Closed-loop direct control of seizure focus in a rodent model of temporal lobe epilepsy via localized electric fields applied sequentially

Direct electrical stimulation of the seizure focus can achieve the early termination of epileptic oscillations. However, direct intervention of the hippocampus, the most prevalent seizure focus in temporal lobe epilepsy is thought to be not practicable due to its large size and elongated shape. Here, in a rat model, we report a sequential narrow-field stimulation method for terminating seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. The effects and regional specificity of this method were demonstrated via electrophysiological and biological responses. Our proposed modality demonstrates spatiotemporal preciseness and selectiveness for modulating the pathological target region which may have potential for further investigation as a therapeutic approach.11Ysciescopu

Table_1_Seasonal variations in biochemical (biomolecular and amino acid) compositions and protein quality of particulate organic matter in the Southwestern East/Japan Sea.docx

The biochemical compositions of marine particulate organic matter (POM) can provide significant information to understanding the physiological conditions of phytoplankton and food quality for their potential consumers. We investigated the seasonal variations in biomolecular and amino acid (AA) compositions of the bulk POM in the southwestern East/Japan Sea from four different sampling months (February, April, August, and October) in 2018. In terms of the biomolecular composition of the POM, overall carbohydrates (CHO) were predominant among three biomolecules accounting for 48.6% followed by lipids (LIP; 35.5%) and proteins (PRT; 15.9%) in the East/Japan Sea. However, markedly seasonal differences in the biomolecular composition of POM were found from February to October, which could be due to seasonally different conditions favorable to phytoplankton growth. Dominant AA constituents to trace POM lability were glycine (GLY), alanine (ALA), and glutamic acid (GLU), suggesting that our POM was the mixtures of decomposing and fresher materials. Furthermore, the significantly negative correlation between the proportion of total essential amino acids (EAAs) and PRT composition (r = -0.627, p< 0.01) was probably reflected by nutrient availability to phytoplankton partitioning EAAs or non-essential AAs (NEAAs). The different biomolecular compounds under un- or favorable growth conditions for phytoplankton could determine the nutritional quality of POM as potential prey as well as degradation status of POM. Therefore, the biochemical compositions of phytoplankton-originated POM hold important ecological implications in various marine ecosystems under ongoing climate changes.</p

A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy.

Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy

Histology of the distal sural nerve.

<p>(A) Transverse semi-thin section showed a normal range of myelinated fibers with loss of large myelinated fibers, onion bulbs (arrows), axonal degeneration with myelin abnormalities (arrow heads), and clusters of regenerative small myelinated fibers (curved arrow). (B) Histogram shows a unimodal distribution pattern. (C, D) Ultrastructural micrograph shows degenerating fibers with various abnormalities of myelin such as abnormal myelin compaction with adaxonal vacuoles, internal and external myelin folding, irregular myelin sheath, and onion bulbs or pseudo-onion bulbs surrounding the myelinated fibers. Magnifications: A, x400; C, x3000; D, x15000.</p

T1-weighted axial MRIs of the upper third (A-C) and lower third (D-F) calf in three patients.

<p>(A, D) III-3 patient at the age of 30 years with disease duration (DD) of 22 years. (B, E) III-1 patient at the age of 32 years with DD of 26 years. (C, F) II-4 patient at the age of 56 years with DD of 38 years. A sequential pattern of muscle involvement associated with disease duration was observed. In the early disease stage, the lateral compartment muscles (arrow) including the peroneus longus and brevis were initially involved, and they showed the most severe fatty hyperintense signal changes. A lesser degree of fatty involvement was observed in the anterior compartment muscles (white arrowhead) including the tibialis anterior, extensor hallucis longus, and extensor digitorum longus. In later stages, the posterior compartment muscles (black arrowhead) including the soleus, gastrocnemius, and tibialis posterior in the calf were relatively unaffected.</p

Clinical manifestations of the three patients with <i>PMP2</i> p.I43N mutation.

<p>Clinical manifestations of the three patients with <i>PMP2</i> p.I43N mutation.</p

Phenotype of <i>PMP2</i> transgenic mice.

<p>(A) Tail suspension test showed hind limb folding into the abdomen in both <i>PMP2</i>-WT and <i>PMP2</i>-I43N transgenic mice. (B) Rotarod test showed significantly reduced performance in both <i>PMP2</i>-WT and <i>PMP2</i>-I43N transgenic mice at 3 months of age. (C) Reduced motor nerve conduction velocity (MNCV) in both transgenic mice. (D) Compound muscle action potential (CMAP). Ten mice from each group were used. Sweep speed, 0.5 ms per division; Amplitude, 10 mV per division. *, <i>p</i> < 0.05; and **, <i>p</i> < 0.01.</p

Abnormal SLI and internodal length in <i>PMP2</i> transgenic mice.

<p>(A) SLI and nuclei of Schwann cells were visualized with phalloidin (red) and DAPI (blue) staining of the teased nerve. More than 2 nuclei could be observed in the teased nerve of the transgenic mice, while only one nucleus at each field could be detected in that of control mice. SLIs were indicated as white arrow heads. (B) Intervals of SLIs were compared among the mice. Control, n = 227; <i>PMP2</i>-WT, n = 270; <i>PMP2</i>-I43N, n = 378. (C) Internodal length in each mouse model was determined by measuring the distance between nuclei (DAPI). Control, n = 164; <i>PMP2</i>-WT, n = 198; <i>PMP2</i>-I43N, n = 283. ***, <i>p</i> < 0.001.</p

An autosomal dominant CMT 1 family with <i>PMP2</i> mutation.

<p>(A) Pedigree of the CMT 1 family (FC183). The genotype of the <i>PMP2</i> mutation is indicated at the bottom of each individual. Arrow indicates the proband. No genetic information was available for the I-3 individual. (B) Sequencing chromatogram of <i>PMP2</i> mutation. c.128T>A (p.I43N) mutation is present in <i>PMP2</i>. (C) Conservation of amino acid sequences at the mutation site in PMP2 protein. Amino acid sequences were from NP_002668.1 (<i>Homo sapiens</i>), NP_001025476.1 (<i>Mus musculus</i>), NP_001102984.1 (<i>Rattus norvegicus</i>), NP_001068707.1 (<i>Bos taurus</i>), NP_001186405.1 (<i>Gallus gallus</i>), and XP_007052997.1 (<i>Chelonia mydas</i>).</p