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Electrical acupoint stimulation (EAS) has been used to treat motor dysfunction of stroke patients with reportedly effective results. When we operate EAS treatment, we can modulate the intensity and frequency of stimulation. The purpose of this study is to evaluate the effect of different frequencies in treating motor dysfunction of ischemic stroke patients with EAS. The subjects of this study were 62 ischemic stroke patients with motor dysfunction in Kyunghee oriental medical center. They have been hospitalized after 1 week to 1 month from onset. They were treated with 2 Hz or 120 Hz EAS for 2 weeks, and had motor evoked potentials (MEPs) tests before and after 2 weeks of EAS treatment. We measured latency, central motor conduction time (CMCT) and amplitude of MEPs. After 2 weeks of treatment, we compared MEPs data of the affected side between the 2 Hz group and the 120 Hz group. The 2 Hz group showed more significant improvement than the 120 Hz group in latency, CMCT and amplitude (p = 0.008, 0.002, 0.002). In the case of the affected side MEPs data divided by normal side MEPs data, the 2 Hz group also showed higher improvement rate than the 120 Hz group in latency, CMCT and amplitude with significant differences (p = 0.003, 0.000, 0.008). These results suggest that low frequency EAS activates the central motor conduction system better than high frequency EAS, and EAS with low frequency could be more helpful for motor recovery after ischemic stroke than that with high frequency. [ABSTRACT FROM AUTHOR]

This study was conducted to test the effectiveness of moxibustion therapy for patients with post-stroke urinary symptoms using International Prostate Symptom Score (IPSS). Stroke patients with urinary symptoms were enrolled and assigned into the moxibustion group (MO group) and the control group by stratified randomization. The MO group received moxibustion treatment on Zhong-Ji (CV-3), Guan-Yuan (CV-4) and Qi-Hai (CV-6) for 10 days, and the control group did not receive it. The effectiveness of urinary symptoms and activities of daily living were measured by IPSS and Barthel Index (BI), respectively. These scales were examined by an independent blinded neurologist before treatment, and 10 days after therapy. Thirty nine subjects (20 in the MO group and 19 in the control group) were included in the final analysis. The MO group showed more improvement on urinary symptoms than the control group. In conclusion, we suggest that moxibustion on Zhong-Ji (CV-3), Guan-Yuan (CV-4) and Qi-Hai (CV-6) is effective to post-stroke urinary symptoms. [ABSTRACT FROM AUTHOR]

This study was to test the importance of patterns identification (PI) and the effectiveness of Hwangryunhaedogtang (Huanglianjiedutang) (HT) treatment for patients with post stroke pathological laughter (PL). Fourteen subjects were enrolled. Eight subjects diagnosed with Yang Excess patterns (YEP) were assigned into group A and 6 subjects who had no YEP to group B. HT was administrated 3 times a day for 14 days to both groups. The duration of PL at one time, the frequency of PL in a day, and pathological laughter scale (PLS) were the primary outcome measures. Barthel index (BI) was the secondary outcome measure. The duration and the frequency of PL in group A were significantly decreased from 10.88 +/- 4.67 to 6.63 +/- 4.07 sec and from 6.38 +/- 2.72 to 3.00 +/- 1.77 times, respectively (p = 0.01) after 14 days administration of HT. PLS in group A was also significantly lowered from 9.13 +/- 1.73 to 4.75 +/- 0.71 points (p = 0.01). However, significant differences were not observed in BI in group A and in the primary and secondary outcome measures in group B. The duration and the frequency of PL and PLS were more markedly reduced in group A than in group B (p = 0.01, 0.02, and < 0.01, respectively). These results suggested that HT could be effective on subjects with post stroke PL diagnosed as YEP and PI, that prescription of herbal medications to such patients should be considered. [ABSTRACT FROM AUTHOR]

Arterial stiffness is an important, independent determinant of cardiovascular risk. Pulse wave velocity (PWV) has been used as a valuable index of arterial stiffness and as a surrogate marker for atherosclerosis. Chunghyul-dan (CHD) has anti-hyperlipidemic activity, anti-inflammatory activity and anti-atherogenic effects. To determine its clinical effect on increased arterial stiffness, we examined whether CHD improves arterial stiffness in patients with increased brachial-ankle PWV (baPWV). Thirty-five subjects with increased baPWV (> 1400 cm/sec) were recruited and randomized to a treatment group (20 subjects) or a control group (15 subjects). The treatment group was administered CHD at a dose of 600 mg three times a day for 8 weeks, and the control group received no medication (observation only). baPWV was assessed using a pulse pressure analyzer at baseline and after 8 weeks. Blood pressure and serum lipid profile were monitored in the treatment group. Our results indicate that baPWV was lowered significantly in the treatment group after 8 weeks of medication (p < 0.05), but not in the control group. Moreover, there were no significant changes in blood pressure and serum lipids profile except triglyceride level suggesting that the effect is largely independent of CHD's lipid-lowering effect or a blood pressure change. In conclusion, CHD appears to improve arterial stiffness in patients with increased PWV. [ABSTRACT FROM AUTHOR]

Hypertension is one of the modifiable risk factors for stroke. Lowering blood pressure is helpful for primary and secondary prevention of stroke. This study is aimed to assess the efficacy of Chunghyul-dan on stroke patients with stage 1 hypertension using 24 hours ambulatory blood pressure monitoring (24ABPM). Forty hospitalized stroke patients with stage 1 hypertension were included in the study and they were randomly assigned into two groups: group A was treated with Chunghyul-dan 1200 mg once a day for 2 weeks, while group B was not. Twelve subjects were dropped out because of unexpected early discharge or data errors, thus the remaining 28 subjects were included in the final analysis (15 in group A and 13 in group B). Blood pressure was monitored every 30 minutes for 24 hours at baseline and 2 weeks after medication. Blood pressure, pulse rate, trough/peak ratio (TPR) [the value calculated by dividing the blood pressure change at trough (22 to 24 hours after drug intake) by the change at peak (2 adjacent hours with a maximal blood pressure reduction between the second and eighth hour after drug intake)] and smoothness index (SI) (the value calculated as the ratio between the average of the 24 hours, treatment-induced blood pressure changes and its standard deviation) were compared to assess the efficacy of Chunghyul-dan. To assess the safety of Chunghyul-dan, any adverse effects during medication period were monitored. There was no significant difference in the baseline assessment between the two groups. Systolic blood pressure was lower in group A than in group B (141.37+/-8.96 mmHg versus 132.28+/-9.46 mmHg, P = 0.03), while diastolic blood pressure and pulse rate had no significant difference between the two groups. Systolic TPR and SI was 0.87 and 1.04 in group A, respectively. This suggests that Chunghyul-dan have anti-hypertensive effect on stroke patients with stage 1 hypertension. [ABSTRACT FROM AUTHOR]

This is the first study that focuses on the effects of intradermal acupuncture on insomnia after stroke. We enrolled hospitalized stroke patients with insomnia and assigned them into a real intradermal acupuncture group (RA group) or a sham acupuncture group (SA group) by randomization. The RA group received intradermal acupuncture on shen-men (He-7) and nei-kuan (EH-6) for 2 days, and the SA group received sham acupuncture on the same points. The effectiveness was measured by the Morning Questionnaire (MQ), Insomnia Severity Index (ISI), and Athens Insomnia Scale (AIS). These scales were examined by an independent, blinded neurologist before, and 1 and 2 days after treatment, repeatedly. Thirty subjects (15 in the RA group and 15 in the SA group) were included in the final analysis. The RA group showed more improvement on insomnia than the SA group. Repeated measures analysis detected that there were significant between-subjects effects in the MQ, the ISI and the AIS. In conclusion, we suggest that intradermal acupuncture on shen-men and nei-kuan is a useful treatment for post stroke-onset insomnia. [ABSTRACT FROM AUTHOR]

Chungpyesagan-tang is one of the most well-known traditional herbal formulations frequently used for treatment of acute stroke in Korea. Therefore, this study aims to assess the clinical safety and efficacy of chungpyesagan-tang on acute ischemic stroke. We recruited acute cerebral infarction subjects within 1 week after onset time. Then, we prescribed chungpyesagan-tang to an Oriental medical treatment group (OM-group) for 2 weeks and enrolled a Western medical treatment group (WM-group) which received only Western biomedical care as a control. In this study, the OM-group was composed of 75 subjects. However, 14 of them dropped out, as two had progressive stroke while 12 complained of diarrhea. Thus, 61 cases were included in the analysis and compared to the 76 cases of the WM-group. The improvement of OM-group was better than that of the WM-group according to the National Institute of Health Stroke Scale (NIHSS), but not by the Modified Barthel Index (MBI). There were no definite abnormalities on labortory safety asessment. Therefore, we suggest that chungpyesagan-tang may have therapeutic effects, acting to reduce the severity of stroke and improving functional recovery without definite hepatic or renal toxicity when given for the first 2 weeks after a stroke. [ABSTRACT FROM AUTHOR]

Background: Bone defects are commonly encountered due to accidents, diseases, or aging, and the demand for effective bone regeneration, particularly for dental implants, is increasing in our aging society. Mesenchymal stem cells (MSCs) are promising candidates for regenerative therapies; however, obtaining sufficient quantities of these cells for clinical applications remains challenging. DW-MSCs, derived from embryonic stem cells and developed by Daewoong Pharmaceutical, exhibit a robust proliferative capacity even after extensive culture., Methods: This study explores the therapeutic potential of DW-MSCs in various animal models of bone defects. DW-MSCs were expanded for over 13 passages for in vivo use in rat and canine models of bone defects and osteomyelitis. The research focused on the in vivo osteogenic differentiation of DW-MSCs, the establishment of a fibrin-based system for bone regeneration, the assessment of bone repair following treatment in animal models, and comparisons with commercially available bone grafts., Results: Results showed that DW-MSCs exhibited superior osteogenic differentiation compared to other materials, and the fibrinization process not only preserved but enhanced their proliferation and differentiation capabilities through a 3D culture effect. In both bone defect models, DW-MSCs facilitated significant bone regeneration, reduced inflammatory responses in osteomyelitis, and achieved effective bone healing. The therapeutic outcomes of DW-MSCs were comparable to those of commercial bone grafts but demonstrated qualitatively superior bone tissue restructuring., Conclusion: Our findings suggest that DW-MSCs offer a promising approach for bone regeneration therapies due to their high efficacy and anti-inflammatory properties., Competing Interests: Declarations. Conflict of interest: The authors declare that there are no commercial or financial conflicts of interest in conducting this research. Ethical statement: All animal study procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Gyeongsang National University (GNU-191015-D0053) and conducted in strict compliance with the Guidelines for Care and Use of Laboratory Animals at the School of Medicine, Gyeongsang National University., (© 2024. Korean Tissue Engineering and Regenerative Medicine Society.)

