (CC-NBS-LRR, CNL), and Toll/interleukin-1 receptor-nucleotide-binding site–leucine-rich repeat type (TIR-NBS-LRR, TNL)-like resistance genes were identified. Furthermore, two resistance genes, Phavu_010G1320001g and Phavu_010G136800g, were also identified on Pv10. Further sequence analysis showed that these genes were homologs to the disease-resistance protein (RLM1A-like) and the putative disease-resistance protein (At4g11170.1) in Arabidopsis. Significant SNPs related to two LRR receptor-like kinases (RLK) were only identified on Pv11 in 2018. Many genes encoding the auxin-responsive protein, TIFY10A protein, growth-regulating factor five-like, ubiquitin-like protein, and cell wall RBR3-like protein related to PM disease resistance were identified nearby significant SNPs. These results suggested that the resistance to PM pathogen involves a network of many genes constitutively co-expressed

The use of Traditional Medicine by Ghanaians in Canada

Peer reviewedPublisher PD

A Kinetic Model of Dopamine- and Calcium-Dependent Striatal Synaptic Plasticity

Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction