Lipopolysaccharide (LPS), the major component of the outer membrane of Gram-negative bacteria, binds Toll-like receptor 4 (TLR4)-MD2 complex and activates innate immune responses. LPS transfer to ...TLR4-MD2 is catalyzed by both LPS binding protein (LBP) and CD14. To define the sequential molecular interactions underlying this transfer, we reconstituted in vitro the entire LPS transfer process from LPS micelles to TLR4-MD2. Using electron microscopy and single-molecule approaches, we characterized the dynamic intermediate complexes for LPS transfer: LBP-LPS micelles, CD14-LBP-LPS micelle, and CD14-LPS-TLR4-MD2 complex. A single LBP molecule bound longitudinally to LPS micelles catalyzed multi-rounds of LPS transfer to CD14s that rapidly dissociated from LPB-LPS complex upon LPS transfer via electrostatic interactions. Subsequently, the single LPS molecule bound to CD14 was transferred to TLR4-MD2 in a TLR4-dependent manner. The definition of the structural determinants of the LPS transfer cascade to TLR4 may enable the development of targeted therapeutics for intervention in LPS-induced sepsis.
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•Observation of dynamic intermediated formed during LPS transfer by TEM•Reconstitution of the entire LPS transfer cascade to TLR4-MD2 on TIRF microscopy•Identification of key charged residues in LBP and CD14 for dynamic LPS transfer•CD14-LPS complex interact with TLR4 LRR13-LRR15 domain for LPS transfer to MD2
Lipopolysaccharide (LPS) of Gram-negative bacteria activates host innate immune responses. Ryu et al. investigates dynamic intermediates in the LBP-CD14-mediated LPS transfer to TLR4-MD2 down to the single-molecule resolution with negative-stain TEM and TIRF analysis, thus identifying the key molecular determinants in LBP, CD14, and TLR4 for efficient LPS transfer.
Mesenchymal stem cells (MSCs) have been proven to be therapeutically effective against atopic dermatitis (AD) in preclinical studies. However, the safety and efficacy of MSCs against AD have not yet ...been investigated in a clinical study. To establish the safety and efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) in AD, 34 adult patients with moderate-to-severe AD were enrolled in two phase trials with a follow-up for 1 month and 3 months, respectively. Patients were randomly allocated to receive low dose (2.5 × 10
) or high dose (5.0 × 10
) of hUCB-MSCs subcutaneously. An Eczema Area and Severity Index (EASI) score, Investigator's Global Assessment (IGA) score, Severity Scoring for Atopic Dermatitis (SCORAD) score, adverse effect assessments, and serum biomarker levels were evaluated as end points. A single treatment of hUCB-MSCs resulted in dose-dependent improvements in AD manifestation. Fifty-five percent of patients in high dose hUCB-MSC-treated group showed a 50% reduction in the EASI score. The IGA score and SCORAD score decreased by 33% and 50%, respectively, in high dose-treated group. Particularly, the administration of high dose hUCB-MSCs reduced the pruritus score by 58%. The serum IgE levels and number of blood eosinophils were downregulated by the treatment. No serious adverse events occurred, and none of the patients discontinued the trial due to adverse events. This is the first report to demonstrate a marked improvement of AD features with cell therapeutics. These data suggest that the infusion of hUCB-MSCs might be an effective therapy for patients with moderate-to-severe AD. Stem Cells 2017;35:248-255.
We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic ...Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).
Background/Aims: Peroral cholangioscopy (POC) has been used to assess intrahepatic duct (IHD) lesions but with a limited role. A new multibending (MB) ultraslim endoscope has been designed to improve ...POC performance. We evaluated the usefulness of POC using the MB ultraslim endoscope for the management of IHD lesions. Methods : Between March 2017 and March 2020, 22 patients underwent direct POC using the MB ultraslim endoscope for IHD lesions documented by previous imaging or cholangiopancreatography. The primary outcome was technical success of POC, and secondary outcomes were technical success of POC-guided interventions, median procedure time, and POC-related adverse events. Results : The technical success rate for POC using the MB ultraslim endoscope for IHD lesions was 95.5% (21/22). Free-hand insertion was successful in 95.2% (20/21). The overall technical success rate for POC-guided intervention was 100% (21/21), including nine diagnostic and 12 therapeutic procedures (eight direct stone removal and four intraductal lithotripsies). The median procedure time was 29 minutes (range, 9 to 79 minutes). There were no procedure-related adverse events. Conclusion : s: Direct POC using the MB ultraslim endoscope allows direct visualization of IHD lesions and may be useful for diagnosis and therapeutic management in selected patients.
Chiral photonics has emerged as a key technology for future optoelectronics, such as quantum information and encryption, by making use of photonic waves from enantiomeric structures. An inevitable ...challenge for realizing such chiral optoelectronics is the development of near‐infrared circularly polarized (NIR CP) light‐sensing photodetectors that convert optical power and circular polarization direction into distinguishable electrical signals. Herein, a simple and promising strategy for high‐performance NIR CP light‐sensing organic phototransistors (NIR CPL‐OPTRs) applicable to highly secure optoelectronic encryption is proposed. By directly assembling a standalone cholesteric liquid‐crystal network film in a thin‐film NIR CPL‐OPTR, remarkable responsivity and distinguishability are achieved. The synergetic effect of amplification of the photocurrent signal by the applied electric field and improved light absorption by the reduced reflection in the multilayered structure leads to high responsivity. As a proof‐of‐concept, the chiral phototransistor arrays are demonstrated as a physically unclonable function device and exhibit enhanced cryptographic characteristics.
High‐performance near‐infrared circularly polarized light‐sensing organic phototransistors are realized by directly assembling a standalone cholesteric liquid‐crystal network film in the near‐infrared‐sensing organic phototransistor based on a small‐bandgap polymer semiconductor. A physical unclonable function device based on the chiral phototransistor arrays can enhance cryptographic characteristics by encoding the polarization direction of the circularly polarized light.
Ruthenium (Ru) is the most widely used metal as an electrocatalyst for nitrogen (N2) reduction reaction (NRR) because of the relatively high N2 adsorption strength for successive reaction. Recently, ...it has been well reported that the homogeneous Ru‐based metal alloys such as RuRh, RuPt, and RuCo significantly enhance the selectivity and formation rate of ammonia (NH3). However, the metal combinations for NRR have been limited to several miscible combinations of metals with Ru, although various immiscible combinations have immense potential to show high NRR performance. In this study, an immiscible combination of Ru and copper (Cu) is first utilized, and homogeneous alloy nanoparticles (RuCu NPs) are fabricated by the carbothermal shock method. The RuCu homogeneous NP alloys on cellulose/carbon nanotube sponge exhibit the highest selectivity and NH3 formation rate of ≈31% and −73 μmol h−1 cm−2, respectively. These are the highest values of the selectivity and NH3 formation rates among existing Ru‐based alloy metal combinations.
An atomic‐scale homogeneous alloy of immiscible metals is first implemented in electrocatalytic nitrogen reduction (NRR) by a unique carbothermal shock method. Atomic‐scale mixing of ruthenium and copper facilitates pivotal reaction steps in NRR, showing high selectivity and formation rate to ammonia. This paves the way for developing numerous potential homogeneous alloys of immiscible metal combinations for future efficient NRR electrocatalysts.
Cholesteric liquid crystal elastomers (CLCEs) are unique anisotropic rubbers that can change their structural color in response to various stimuli such as heat, chemicals, electric fields, and ...mechanical stress. Methods such as anisotropic deswelling and surface alignment have been adopted to prepare CLCEs; however, they have limitations in creating spatially controlled CLCE geometries. In this work, a direct ink writing (DIW)‐based 3D‐printable CLCE that can be prepared by extruding viscous CLC ink is developed through a 3D printer nozzle, followed by photopolymerization. Interestingly, the helical axis is inclined to the printing direction by ≈32° due to a combination of the shear‐induced alignment causes during extrusion and the elongational force generated during deposition onto the substrate. This unusual helical axis distortion leads to both blue and red shifts of the reflection color depending on the direction of observation relative to the printing axis. Notably, the printed CLCE exhibits anisotropic mechanochromism upon stretching, because of the stretching‐direction‐dependent variations in the slant angle of the helical axis. This anisotropic mechanochromism can be harnessed to develop a unique CLCE‐based strain sensor displaying intricate color patterns upon stretching, with significant application potential in encryption, anticounterfeiting, and structural health monitoring.
Cholesteric liquid crystal elastomers (CLCEs) with slanted helices are prepared by direct ink writing‐based 3D printing. The anisotropic mechanochromic response of the printed CLCE to being stretched relative to the printing direction has been observed for the first time, thereby enabling the creation of a unique strain sensor displaying intricate color patterns.
Abstract
The study evaluated the efficacy of ID-JPL934, a probiotic preparation containing
Lactobacillus johnsonii
IDCC 9203,
Lactobacillus plantarum
IDCC 3501 and
Bifidobacterium lactis
IDCC 4301, ...in relieving lower gastrointestinal symptoms. A total of 112 subjects with lower gastrointestinal symptoms were consecutively enrolled. They were randomized into either ID-JPL934 administration group or placebo group. Bristol stool form, stool frequency, and abnormal bowel movement symptoms were recorded at baseline and week 2, 6, and 8. Primary endpoint was improvement in overall symptoms at week 8. Fecal samples were collected to measure the probiotic levels in feces using quantitative polymerase chain reaction (qPCR), and to perform metagenomic analysis of microbiome originating from bacteria-derived extracellular vesicles and bacterial cells via 16S rDNA sequencing. Of the 112 subjects, 104 (54 in ID-JPL934 group and 50 in placebo group) completed the entire study protocol. A higher relief of overall symptoms was found in ID-JPL934 group than in placebo group (
p
= 0.016). Among lower gastrointestinal symptoms, abdominal pain and bloating scores were more decreased in ID-JPL934 group than in placebo group (
p
< 0.05). The fecal microbiome profiles of the two groups did not differ. However, the qPCR analysis showed significant increase in the levels of
Lactobacillus johnsonii
and
Bifidobacterium lactis
in feces post-treatment in ID-JPL934 group than in placebo group (
p
< 0.05 by repeated measure ANOVA). In conclusion, ID-JPL934 is effective in relieving lower gastrointestinal symptoms. Exposure to ID-JPL934 may increase the abundance of
Lactobacillus johnsonii
and
Bifidobacterium lactis
in the gut.
Trial registration:
ClinicalTrials.gov number, NCT03395626.
The potent core: A new approach to preparing highly magnetic nanoparticles consisting of a ferromagnetic core (Fe) and an artificial ferrite shell was developed. The monometallic core contributes to ...high overall magnetization. The superparamagnetic ferrite shell protects the core against oxidation and further increases magnetization while minimizing particle aggregation.
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