Lung tissue-resident memory T (T RM ) cells induced by influenza vaccination are crucial for heterosubtypic immunity upon re-exposure to the influenza virus, enabling rapid and robust responses upon reactivation. To enhance the efficacy of influenza vaccines, we induce the generation of lung T RM cells following intranasal vaccination with a commercial influenza vaccine adjuvanted with NexaVant (NVT), a TLR3 agonist-based adjuvant. We demonstrate that intranasal immunization with the NVT-adjuvanted vaccine provides improved protection against influenza virus infections by inducing the generation of CD4 + T RM cells in the lungs in a type I interferon-dependent manner. These pulmonary CD4 + T RM cells provide potent mucosal immunity and cross-protection against heterosubtypic infections in both mouse and ferret models. This vaccine platform has the potential to significantly improve conventional intramuscular influenza vaccines by providing broader protection., Competing Interests: Competing interests: K.H.K., H.S.B., D.-H.K., and S.B.C. are employees of the NA Vaccine Institute Research and Development Center. J.H. and H.P. are employees of Il-Yang Pharmaceutical. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Artificial photosynthesis of hydrogen peroxide (H 2 O 2 ) presents a promising environmentally friendly alternative to the industrial anthraquinone process. This work designed ultrathin metal-organic framework (MOF) nanosheets on which porphyrin ligand as an electron donor (D) and anthraquinone (AQ) as an electron acceptor (A) are integrated as the D-A complexes. The porphyrin component allows the MOF nanosheets to absorb full-spectrum solar light while the acceptor AQ motif promotes central aluminum ion coordination, hindering layer stacking to achieve a thickness of 1.0 nm. The ultrathin D-A design facilitates the separation of electrons from the MOF skeleton to the AQ motif, which induces the direct two-electron oxygen reduction reaction (ORR) mediated by the reversible redox couple of AQ-AQH 2 and multielectron water oxidation reaction (WOR) driven by holes remaining on the porphyrin part. In O 2 -saturated water, the ultrathin MOF nanosheets outperformed the AQ-free bulk and multilayered counterparts by 2.9 and 2.6 times in H 2 O 2 production, respectively, achieving the apparent quantum yield of 4.8% at 420 nm. It also surpasses other benchmark photocatalysts, including the typical MOF photocatalyst, MIL-125-NH 2 , and organic polymeric photocatalysts. The ultrathin D-A MOF photocatalyst generated H 2 O 2 via both two-electron ORR as a major path and two-electron WOR as a minor path. This approach presents a promising strategy for the rational design of efficient nanostructured photocatalysts for solar fuels and chemicals.

We performed intra- and intermolecular charge transfer (CT) excitation energy calculations of (a) conjugated carbon chain [H 2 N-(CH=CH) n -X] and (b) its equidistant H 2 NH∙∙∙H X ( n = 2~8) with various electron acceptors ( X = NH 2 , OH, Cl, CHO, CN, and NO 2 ) using EOM-CCSD, time-dependent (TD) Hartree-Fock (HF) and various density functional theory (DFT) functionals, such as BLYP, B3LYP, long-range corrected (LC) DFT, and LC-DFT with an optimally tuned (OT) range separation parameter ( µ ) using Koopman's theorem to investigate the effect of the electron-withdrawing (or -donating) strength of end-capped functional group ( X ) and CT distance ( R ) on intra- and intermolecular CT excitation energies. As the electron-withdrawing strength of X increases, both intra- and intermolecular CT excitation energies tend to decrease, since energy gaps between orbitals corresponding to CT excitations (e.g., HOMO and LUMO) decrease. However, the effect of the electron-withdrawing group on intramolecular CT excitation energy is negligible (at most 0.5 eV). OT-LC-DFT shows accurate intermolecular CT excitation energy, but worse results in intramolecular CT excitation energy than LC-DFT with the default µ value (0.47). Therefore, we conclude that the optimal tuning method is not effective in predicting intramolecular CT excitation energy. While intermolecular CT excitation energy has excitonic binding energy with asymptotic behavior to CT distance that is not affected by the choice of range separation parameter, intramolecular CT excitation energy is affected by orbital relaxation energy, which strongly depends on the choice of range separation parameter, which makes the OT method of range separation parameter ineffective in predicting intramolecular CT excitation energy as well as local excitation with high accuracy.

The electrocatalytic conversion of NO offers a promising technology for not only removing the air pollutant but also synthesizing valuable chemicals. We design an integrated-electrocatalysis cell featuring metal organic framework (MOF)-modified gas diffusion electrodes for simultaneous capture of NO and generation of NH 4 NO 3 under low-concentration NO flow conditions. Using 2% NO gas, the modified cathode exhibits a higher NH 4 + yield and Faradaic efficiency than an unmodified cathode. Notably, the modified cathode shows a twofold increase in NH 4 + production with 20 ppm NO gas supply. Theoretical calculations predict favorable transfer of adsorbed NO from the adsorption layer to the catalyst layer, which is experimentally confirmed by enhanced NO mass transfer from gas to electrolyte across the modified electrode. The adsorption layer-modified anode also exhibits a higher NO 3 - yield for NO electro-oxidation compared to the unmodified electrode under low NO concentration flow. Among various integrated-cell configurations, a single-chamber setup produces a higher NH 4 NO 3 yield than a double-chamber setup. Furthermore, a higher NO utilization efficiency is obtained with a single-gasline operation mode, where the NO-containing gas flows sequentially from the cathode to the anode., (© 2024. The Author(s).)

