The Molecular Basis and Pathophysiology of Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology.

Ultrasound-guided regional anesthesia: feasibility and effectiveness of teaching via telesimulation in Ethiopia.

Background: Acute pain management in resource-poor countries remains a challenge. Ultrasound-guided regional anesthesia is a cost-effective way of delivering analgesia in these settings. However, for financial and logistical reasons, educational workshops are inaccessible to many physicians in these environments.

Functionally distinct roles for TET-oxidized 5-methylcytosine bases in somatic reprogramming to pluripotency.

Active DNA demethylation via ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming in cell state transitions. TET enzymes catalyze up to three successive oxidations of 5-methylcytosine (5mC), generating 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), or 5-carboxycytosine (5caC). Although these bases are known to contribute to distinct demethylation pathways, the lack of tools to uncouple these sequential oxidative events has constrained our mechanistic understanding of the role of TETs in chromatin reprogramming.

Information about contact force and surface texture is mixed in the firing rates of cutaneous afferent neurons.

Cutaneous mechanoreceptors in our hands gather information about the objects we handle. Tactile fibers encode mixed information about contact events and object properties. Neural coding in tactile afferents is typically studied by varying a single aspect of tactile stimuli, avoiding the confounds of real-world haptic interactions.

A comparison of provider perspectives on cultural competency training: A mixed methods study.

Background: We aimed to identify differences in training among colorectal cancer physicians and advanced practice providers with high and low cultural competency METHODS: Using explanatory sequential mixed methods, we surveyed providers and dichotomized into high and low cultural competency (CC) groups, conducted qualitative interviews, and analyzed verbatim transcripts using deductive and inductive codes to compared findings across groups using a joint display.

Results: Fifty-four of 92 providers (59%) responded; 10 respondents from each group (20/36 invited) completed semi-structured interviews about previous CC trainings. Low CC providers' training included explanations of cultural differences that, in practice, improved awareness and utilization of communication tools, but they also desired decision-making tools and cultural exposure.

TET-mediated 5-methylcytosine oxidation in tRNA promotes translation.

Oxidation of 5-methylcytosine (5mC) in DNA by the ten-eleven translocation (TET) family of enzymes is indispensable for gene regulation in mammals. More recently, evidence has emerged to support a biological function for TET-mediated mC oxidation in messenger RNA. Here, we describe a previously uncharacterized role of TET-mediated mC oxidation in transfer RNA (tRNA).

A wearable neural interface for detecting and decoding attempted hand movements in a person with tetraplegia.

We are developing a wearable neural interface based on high-density surface electromyography (HDEMG) for detecting and decoding signals from spared motor units in the forearms of people with tetraplegia after spinal cord injury (SCI). A lightweight, form-fitting garment containing 150 disc electrodes and covering the entire forearm was used to map the myoelectric activity of forearm muscles during a wide range of voluntary tasks of a person with chronic tetraplegia after SCI (C5 motor and C6 sensory American Spinal Injury Association Impairment Scale B spinal cord injury). Despite exhibiting no overt finger motion, myoelectric signals were detectable for attempted movements of individual digits and were highly discriminable.

Hindlimb motor responses evoked by microstimulation of the lumbar dorsal root ganglia during quiet standing.

Unlabelled: Somatosensory afferent pathways have been a target for neural prostheses that seek to restore sensory feedback from amputated limbs and to recruit muscles paralyzed by neurological injury. These pathways supply inputs to spinal reflex circuits that are necessary for coordinating muscle activity in the lower limb. The dorsal root ganglia (DRG) is a potential site for accessing sensory neurons because DRG microstimulation selectively recruits major nerve branches of the cat hindlimb.

Exploiting Substrate Promiscuity To Develop Activity-Based Probes for Ten-Eleven Translocation Family Enzymes.

Ten-eleven translocation (TET) enzymes catalyze repeated oxidations of 5-methylcytosine in genomic DNA. Because of the challenges of tracking reactivity within a complex DNA substrate, chemical tools to probe TET activity are limited, despite these enzyme's crucial role in epigenetic regulation. Here, building on precedents from related Fe(II)/α-ketoglutarate-dependent dioxygenases, we show that TET enzymes can promiscuously act upon cytosine bases with unnatural 5-position modifications.

Selectivity and Promiscuity in TET-Mediated Oxidation of 5-Methylcytosine in DNA and RNA.

Enzymes of the ten-eleven translocation (TET) family add diversity to the repertoire of nucleobase modifications by catalyzing the oxidation of 5-methylcytosine (5mC). TET enzymes were initially found to oxidize 5-methyl-2'-deoxycytidine in genomic DNA, yielding products that contribute to epigenetic regulation in mammalian cells, but have since been found to also oxidize 5-methylcytidine in RNA. Considering the different configurations of single-stranded (ss) and double-stranded (ds) DNA and RNA that coexist in a cell, defining the scope of TET's preferred activity and the mechanisms of substrate selectivity is critical to better understand the enzymes' biological functions.

