Contactins are a group of cell adhesion molecules that are mainly expressed in the brain and play pivotal roles in the organization of axonal domains, axonal guidance, neuritogenesis, neuronal ...development, synapse formation and plasticity, axo-glia interactions and neural regeneration. Contactins comprise a family of six members. Their absence leads to malformed axons and impaired nerve conduction. Contactin mediated protein complex formation is critical for the organization of the axon in early central nervous system development. Mutations and differential expression of contactins have been identified in neuro-developmental or neurological disorders. Taken together, contactins are extensively studied in the context of nervous system development. This review summarizes the physiological roles of all six members of the Contactin family in neurodevelopment as well as their involvement in neurological/neurodevelopmental disorders.
Background:
Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS).
Objective:
To study serum contactin-1 (sCNTN1) as a novel biomarker for ...disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients.
Methods:
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria.
Results:
Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) (p = 0.017) for progression during follow-up.
Conclusion:
Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.
is an obligate plant-parasitic nematode causing serious damage to agricultural crops. Major constraints in nematode management arose due to the limited availability of non-fumigant nematicides in ...conjunction with the considerable ill effects of fumigants on human and non-target organisms. Recently, fluensulfone has been reported to be an effective non-fumigant nematicide against plant-parasitic nematodes and the model nematode
The nematicidal efficacy varies according to its concentration at the time of application, exposure timing, nematode species variability, and even across subpopulations within the same species. It interferes with the key physiological processes of nematodes, like motility, behavior, chemosensation, stylet thrusting, infectivity, metabolism, lipid consumption, tissue integrity, oviposition, egg hatching, and survival. However, the molecular basis of these multivariate physiological anomalies is still largely unknown. Quantitative real-time PCR was carried out to understand the acute transcriptional perturbation of 30 functional genes associated with key physiological and life processes in a
population, following exposure of 10, 50, and 100 ppm of fluensulfone for 5 and 10 hr. The chemical treatment resulted in significant downregulation of all the neuropeptidergic genes, with concomitant repression of majority of genes related to chemosensation, esophageal gland secretion, parasitism, fatty acid metabolism, and G-protein coupled receptors. Collectively, the parasitism genes were found to be perturbed at highest magnitude, followed by the GPCRs and neuropeptidergic genes. These results establish the wide ranging effect of fluensulfone on various metabolic and physiological pathways of nematode.
Insect pests are one of the major biotic stresses limiting yield in commercially important crops. The lepidopteran polyphagous spotted pod borer,
Maruca vitrata
causes significant economic losses in ...legumes including pigeonpea. RNA interference (RNAi)-based gene silencing has emerged as one of the potential biotechnological tools for crop improvement. We report in this paper, RNAi in
M. vitrata
through exogenous administration of dsRNA with sequence specificity to three functionally important genes, Alpha-amylase (
α-amylase
), Chymotrypsin-like serine protease (
CTLP
) and Tropomyosin (
TPM
) into the larval haemolymph and their host-delivered RNAi in pigeonpea. Significant decline in the expression of selected genes supported by over-expression of
DICER
and generation of siRNA indicated the occurrence of RNAi in the dsRNA-injected larvae. Additionally, the onset of RNAi in the herbivore was demonstrated in pigeonpea, one of the prominent hosts, by host-delivered dsRNA. Transgenics in pigeonpea (cv. Pusa 992), a highly recalcitrant crop, were developed through a shoot apical meristem-targeted
in planta
transformation strategy and evaluated. Plant level bioassays in transgenic events characterized and selected at molecular level showed mortality of
M
.
vitrata
larvae as well as reduced feeding when compared to wild-type. Furthermore, molecular evidence for down regulation of target genes in the insects that fed on transgenic plants authenticated RNAi. Considering the variability of gene silencing in lepidopteran pests, this study provided corroborative proof for the possibility of gene silencing in
M. vitrata
through both the strategies.
The polyphagous spotted pod borer,
Maruca vitrata
is an important agricultural pest that causes extensive damage on various food crops. Though the pest is managed by synthetic chemicals, exploration ...of biotechnological approaches for its control is important. RNAi-based gene silencing is one such tool that has been extensively used for functional genomics and is highly variable in insects. In view of this, we have attempted to demonstrate RNAi in
M. vitrata
through exogenous double-stranded RNA (dsRNA) administration targeting seven genes associated with midgut, chemosensory, cell signalling and development
.
Two modes of exogenous dsRNA delivery by either haemolymph injection and/or ingestion into third and late third instar larval stages respectively exhibited efficient silencing of specific transcripts. Furthermore, dsRNA injection into the haemolymph showed significant reduction of target gene expression compared to negative controls establishing this mode of delivery to be more efficient. Interestingly, haemolymph injection required lesser dsRNA and led to higher reduction of transcript level vis-à-vis ingestion as demonstrated in dsRNA Serine Protease 33 (ds-
SP33
)-fed larvae. Over-expression of key RNAi component
DICER
and detection of siRNA authenticated the presence of RNAi in
M. vitrata
. Additionally, we have identified inhibitor molecules like morpholine, piperidine, carboxamide and piperidine–carboxamide through in silico analysis for blocking the function of
SP33
to demonstrate the utility of functional genomics. Thus, the present study establishes the usefulness of injection and ingestion approaches for exogenous dsRNA delivery into
M. vitrata
larvae for effective RNAi
.