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs)., Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment., Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed., Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure., Clinical Trial Number: NCT03780543., Impact and Implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir., Competing Interests: M-FY reports being an advisor/consultant for AbbVie, AiCuris, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Roche, Sysmex Corporation, Tune Therapeutics, Vir Biotechnology, and Visirna Therapeutics and receiving grant/research support from AbbVie, Arrowhead Pharmaceuticals, Assembly Biosciences, Fujirebio Incorporation, Gilead Sciences, Immunocore, Roche, and Sysmex Corporation. SF reports receiving fees for speaking and teaching and/or serving on advisory committees for AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, Lupin, Novo Nordisk, Pfizer, and Springbank Pharma. XM reports being a consultant and being on the speakers' bureau for Gilead Sciences. TTN reports receiving research grant support from Assembly Biosciences and Gilead Sciences. TH reports being on the advisory committee, review panel, or consulting for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Mallinckrodt Pharmaceuticals, Merck, and Organovo and receiving research support from AbbVie, Allergan, Assembly Biosciences, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CARA, Cytodyn, DURECT Corporation, Enanta Pharmaceuticals, Galectin Therapeutics, Gilead Sciences, Grifols, Intercept Pharmaceuticals, Janssen, Merck, Mirum, Novartis, Novo Nordisk, Nucorion Pharmaceuticals, Pfizer, Salix Pharmaceuticals, Sonic Incytes, Terns Pharmaceuticals, and Valeant. H-WH reports serving on the National Advisory Board and receives research grant support from Gilead Sciences. ME reports receiving grants from AbbVie, Bristol-Myers Squibb, Eisai, Gilead Sciences, and Roche and serving on advisory boards for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. RGN reports having served on advisory boards and as a speaker for Gilead Sciences, Janssen, and Merck and having conducted research for AbbVie, Gilead Sciences, Janssen, and Merck. JSP reports receiving research grants from Assembly Biosciences and GlaxoSmithKline and consulting fees from Gilead Sciences. IMJ reports being a consultant or on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Gilead Sciences, Intercept Pharmaceuticals, Janssen, and Roche; having conducted research (all payments to institution) for Assembly Biosciences, Bristol-Myers Squibb, Cymabay, Eli Lilly, Enanta Pharmaceuticals, Genfit, Gilead Sciences, Intercept, Janssen, Merck, and Novo Nordisk; receiving payment from the Chronic Liver Disease Foundation for manuscript preparation; and participating on a Data Monitoring Committee for Altimmune, Arrowhead Pharmaceuticals, Galmed, GlaxoSmithKline, and Takeda. WSA reports being a member of the speaking bureau for Gilead Sciences and Intercept Pharmaceuticals and has received research grants from Genfit, GlaxoSmithKline, Intercept Pharmaceuticals, Ipsen, Madrigal, Mirum, Pfizer, and Zydus. S-HH reports being a consultant and being on the speakers' bureau for Gilead Sciences. EJG reports serving on advisory boards for AbbVie, Aligos Therapeutics, Assembly Biosciences, Gilead Sciences, GlaxoSmithKline, Intellia, Janssen, Roche, Vir Biotechnology, and Virion and having served as a speaker for Abbott Diagnostics, AbbVie, and Gilead Sciences. KZ, RY, and SJK report being employees of and holding stock interest in Assembly Biosciences. JM and LMS report being former employees of and holding stock interest in Assembly Biosciences. MBo reports being a member of the speaking bureau for AbbVie, Gilead Sciences, and Intercept Pharmaceuticals and has received research support from Assembly Biosciences, Boehringer Ingelheim, Gilead Sciences, Intercept Pharmaceuticals, Inventiva, and Viking Therapeutics. FW reports being a study investigator for AbbVie. AR reports receiving grant support, lecture fees, and advisory board fees from AbbVie, Celgene, Gilead Sciences, Intercept Pharmaceuticals, Merck, and Novartis. MBe reports having no conflicts of interest. NR reports advising, being on the speakers’ bureau for, and receiving grants from AbbVie and Gilead Sciences; being on the speakers’ bureau for Onyx and Salix; and having received grants from Bristol-Myers Squibb and Merck. SC reports receiving clinical trial–related payments from Assembly Biosciences. DTD reports being a consultant for Gilead Sciences and Intercept Pharmaceuticals. PYK reports being an advisor/consultant for AbbVie, Aligos Therapeutics, Antios Therapeutics, Enanta Pharmaceuticals, Gilead Sciences, and Janssen and receives grant/research supports from Altimmune, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Eiger Biopharmaceuticals, and Target Registries. ERS reports receiving research and grant support from Assembly Biosciences, Celgene, the University of Florida (TARGET), and Vir Biotechnology and receives royalties from the Schiff Diseases of the Liver, 12th edition. HSB reports having consultancy agreements with and receiving research support from Bristol-Myers Squibb and Gilead Sciences. JL reports having no conflicts of interest. KA reports being on the advisory board, a consultant, and a speaker for AbbVie, Aligos, Arbutus Biopharma, Assembly Biosciences, Bristol-Myers Squibb, Gilead Sciences, Immunocore, Janssen, Merck, Novartis, Roche, Shinogi, Sobi, and Vir Biotechnology and receiving grants from Bristol-Myers Squibb, Gilead Sciences, and Roche. MSS reports receiving grants from AbbVie, Assembly Biosciences, GlaxoSmithKline, Janssen, the National Institutes of Health, and Vir Biotechnology and receiving personal fees from AbbVie, Antios Therapeutics, Arbutus Biopharma, Atea Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, F2G, Immunocore, Precision Biosciences, and Virion Therapeutics. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Background: Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that play an important role in cancer progression. Although the mechanism by which CAFs promote tumorigenesis has been well investigated, the underlying mechanism of CAFs activation by neighboring cancer cells remains elusive. In this study, we aim to investigate the signaling pathways involved in CAFs activation by gastric cancer cells (GC) and to provide insights into the therapeutic targeting of CAFs for overcoming GC., Methods: Alteration of receptor tyrosine kinase (RTK) activity in CAFs was analyzed using phospho-RTK array. The expression of CAFs effector genes was determined by RT-qPCR or ELISA. The migration and invasion of GC cells co-cultured with CAFs were examined by transwell migration/invasion assay., Results: We found that conditioned media (CM) from GC cells could activate multiple receptor tyrosine kinase signaling pathways, including ERK, AKT, and STAT3. Phospho-RTK array analysis showed that CM from GC cells activated PDGFR tyrosine phosphorylation, but only AKT activation was PDGFR-dependent. Furthermore, we found that connective tissue growth factor (CTGF), a member of the CCN family, was the most pronouncedly induced CAFs effector gene by GC cells. Knockdown of CTGF impaired the ability of CAFs to promote GC cell migration and invasion. Although the PDGFR-AKT pathway was pronouncedly activated in CAFs stimulated by GC cells, its pharmacological inhibition affected neither CTGF induction nor CAFs-induced GC cell migration. Unexpectedly, the knockdown of SRC and SRC-family kinase inhibitors, dasatinib and saracatinib, significantly impaired CTGF induction in activated CAFs and the migration of GC cells co-cultured with CAFs. SRC inhibitors restored the reduced expression of epithelial markers, E-cadherin and Zonula Occludens-1 (ZO-1), in GC cells co-cultured with CAFs, as well as CAFs-induced aggregate formation in a 3D tumor spheroid model., Conclusions: This study provides a characterization of the signaling pathways and effector genes involved in CAFs activation, and strategies that could effectively inhibit it in the context of GC. Video Abstract., (© 2023. The Author(s).)

