Safety and Tolerability of Accelerated Low-Frequency Repetitive Transcranial Magnetic Stimulation Over the Primary Motor Cortex–A Pilot Study

Low-frequency repetitive transcranial magnetic stimulation (rTMS) is capable of inducing changes in the functional organization of underlying brain regions, however, often at the cost of long stimulation protocols over several weeks. As these protocols can be difficult to implement in clinical settings, the aim of the present pilot study was to show the feasibility and safety of an accelerated low-frequency rTMS protocol applying multiple sessions daily. To this purpose, nine healthy subjects received 14 sessions of rTMS (1 Hz, 30 min, 110% RMT) to the hand motor hotspot. Subjects received stimulation for either 14 days once daily [classical rTMS (c-rTMS)], 7 days twice daily (accelerated rTMS; a-rTMS), or sham stimulation for 14 days once daily (s-rTMS). Daily stimulation sessions in the a-rTMS group were delivered with a 90-min break in between. In total, 74% of rTMS sessions in the c-rTMS group, 89% in the a-rTMS group, and 98% in the s-rTMS group were free of any side effects. Brief headaches and fatigue in stimulated muscle groups were the most frequent side effects. All side effects were reported to be at maximum mild and of short duration. Thus, accelerated low-frequency rTMS of the motor cortex seems to be a safe and feasible method, previously shown to induce a functional reorganization of the motor system. By shortening treatment duration in days, this approach can potentially make rTMS protocols more accessible to a wider range of patients.Peer Reviewe

Gas Phase Reactivity of Isomeric Hydroxylated Polychlorinated Biphenyls.

peer reviewedIdentification of stereo- and positional isomers detected with high-resolution mass spectrometry (HRMS) is often challenging due to near-identical fragmentation spectra (MS2), similar retention times, and collision cross-section values (CCS). Here we address this challenge on the example of hydroxylated polychlorinated biphenyls (OH-PCBs) with the aim to (1) distinguish between isomers of OH-PCBs using two-dimensional ion mobility spectrometry (2D-IMS) and (2) investigate the structure of the fragments of OH-PCBs and their fragmentation mechanisms by ion mobility spectrometry coupled to high-resolution mass spectrometry (IMS-HRMS). The MS2 spectra as well as CCS values of the deprotonated molecule and fragment ions were measured for 18 OH-PCBs using flow injections coupled to a cyclic IMS-HRMS. The MS2 spectra as well as the CCS values of the parent and fragment ions were similar between parent compound isomers; however, ion mobility separation of the fragment ions is hinting at the formation of isomeric fragments. Different parent compound isomers also yielded different numbers of isomeric fragment mobilogram peaks giving new insights into the fragmentation of these compounds and indicating new possibilities for identification. For spectral interpretation, Gibbs free energies and CCS values for the fragment ions of 4'-OH-CB35, 4'-OH-CB79, 2-OH-CB77 and 4-OH-CB107 were calculated and enabled assignment of structures to the isomeric mobilogram peaks of [M-H-HCl]- fragments. Finally, further fragmentation of the isomeric fragments revealed different fragmentation pathways depending on the isomeric fragment ions

Human Galectins Induce Conversion of Dermal Fibroblasts into Myofibroblasts and Production of Extracellular Matrix: Potential Application in Tissue Engineering and Wound Repair

Members of the galectin family of endogenous lectins are potent adhesion/growth-regulatory effectors. Their multi-functionality opens possibilities for their use in bioapplications. We studied whether human galectins induce the conversion of human dermal fibroblasts into myofibroblasts (MFBs) and the production of a bioactive extracellular matrix scaffold is suitable for cell culture. Testing a panel of galectins of all three subgroups, including natural and engineered variants, we detected activity for the proto-type galectin-1 and galectin-7, the chimera-type galectin-3 and the tandem-repeat-type galectin-4. The activity of galectin-1 required the integrity of the carbohydrate recognition domain. It was independent of the presence of TGF-beta 1, but it yielded an additive effect. The resulting MFBs, relevant, for example, for tumor progression, generated a matrix scaffold rich in fibronectin and galectin-1 that supported keratinocyte culture without feeder cells. Of note, keratinocytes cultured on this substratum presented a stem-like cell phenotype with small size and keratin-19 expression. In vivo in rats, galectin-1 had a positive effect on skin wound closure 21 days after surgery. In conclusion, we describe the differential potential of certain human galectins to induce the conversion of dermal fibroblasts into MFBs and the generation of a bioactive cell culture substratum. Copyright (C) 2011 S. Karger AG, Base

Mouse Heterochromatin Adopts Digital Compaction States without Showing Hallmarks of HP1-Driven Liquid-Liquid Phase Separation

Mouse cells package heterochromatin into compact foci. Erdel et al. show that these foci lack hallmarks of liquid droplets and rather resemble collapsed polymer globules. Their size, accessibility, and compaction are independent of HP1. They can adopt two distinct folding states that possibly represent the fundamental modes of chromatin compaction

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination

Sektory mobilności i logistyki w nowych ramach działania

Celem monografi jest nakreślenie kierunków zmian oraz przedstawienie dobrych praktyk z obszaru mobilności i logistyki, poszerzą wiedzę na temat aktualnej sytuacji, oraz zainspirują do kolejnych działań przybliżających nas do niskoemisyjnej gospodarki. Książka jest uhonorowaniem środowiska akademickiego prof. dr. hab. Wojciecha Paprockiego, który świętuje jubileusz 45‑lecia pracy naukowo-dydaktycznej.1-37

Twist exome capture allows for lower average sequence coverage in clinical exome sequencing

Background Exome and genome sequencing are the predominant techniques in the diagnosis and research of genetic disorders. Sufficient, uniform and reproducible/consistent sequence coverage is a main determinant for the sensitivity to detect single-nucleotide (SNVs) and copy number variants (CNVs). Here we compared the ability to obtain comprehensive exome coverage for recent exome capture kits and genome sequencing techniques. Results We compared three different widely used enrichment kits (Agilent SureSelect Human All Exon V5, Agilent SureSelect Human All Exon V7 and Twist Bioscience) as well as short-read and long-read WGS. We show that the Twist exome capture significantly improves complete coverage and coverage uniformity across coding regions compared to other exome capture kits. Twist performance is comparable to that of both short- and long-read whole genome sequencing. Additionally, we show that even at a reduced average coverage of 70× there is only minimal loss in sensitivity for SNV and CNV detection. Conclusion We conclude that exome sequencing with Twist represents a significant improvement and could be performed at lower sequence coverage compared to other exome capture techniques

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock