Objective. A critical feature for the maintenance of precise skeletal muscle force production by the human brain is its ability to configure motor function activity dynamically and adaptively in ...response to visual and somatosensory information. Existing studies have concluded that not only the sensorimotor area but also distributed cortical areas act cooperatively in the generation of motor commands for voluntary force production to the desired level. However, less attention has been paid to such physiological mechanisms in conventional brain-computer interface (BCI) design and implementation. We proposed a new, physiologically inspired two-stage decoding method to see its contribution on accuracy improvement of BCI. Approach. We performed whole-head high-density scalp electroencephalographic (EEG) recording during a right finger force-matching task at three strength levels (20%, 40%, and 60% maximal voluntary contraction following a resting state). A two-stage regression approach was employed that decodes muscle contraction level from EEG signals in the multi-level force-matching task and translates them into: (1) presence/absence of muscle contraction as a first stage; and (2) muscle contraction level as a second stage. Dimensionality reduction of the EEG signals, using principal component analysis, avoided multicollinearity during multiple regression, and data-driven stepwise multiple regression identified EEG components that were involved in the multi-level force-matching task. Main results. An alternatively tuned two-stage regressor accurately decoded muscle contraction level with online processing rather than the conventional decoders, and identified EEG components that were related to voluntary force production. Relaxation/contraction state-dependent EEG components were localized dominantly in the contralateral parieto-temporal regions, whereas multi-level force regulation-dependent EEG components came from the fronto-parietal regions. Significance. Our findings identify respective cortical signalings during relaxation/contraction and multi-level force regulation using a sensor-based approach with EEG. Simulation-based assessment of the current physiologically inspired decoding technique proved improved accuracy in online BCI control.
The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially ...substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103
dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases.
Automated object recognition in medical images can facilitate medical diagnosis and treatment. In this paper, we automatically segmented supraclavicular nerves in ultrasound images to assist in ...injecting peripheral nerve blocks. Nerve blocks are generally used for pain treatment after surgery, where ultrasound guidance is used to inject local anesthetics next to target nerves. This treatment blocks the transmission of pain signals to the brain, which can help improve the rate of recovery from surgery and significantly decrease the requirement for postoperative opioids. However, Ultrasound Guided Regional Anesthesia (UGRA) requires anesthesiologists to visually recognize the actual nerve position in the ultrasound images. This is a complex task given the myriad visual presentations of nerves in ultrasound images, and their visual similarity to many neighboring tissues. In this study, we used an automated nerve detection system for the UGRA Nerve Block treatment. The system can recognize the position of the nerve in ultrasound images using Deep Learning techniques. We developed a model to capture features of nerves by training two deep neural networks with skip connections: two extended U-Net architectures with and without dilated convolutions. This solution could potentially lead to an improved blockade of targeted nerves in regional anesthesia.
Abstract New anti-cancer therapy with boron neutron capture therapy (BNCT) is based on the nuclear reaction of boron-10 with neutron irradiation. The median survival of BNCT patients with ...glioblastoma was almost twice as long as those receiving standard therapy in a Japanese BNCT clinical trial. In this clinical trial, two boron compounds, BPA (boronophenylalanine) and BSH (sodium borocaptate), were used for BNCT. BPA is taken up into cells through amino acid transporters that are expressed highly in almost all malignant cells, but BSH cannot pass through the cell membrane and remains outside the cell. We simulated the energy transfer against the nucleus at different locations of boron from outside the cell to the nuclear region with neutron irradiation and concluded that there was a marked difference between inside and outside the cell in boron localization. To overcome this disadvantage of BSH in BNCT, we used a cell-penetrating peptide system for transduction of BSH. CPP (cell-membrane penetrating peptide) is very common peptide domains that transduce many physiologically active substances into cells in vitro and in vivo . BSH-fused CPPs can penetrate the cell membrane and localize inside a cell. To increase the boron ratio in one BSH-peptide molecule, 8BSH fused to 11R with a dendritic lysine structure was synthesized and administrated to malignant glioma cells and a brain tumor mouse model. 8BSH-11R localized at the cell nucleus and showed a very high boron value in ICP results. With neutron irradiation, the 8BSH-11R administrated group showed a significant cancer killing effect compared to the 100 times higher concentration of BSH-administrated group. We concluded that BSH-fused CPPs were one of the most improved and potential boron compounds in the next-stage BNCT trial and 8BSH-11R may be applied in the clinical setting.
Lipid nanoparticles (LNPs) are one of the most successful technologies in messenger RNA (mRNA) delivery. While the liver is the most frequent target for LNP delivery of mRNA, technologies for ...delivering mRNA molecules to extrahepatic tissues are also important. Herein, it is reported on the development of an LNP that targets secondary lymphoid tissues. New types of alcohol‐soluble phosphatidylserine (PS) derivatives are designed as materials that target immune cells and then incorporated into LNPs using a microfluidic technique with a high degree of scalability and reproducibility. The resulting LNP that contained the synthesized PS delivered mRNA to the spleen much more efficiently compared to a control LNP. A sub‐organ analysis revealed that the PS‐loaded LNP is extensively taken up by tissue‐resident macrophages in the red pulp and the marginal zone of the spleen. Thus, the PS‐loaded LNP reported in this study will be a promising strategy for clinical applications that involve delivering mRNA to the spleen.
The alcohol‐soluble phosphatidylserine (PS) derivatives are synthesized and then loaded with lipid nanoparticles (LNP). The PS‐loaded LNPs efficiently accumulate in the spleen and deliver the messenger RNA cargo after intravenous injection. A sub‐organ analysis reveals that the PS‐loaded LNPs are extensively taken up by spleen‐resident macrophages localized in the red pulp and the marginal zone.
The post‐translational acetylation of lysine residues is found in many nonhistone proteins and is involved in a wide range of biological processes. Recently, we showed that the nucleoprotein of the ...influenza A virus is acetylated by histone acetyltransferases (HATs), a phenomenon that affects viral transcription. Here, we report that the PA subunit of influenza A virus RNA‐dependent RNA polymerase is acetylated by the HATs, P300/CREB‐binding protein‐associated factor (PCAF), and general control nonderepressible 5 (GCN5), resulting in accelerated endonuclease activity. Specifically, the full‐length PA subunit expressed in cultured 293T cells was found to be strongly acetylated. Moreover, the partial recombinant protein of the PA N‐terminal region containing the endonuclease domain was also acetylated by PCAF and GCN5 in vitro, which facilitated its endonuclease activity. Mass spectrometry analyses identified K19 as a candidate acetylation target in the PA N‐terminal region. Notably, the substitution of the lysine residue at position 19 with glutamine, a mimic of the acetyl‐lysine residue, enhanced its endonuclease activity in vitro; this point mutation also accelerated influenza A virus RNA‐dependent RNA polymerase activity in the cell. Our findings suggest that PA acetylation is important for the regulation of the endonuclease and RNA polymerase activities of the influenza A virus.
The PA subunit of influenza A virus possesses an endonuclease activity, which plays an important role for ‘cap snatching’. In this report, we discovered that PA endonuclease domain is acetylated by the host acetyltransferases P300/CREB‐binding protein‐associated factor and general control nonderepressible 5, which facilitate PA endonuclease activity. This modification is suggested to accelerate viral RNA polymerase activity in the cell. Our findings might provide new insights to understand regulation of viral transcription and replication.
Novel anion-conductive polymers containing perfluoroalkyl and ammonium-functionalized fluorene groups were synthesized and characterized. The quaternized polymers synthesized using a dimethylaminated ...fluorene monomer had a well-defined chemical structure in which each fluorenyl group was substituted with two ammonium groups at specific positions. The resulting polymers had a high molecular weight (M n = 8.9–13.8 kDa, M w = 13.7–24.5 kDa) to provide bendable thin membranes with the ion-exchange capacity (IEC) ranging from 0.7 to 1.9 mequiv g–1 by solution casting. Both transmission electron microscopy images and small-angle X-ray scattering patterns suggested that the polymer membranes possessed a nanoscale phase-separated morphology based on the hydrophilic/hydrophobic differences in the polymer components. Unlike typical anion-exchange membranes found in the literature, hydroxide ion conductivity of the membranes did not increase with increasing IEC because of their high swelling capability in water. The membrane with IEC = 1.2 mequiv g–1 showed balanced properties of high hydroxide ion conductivity (81 mS cm–1 at 80 °C in water) and mechanical strength (>100% elongation and 14 MPa maximum stress at 80 °C, 60% relative humidity). The polymer main chains were stable in 4 M KOH for 1000 h, whereas the trimethylbenzyl-type ammonium groups degraded under the conditions to cause loss in the hydroxide ion conductivity. An H2/O2 fuel cell with the membrane with IEC = 1.2 mequiv g–1 exhibited a maximum power density of 242 mW cm–2 at 580 mA cm–2 current density.
Anion exchange membrane fuel cells (AEMFCs) are one of the promising energy conversion devices because of their high efficiency and possible use of non-precious metal catalysts. However, the existing ...anion exchange membranes, main component of AEMFCs, do not show sufficient ion conductivity and stability. In this study, we report a novel series of AEMs composed of perfluoroalyl chains and ammonium-functionalized fluorenyl groups (Fig. 1). The perfluoroalkyl groups are expected to provide chemical stability as well as flexible membrane forming capability, while the ammonium-functionalized fluorenyl groups contain high ionic density for high ion conductivity. We have investigated in details synthetic procedure, structure, and properties of the title AEMs.
The hydrophobic monomer containing perfluroaklyl groups was synthesized by Cu-catalyzed Ullmann coupling reaction, and fluorenyl-containing monomers were synthesized by Sandmeyer reaction. Precursor polymers were synthesized by Ni-mediated Ullman coupling reaction. Then, chloromethyl groups were introduced onto the precursor polymers by Friedel-Crafts reaction. The chloromethyl groups were quarternized with trimethyl amine by Menshutkin reaction.
It is known that the chloromethylation reaction often accompanies with unfavorable side reactions such as cross-linking. By carefully optimizing the Friedel-Crafts reaction conditions, we have successfully controlled the degree of chloromethylation. In fact, the number and the position of chloromethyl groups substituted on fluorenyl groups were controllable.
The chloromethylated precursors were soluble in organic solvent and the solutions were cast to thin films. The ion exchange capacities obtained by titration were lower than calculate from DC. The difference of IEC value was increased with increase of DC. It is suggest that when ionic group density becomes higher, there is an ammonium group which is not functioning as ionic groups by their steric hindrance. The quaternized polymer membranes exhibited high hydroxide ion conductivity and the maximum conductivity was 29 mS/cm in water at 80 °C for the membrane with IEC = 1.6 meq/g. It was found that meta-linked polymers in the hydrophilic component showed slightly higher ion conductivity than that of para-linked polymers. Other properties such as morphologies and stabilities will also be reported.
Acknowledgement
This work was partly supported by Japanese Science and Technology Agency (JST), CREST.
References
1) Manai Shimada, Shigefumi Shimada, Junpei Miyake, Makoto Uchida, Kenji Miyatake,
J. Polym. Sci., A: Polym. Chem.,
2015
, 7,935-944.
2) Hideaki Ono, Junpei Miyake, Shigehumi Shimada, Makoto Uchida and Kenji Miyatake,
J. Mater. Chem. A
,
2015
, 3, 21779–21788.
Figure 1
PDF