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC BMP2 ) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC BMP2 were associated with migration and growth. MSC BMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC BMP2 . MSC BMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3 + CD25 + Treg of CD4 + cells were further increased in ALI mice treated with MSC BMP2 . In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC BMP2 . Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC BMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2023. The Korean Association of Immunologists.)

Purpose of this study was to compare the complication rates between reverse-tapered and nontapered peripherally inserted central catheters (PICCs). In total, 407 patients who had an inpatient clinic-based PICC insertion between September 2019 and November 2019 were retrospectively analyzed. Seven PICC types were used (4 reverse tapered: 4-Fr single-lumen (n = 75), 5-Fr single-lumen (n = 78), 5-Fr double-lumen (n = 62), and 6-Fr triple-lumen (n = 61); 3 nontapered: 4-Fr single-lumen (n = 73), 5-Fr double-lumen (n = 30), and 6-Fr triple-lumen (n = 23)). Complications such as periprocedural bleeding, delayed bleeding, inadvertent removal, catheter obstruction by thrombosis, infection, and leakage were investigated. The overall complication rate was 27.1%. The complication rate was significantly higher for nontapered PICCs than reverse-tapered PICCs (50.0% vs 16.7%, P < 0.001). The overall periprocedural bleeding rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (27.0% vs 6.2%, P <0.001). The overall inadvertent removal rate was significantly higher for nontapered PICCs than for reverse-tapered PICCs (15.1% vs 3.3%, P < 0.001). There were no other significant differences in complication rates. Nontapered PICCs were associated with higher rates of periprocedural bleeding and inadvertent removal than reverse-tapered PICCs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bae et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