OGT binds a conserved C-terminal domain of TET1 to regulate TET1 activity and function in development.

TET enzymes convert 5-methylcytosine to 5-hydroxymethylcytosine and higher oxidized derivatives. TETs stably associate with and are post-translationally modified by the nutrient-sensing enzyme OGT, suggesting a connection between metabolism and the epigenome. Here, we show for the first time that modification by OGT enhances TET1 activity in vitro.

Nondestructive, base-resolution sequencing of 5-hydroxymethylcytosine using a DNA deaminase.

Here we present APOBEC-coupled epigenetic sequencing (ACE-seq), a bisulfite-free method for localizing 5-hydroxymethylcytosine (5hmC) at single-base resolution with low DNA input. The method builds on the observation that AID/APOBEC family DNA deaminase enzymes can potently discriminate between cytosine modification states and exploits the non-destructive nature of enzymatic, rather than chemical, deamination. ACE-seq yielded high-confidence 5hmC profiles with at least 1,000-fold less DNA input than conventional methods.

Harnessing natural DNA modifying activities for editing of the genome and epigenome.

The introduction of site-specific DNA modifications to the genome or epigenome presents great opportunities for manipulating biological systems. Such changes are now possible through the combination of DNA-modifying enzymes with targeting modules, including dCas9, that can localize the enzymes to specific sites. In this review, we take a DNA modifying enzyme-centric view of recent advances.

A Small-Molecule Inducible Synthetic Circuit for Control of the SOS Gene Network without DNA Damage.

The bacterial SOS stress-response pathway is a pro-mutagenic DNA repair system that mediates bacterial survival and adaptation to genotoxic stressors, including antibiotics and UV light. The SOS pathway is composed of a network of genes under the control of the transcriptional repressor, LexA. Activation of the pathway involves linked but distinct events: an initial DNA damage event leads to activation of RecA, which promotes autoproteolysis of LexA, abrogating its repressor function and leading to induction of the SOS gene network.

Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine.

Ten-eleven translocation (TET) enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) to yield 5-hydroxymethylcytosine (hmC) and the rarer bases 5-formylcytosine (fC) and 5-carboxylcytosine (caC). Stepwise oxidation obscures how each individual base forms and functions in epigenetic regulation, and prompts the question of whether TET enzymes primarily serve to generate hmC or are adapted to produce fC and caC as well. By mutating a single, conserved active site residue in human TET2, Thr1372, we uncovered enzyme variants that permit oxidation to hmC but largely eliminate fC and caC.

The expanding scope and impact of epigenetic cytosine modifications.

Chemical modifications to genomic DNA can expand and shape its coding potential. Cytosine methylation in particular has well-established roles in regulating gene expression and defining cellular identity. The discovery of TET family enzymes opened a major frontier beyond DNA methylation, revealing three oxidized forms of cytosine that could mediate DNA demethylation or encode independent epigenetic functions.

Tet2 Catalyzes Stepwise 5-Methylcytosine Oxidation by an Iterative and de novo Mechanism.

Modification of cytosine-guanine dinucleotides (CpGs) is a key part of mammalian epigenetic regulation and helps shape cellular identity. Tet enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) in CpGs to 5-hydroxymethylcytosine (hmC), or onward to 5-formylcytosine (fC) or 5-carboxylcytosine (caC). The multiple mC oxidation products, while intricately linked, are postulated to play independent epigenetic roles, making it critical to understand how the products of stepwise oxidation are established and maintained.

Superiority of chlorhexidine 2%/alcohol 70% wipes in decontaminating ultrasound equipment.

Ultrasound equipment is known to act as a reservoir for potentially pathogenic organisms. The aims of these studies were to establish current cleaning practices, to review the extent of bacterial contamination of ultrasound equipment in our hospital, to establish an effective cleaning regimen and to ensure that cleaning does not cause damage. A questionnaire was sent to all acute NHS hospitals in England to establish current cleaning practices.

Activation of complement by monoclonal antibodies that target cell-associated β₂-microglobulin: implications for cancer immunotherapy.

β₂-Microglobulin (β2M), the light chain of the class I major histocompatibilty complex (MHC-I), is a promising tumor target for monoclonal antibodies (mAbs) in cancer immunotherapy. Several reports indicate that chelation of cell-associated β2M by specific mouse mAbs promotes tumor cell destruction by inducing apoptosis or other cytotoxic signaling pathways. Human mAbs employed in cancer therapy are usually IgG1, which mediates cell-killing by effector mechanisms including complement dependent cytotoxicity (CDC).