Distinct CholinomiR Blood Cell Signature as a Potential Modulator of the Cholinergic System in Women with Fibromyalgia Syndrome.

Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.

Countering information leakage in the Concealed Information Test: The effects of item detailedness.

Concealed Information Tests (CIT) are administered to verify whether suspects recognize certain features from a crime. Whenever it is presumed that innocent suspects were contaminated with critical information (e.g., the perpetrator had a knife), the examiner may ask more detailed questions (e.g., specific types of knives) to prevent false positives. However, this may increase the number of false negatives if the true perpetrator fails to discern specific details from its plausible irrelevant controls, or because detailed crime-scene information may be forgotten. We examined whether presenting items at the exemplar level protects against contamination, and whether it compromises the sensitivity in a physiological CIT. Participants (N = 142) planned a mock-robbery, with critical items encoded either at the category or at the exemplar level. The CIT was administered immediately or after a 1-week-delay, with questions phrased at the categorical or exemplar level. There were no effects of time delay. Results revealed that when item detailedness was congruent at encoding and testing, the SCR, HR, and RLL showed larger differential responses, as compared with incongruent conditions. Participants contaminated with crime knowledge at the categorical level did not show a CIT-effect for crime details at the exemplar level, suggesting detailed questions may counter the leakage problem. Asking questions at the exemplar level did not reduce the CIT detection efficiency as compared to asking questions at the categorical level. The importance of congruency between encoding and testing provides examiners with a challenge, as it is difficult to estimate how details are naturally encoded.

A Parkinson's disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress.

Circular RNAs (circRNAs) are brain-abundant RNAs of mostly unknown functions. To seek their roles in Parkinson's disease (PD), we generated an RNA sequencing resource of several brain region tissues from dozens of PD and control donors. In the healthy substantia nigra (SN), circRNAs accumulate in an age-dependent manner, but in the PD SN this correlation is lost and the total number of circRNAs reduced. In contrast, the levels of circRNAs are increased in the other studied brain regions of PD patients. We also found circSLC8A1 to increase in the SN of PD individuals. CircSLC8A1 carries 7 binding sites for miR-128 and is strongly bound to the microRNA effector protein Ago2. Indeed, RNA targets of miR-128 are also increased in PD individuals, suggesting that circSLC8A1 regulates miR-128 function and/or activity. CircSLC8A1 levels also increased in cultured cells exposed to the oxidative stress-inducing agent paraquat but were decreased in cells treated with the neuroprotective antioxidant regulator drug Simvastatin. Together, our work links circSLC8A1 to oxidative stress-related Parkinsonism and suggests further exploration of its molecular function in PD.

Central and peripheral anti-inflammatory effects of acetylcholinesterase inhibitors.

Acetylcholinesterase (AChE) inhibitors modulate acetylcholine hydrolysis and hence play a key role in determining the cholinergic tone and in implementing its impact on the cholinergic blockade of inflammatory processes. Such inhibitors may include rapidly acting small molecule AChE-blocking drugs and poisonous anti-AChE insecticides or war agent inhibitors which penetrate both body and brain. Notably, traumatized patients may be hyper-sensitized to anti-AChEs due to their impaired cholinergic tone, higher levels of circulation pro-inflammatory cytokines and exacerbated peripheral inflammatory responses. Those largely depend on the innate-immune system yet reach the brain via vagus pathways and/or disrupted blood-brain-barrier. Other regulators of the neuro-inflammatory cascade are AChE-targeted microRNAs (miRs) and synthetic chemically protected oligonucleotide blockers thereof, whose size prevents direct brain penetrance. Nevertheless, these larger molecules may exert parallel albeit slower inflammatory regulating effects on brain and body tissues. Additionally, oligonucleotide aptamers interacting with innate immune Toll-Like Receptors (TLRs) may control inflammation through diverse routes and in different rates. Such aptamers may compete with the action of both small molecule inhibitors and AChE-inhibiting miRs in peripheral tissues including muscle and intestine. However, rapid adaptation processes, visualized in neuromuscular junctions enable murine survival under otherwise lethal anti-cholinesterase exposure; and both miR inhibitors and TLR-modulating aptamers may exert body-brain signals protecting experimental mice from acute inflammation. The complex variety of AChE inhibiting molecules identifies diverse body-brain communication pathways which may rapidly induce long-lasting central reactions to peripheral stressful and inflammatory insults in both mice and men. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.