ConspectusEmploying semiconductor materials is a popular engineering method to harvest solar energy, which is widely investigated for photocatalysis (PC) and photoelectrocatalysis (PEC) that convert solar light to chemical energy. In particular, environmental photo(electro)catalysis has been extensively studied as a sustainable method for water treatment, air purification, and resource recovery. Environmental PC/PEC processes working in ambient conditions are initiated mainly through hole transfer to water (water oxidation) and electron transfer to dioxygen (O 2 reduction) and the subsequent photoredox transformation of water and dioxygen serves as a base of various PC/PEC systems. Through the redox transformations, different products can be generated depending on the number of transferred electrons and holes. The single electron/hole transfer generates radical species and reactive oxygen species (ROS) which initiate the degradation/transformation of various pollutants in water and air, while the multicharge transfer can generate energy-rich chemicals (e.g., H 2 , H 2 O 2 ). Therefore, understanding the characteristics of the photoredox reactions of water and dioxygen on the semiconductor surface is critically important in controlling the selectivity and efficiency of photoconversion processes.In this Account, we describe various environmental PC/PEC conversions with a particular focus on how the phototransformation of dioxygen and water is related to the overall processes occurring on diverse semiconductor materials. The activation of water or dioxygen can be controlled by modifying the properties of semiconductors, changing the kind of counterpart half-reaction and the experimental conditions. If water can be used as a ubiquitous reductant under solar irradiation, many kinds of reductive transformations can be carried out under ambient environmental conditions. For example, various toxic oxyanions (or metal ions) can be reductively transformed to harmless or less harmful species or useful chemicals/fuels can be synthesized under ambient conditions if water can provide electrons and protons via solar water oxidation. On the other hand, dioxygen can turn into reactive oxygen species (ROS) as a versatile oxidant or to a chemical like H 2 O 2 . There should be many more possibilities of utilizing the photoconversion of water and dioxygen for environmentally significant purposes, which are yet to be further developed and demonstrated. In this Account, we highlight the recent strategies and the novel functional materials for effective activation of water and dioxygen in environmental PC/PEC systems. Design of environmentally functional PC/PEC systems should be based on better understanding of water and dioxygen activation.

Synthetic double-stranded RNA analogs recognized by Toll-like receptor 3 (TLR3) are an attractive adjuvant candidate for vaccines, especially against intracellular pathogens or tumors, because of their ability to enhance T cell and antibody responses. Although poly(I:C) is a representative dsRNA with potent adjuvanticity, its clinical application has been limited due to heterogeneous molecular size, inconsistent activity, poor stability, and toxicity. To overcome these limitations, we developed a novel dsRNA-based TLR3 agonist named NexaVant (NVT) by using PCR-coupled bidirectional in vitro transcription. Agarose gel electrophoresis and reverse phase-HPLC analysis demonstrated that NVT is a single 275-kDa homogeneous molecule. NVT appears to be stable since its appearance, concentration, and molecular size were unaffected under 6 months of accelerated storage conditions. Moreover, preclinical evaluation of toxicity under good laboratory practices showed that NVT is a safe substance without any signs of serious toxicity. NVT stimulated TLR3 and increased the expression of viral nucleic acid sensors TLR3, MDA-5, and RIG-1. When intramuscularly injected into C57BL/6 mice, ovalbumin (OVA) plus NVT highly increased the migration of dendritic cells (DCs), macrophages, and neutrophils into inguinal lymph node (iLN) compared with OVA alone. In addition, NVT substantially induced the phenotypic markers of DC maturation and activation including MHC-II, CD40, CD80, and CD86 together with IFN-β production. Furthermore, NVT exhibited an appropriate adjuvanticity because it elevated OVA-specific IgG, in particular, higher levels of IgG2c (Th1-type) but lower IgG1 (Th2-type). Concomitantly, NVT increased the levels of Th1-type T cells such as IFN-γ + CD4 + and IFN-γ + CD8 + cells in response to OVA stimulation. Collectively, we suggest that NVT with appropriate safety and effectiveness is a novel and promising adjuvant for vaccines, especially those requiring T cell mediated immunity such as viral and cancer vaccines., Competing Interests: Author KK, SC, S-HL, HB, CH, M-GL and D-HK are employed by NA Vaccine Institute Research and Development Center. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ko, Cha, Lee, Bae, Ham, Lee, Kim and Han.)

Aim: This study aims to develop a cardiac arrest prediction model using deep learning (CAPD) algorithm and to validate the developed algorithm by evaluating the change in out-of-hospital cardiac arrest patient prognosis according to the increase in scene time interval (STI)., Methods: We conducted a retrospective cohort study using smart advanced life support trial data collected by the National Emergency Center from January 2016 to December 2019. The smart advanced life support data were randomly partitioned into derivation and validation datasets. The performance of the CAPD model using the patient's age, sex, event witness, bystander cardiopulmonary resuscitation (CPR), administration of epinephrine, initial shockable rhythm, prehospital defibrillation, provision of advanced life support, response time interval, and STI as prediction variables for prediction of a patient's prognosis was compared with conventional machine learning methods. After fixing other values of the input data, the changes in prognosis of the patient with respect to the increase in STI was observed., Results: A total of 16,992 patients were included in this study. The area under the receiver operating characteristic curve values for predicting prehospital return of spontaneous circulation (ROSC) and favorable neurological outcomes were 0.828 (95% confidence interval 0.826-0.830) and 0.907 (0.914-0.910), respectively. Our algorithm significantly outperformed other artificial intelligence algorithms and conventional methods. The neurological recovery rate was predicted to decrease to 1/3 of that at the beginning of cardiopulmonary resuscitation when the STI was 28 min, and the prehospital ROSC was predicted to decrease to 1/2 of its initial level when the STI was 30 min., Conclusion: The CAPD exhibits potential and effectiveness in identifying patients with ROSC and favorable neurological outcomes for prehospital resuscitation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2022. Published by Elsevier Inc.)