Increasing evidence suggests that cerebral vascular dysfunction is associated with the early stages of Alzheimer's disease (AD). Vascular endothelial growth factor (VEGF) is one of the key players ...involved in the development and maintenance of the vasculature. Here, we hypothesized that VEGF levels in cerebrospinal fluid (CSF) may be altered in AD patients with vascular involvement, characterized by the presence of microbleeds (MB), and in vascular dementia (VaD) patients compared to controls.
VEGF levels were determined by electrochemilumiscence Meso Scale Discovery (MULTI-SPOT Assay System) in CSF from age-matched groups of controls with subjective cognitive decline (n = 21), AD without MB (n = 25), AD with MB (n = 25), and VaD (n = 21) patients.
The average level of VEGF in the different groups was 2.8 ± 1 pg/ml CSF. Adjusted for age and gender, no significant differences were detected between groups (p > 0.5). However, we detected a significant correlation between the concentration of VEGF in the CSF and age (r = 0.22, p = 0.03). In addition, males (n = 54) revealed higher VEGF levels in their CSF compared to females (n = 38) (males = 3.08 ± 0.769 pg/ml (mean ± SD), females = 2.6 ± 0.59; p = 0.006), indicating a gender-related regulation.
Our study suggests that VEGF levels in the CSF do not reflect the cerebral vascular alterations in either AD or VaD patients. The observed associations of VEGF with age and gender may indicate that VEGF reflects normal aging and that males and females may differ in their aging process.
Plant–parasitic root-knot nematode
Meloidogyne incognita
uses an array of effector proteins to establish successful plant infections.
Mi-msp-1
and
Mi-msp-20
are two known effectors secreted from ...nematode subventral oesophageal glands;
Mi-msp-1
being a putative secretory venom allergen AG5-like protein, whereas
Mi-msp-20
is a pioneer gene with a coiled-coil motif. Expression of specific effector is known to cause disturbances in the expression of other effectors. Here, we used RNA-Seq to investigate the pleiotropic effects of silencing
Mi-msp-1
and
Mi-msp-20
. A total of 25.1–51.9 million HQ reads generated from
Mi-msp-1
and
Mi-msp-20
silenced second-stage juveniles (J2s) along with freshly hatched J2s were mapped to an already annotated
M. incognita
proteome to understand the impact on various nematode pathways. As compared to control, silencing of
Mi-msp-1
caused differential expression of 29 transcripts, while
Mi-msp-20
silencing resulted in differential expression of a broader set of 409 transcripts. In the
Mi-msp-1
silenced J2s, cytoplasm (GO:0005737) was the most enriched gene ontology (GO) term, whereas in the
Mi-msp-20
silenced worms, embryo development (GO:0009792), reproduction (GO:0000003) and nematode larval development (GO:0002119) were the most enriched terms. Limited crosstalk was observed between these two effectors as a sheer 5.9% of the up-regulated transcripts were common between
Mi-msp-1
and
Mi-msp-20
silenced nematodes. Our results suggest that in addition to the direct knock-down caused by silencing of
Mi-msp-1
and
Mi-msp-20
, the cascading effect on other genes might also be contributing to a reduction in nematode's parasitic abilities.
Synaptic and axonal loss are two major mechanisms underlying Alzheimer's disease (AD) pathogenesis, and biomarkers reflecting changes in these cellular processes are needed for early diagnosis and ...monitoring the progression of AD. Contactin-2 is a synaptic and axonal membrane protein that interacts with proteins involved in the pathology of AD such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1). We hypothesized that AD might be characterized by changes in contactin-2 levels in the cerebrospinal fluid (CSF) and brain tissue. Therefore, we aimed to investigate the levels of contactin-2 in the CSF and evaluate its relationship with disease pathology.
Contactin-2 was measured in CSF from two cohorts (selected from the Amsterdam Dementia Cohort), comprising samples from controls (cohort 1, n = 28; cohort 2, n = 20) and AD (cohort 1, n = 36; cohort 2, n = 70) using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). The relationship of contactin-2 with cognitive decline (Mini-Mental State Examination (MMSE)) and other CSF biomarkers reflecting AD pathology were analyzed. We further characterized the expression of contactin-2 in postmortem AD human brain (n = 14) versus nondemented controls (n = 9).
CSF contactin-2 was approximately 1.3-fold reduced in AD patients compared with controls (p < 0.0001). Overall, contactin-2 levels correlated with MMSE scores (r = 0.35, p = 0.004). We observed that CSF contactin-2 correlated with the levels of phosphorylated tau within the control (r = 0.46, p < 0.05) and AD groups (r = 0.31, p < 0.05). Contactin-2 also correlated strongly with another synaptic biomarker, neurogranin (control: r = 0.62, p < 0.05; AD: r = 0.60, p < 0.01), and BACE1, a contactin-2 processing enzyme (control: r = 0.64, p < 0.01; AD: r = 0.46, p < 0.05). Results were further validated in a second cohort (p < 0.01). Immunohistochemical analysis revealed that contactin-2 is expressed in the extracellular matrix. Lower levels of contactin-2 were specifically found in and around amyloid plaques in AD hippocampus and temporal cortex.
Taken together, these data reveal that the contactin-2 changes observed in tissues are reflected in CSF, suggesting that decreased contactin-2 CSF levels might be a biomarker reflecting synaptic or axonal loss.
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