Background & Aims: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV., Methods: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log 10 HBV DNA from Baseline to Week 12 and 24., Results: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log 10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log 10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury., Conclusions: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile., Clinical Trial Number: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted., Competing Interests: Conflict of interest Mark S. Sulkowski reports receiving grants from AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and the National Institutes of Health; and receiving personal fees from AbbVie, Antios Therapeutics, Arbutus Biopharma, Atea Pharmaceuticals, Gilead Sciences, FH360, and Immunocore. Kosh Agarwal reports being on the advisory board, a consultant, and a speaker for AbbVie, Assembly Biosciences, Aligos, Arbutus, Bristol-Myers Squibb, Gilead Sciences, Immunocore, Janssen, Merck, Novartis, Roche, Sobi, Shinoigi, and Vir; and receiving grants from Bristol-Myers Squibb, Gilead Sciences, and Roche. Xiaoli Ma reports being a consultant and being on the speakers bureau for Gilead Sciences. Tuan T. Nguyen reports receiving research grant support from Gilead Sciences and Assembly Biosciences. Eugene R. Schiff reports receiving research and grant support from Assembly Biosciences, Celgene, and the University of Florida (TARGET) and receives royalties from the Schiff Diseases of the Liver, 12th edition. Hie-Won L. Hann reports serving on the National Advisory Board and receives research grant support from Gilead Sciences. Douglas T. Dieterich reports being a consultant for Gilead Sciences and Intercept Pharmaceuticals. Ronald G. Nahass reports having served on advisory boards and as a speaker for Gilead Sciences, Merck, and Janssen; and having conducted research for Gilead Sciences, Merck, Janssen, and AbbVie. James S. Park reports receiving research grants from Assembly Biosciences and GlaxoSmithKline and consulting fees from Gilead Sciences. Sing Chan reports receiving clinical trial–related payments from Assembly Biosciences. Steven-Huy Han reports being a consultant and being on the speakers bureau for Gilead Sciences. Edward J. Gane reports serving on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Avilia Therapeutics, Clear B Therapeutics, Dicerna, Enanta Pharmaceuticals, Finch Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunocore, Janssen, Roche, Silverback, and Vir Bio; and having served as a speaker for Gilead Sciences, AbbVie, and Roche. Michael Bennett reports having no conflicts of interest. Katia Alves reports being a former employee of and holding stock interest in Assembly Biosciences. Marc Evanchik reports having been an employee of and holding stock interest in Assembly Biosciences and is currently an employee of Edgewise Therapeutics. Ran Yan reports being an employee of and holding stock interest in Assembly Biosciences. Qi Huang reports being an employee of and holding stock interest in Assembly Biosciences. Uri Lopatin reports being a former employee and holding stock interest in Assembly Biosciences. Richard Colonno reports being an employee of and holding stock interest in Assembly Biosciences. Julie Ma reports being an employee of and holding stock interest in Assembly Biosciences. Steven J. Knox reports being an employee of and holding stock interest in Assembly Biosciences. Luisa M. Stamm reports being an employee of and holding stock interest in Assembly Biosciences. Maurizio Bonacini reports being a member of the speaking bureau for Intercept Pharmaceuticals, Gilead Sciences, and AbbVie and has received research support from Assembly Biosciences, Intercept Pharmaceuticals, Viking Therapeutics, and Boehringer Ingelheim. Ira M. Jacobson reports being a consultant or on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Gilead Sciences, Janssen, Madrigal and Virion; having conducted research (all payments to institution) for Assembly Biosciences, Bristol-Myers Squib, Eli Lilly, Enanta Pharmaceuticals, Gilead Sciences, Janssen, Merck, and Novo Nordisk; receiving payment from the Chronic Liver Disease Foundation for manuscript preparation; and reports participation on a Data Safety Monitoring Board for GSK, Redhill, Galmed, NeuroBo, and Arrowhead Pharmaceuticals. Walid S. Ayoub reports being a member of the speaking bureau for both Gilead Sciences and Intercept Pharmaceuticals and has conducted research for Assembly Biosciences, Intercept Pharmaceuticals, Enanta Pharmaceuticals, and Gilead Sciences. Frank Weilert reports being a study investigator for AbbVie. Natarajan Ravendhran reports advising, being on the speakers’ bureau for, and receiving grants from Gilead Sciences and AbbVie; being on the speakers' bureau for Salix and Onyx; and having received grants from Bristol-Myers Squibb and Merck. Alnoor Ramji reports receiving grant support, lecture fees, and advisory board fees from AbbVie, Celgene, Gilead Sciences, Intercept Pharmaceuticals, Novartis, and Merck. Paul Yien Kwo reports being an advisor/consultant for AbbVie, Aligos Therapeutics, Antios Therapeutics, Enanta Pharmaceuticals, Gilead Sciences, Janssen, and receives grant/research supports from Assembly Biosciences, Arrowhead Pharmaceuticals, Eiger Biopharmaceuticals, Bristol-Myers Squibb, Altimmune, and Target Registries. Magdy Elkhashab reports receiving grants from AbbVie, Bristol-Myers Squibb, Eisai, Gilead Sciences, and Roche; and serving on advisory boards for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. Tarek Hassanein reports being on the advisory committee, review panel, or consulting for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Mallinckrodt Pharmaceuticals, Merck, and Organovo and receiving research support from AbbVie, Allergan, Cytodyn, Assembly Biosciences, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CARA, DURECT Corporation, Enanta Pharmaceuticals, Galectin Therapeutics, Gilead Sciences, Grifols, Intercept Pharmaceuticals, Janssen, Merck, Mirum, Novartis, Novo Nordisk, Nucorion Pharmaceuticals, Pfizer, Salix Pharmaceuticals, Sonic Incytes, Terns Pharmaceuticals, and Valeant. Ho S. Bae reports having consultancy agreements with and receiving research support from Bristol-Myers Squibb and Gilead Sciences. Jacob P. Lalezari reports having no conflicts of interest. Scott K. Fung reports receiving fees for speaking and teaching and/or serving on advisory committees for AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and Springbank Pharma. Man-Fung Yuen reports being an advisor/consultant for and/or having received grant/research support from AbbVie, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Roche, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex Corporation and Vir Biotechnology. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Tooth development includes numerous cell divisions and cell-cell interactions generating the stem cell niche. After an indefinite number of divisions, pluripotent cells differentiate into various types of cells. Nuclear factor I (NFI) transcription factors are known as crucial regulators in various organ development and stem cell biology. Among its members, nuclear factor I-C (NFI-C) has been reported to play an essential role in odontogenesis. Nfic knockout mice show malformation in all mineralized tissues, but it remains unclear which stage of development Nfic is involved in. We previously reported that Nfic induces the differentiation of ameloblast, odontoblast, and osteoblast. However, the question remains whether Nfic participates in the late stage of development, perpetuating the proliferation of stem cells. This study aimed to elucidate the underlying mechanism of NFI-C function in stem cells capable of forming hard tissues. Here, we demonstrate that Nfic regulates Sox2 and cell proliferation in diverse mineralized tissue stem cells such as dental epithelial stem cells (DESCs), dental pulp stem cells, and bone marrow stem cells, but not in fibroblasts. It was also involved in the expression of pluripotency genes Lin28 and NANOG. Especially in DESCs, Nfic regulates the proliferation of epithelial cells via epithelial-mesenchymal interactions, which are the Fgf8-Nfic-Sox2 pathway in epithelium and Nfic-Fgf10 in the mesenchyme. Moreover, Nfic slightly increased reprogramming efficiency in induced pluripotent stem cells of mineralized tissues, but not in soft tissues. In conclusion, these results suggest that Nfic is a crucial factor for maintaining the stem cell niche of mineralized tissues and provides a possibility for Nfic as an additional factor in improving reprogramming efficiency., Competing Interests: Dong-Seol Lee, Yeo Joon Song, Hye Ri Gug, and Ji-Hyun Lee are employed by the company HysensBio Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest., (Copyright © 2022 Dong-Seol Lee et al.)

Background & Aims: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs., Methods: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks., Results: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported., Conclusions: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone., Clinical Trials Number: NCT03576066., Lay Summary: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated., Competing Interests: Conflict of interest Man-Fung Yuen reports being an advisor/consultant for and/or having received grant/research support from AbbVie, Aligos Therapeutics, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Bristol-Myers Squibb, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmithKline, Gilead Sciences, Immunocore, Janssen, Merck Sharp and Dohme, Roche, Springbank Pharmaceuticals, Silverback Therapeutics, Sysmex Corporation, and Vir Biotechnology. Kosh Agarwal reports being on the advisory board, a consultant, and a speaker for AbbVie, Assembly Biosciences, Aligos, Arbutus, Bristol-Myers Squibb, Gilead Sciences, Immunocore, Janssen, Merck, Novartis, Roche, Sobi, Shinoigi, and Vir; and receiving grants from Bristol-Myers Squibb, Gilead Sciences, and Roche. Xiaoli Ma reports being a consultant and being on the speakers bureau for Gilead Sciences. Tuan T. Nguyen reports receiving research grant support from Gilead Sciences and Assembly Biosciences. Eugene R. Schiff reports receiving research and grant support from Assembly Biosciences, Celgene, and the University of Florida (TARGET) and receives royalties from the Schiff Diseases of the Liver, 12th edition. Hie-Won L. Hann reports serving on the National Advisory Board and receives research grant support from Gilead Sciences. Douglas T. Dieterich reports being a consultant for Gilead Sciences and Intercept Pharmaceuticals. Ronald G. Nahass reports having served on advisory boards and as a speaker for Gilead Sciences, Merck, and Janssen; and having conducted research for Gilead Sciences, Merck, Janssen, and AbbVie. James S. Park reports receiving research grants from Assembly Biosciences and GlaxoSmithKline and consulting fees from Gilead Sciences. Sing Chan reports receiving clinical trial-related payments from Assembly Biosciences. Steven-Huy Han reports being a consultant and being on the speakers bureau for Gilead Sciences. Edward J. Gane reports serving on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Avilia Therapeutics, Clear B Therapeutics, Dicerna, Enanta Pharmaceuticals, Finch Therapeutics, Gilead Sciences, GlaxoSmithKline, Immunocore, Janssen, Roche, Silverback, and Vir Bio. and having served as a speaker for Gilead Sciences, AbbVie, and Roche. Michael Bennett reports having no conflicts of interest. Katia Alves reports being a former employee of and holding stock interest in Assembly Biosciences. Marc Evanchik reports having been an employee of and holding stock interest in Assembly Biosciences and is currently an employee of Edgewise Therapeutics. Ran Yan reports being an employee of and holding stock interest in Assembly Biosciences. Qi Huang reports being an employee of and holding stock interest in Assembly Biosciences. Uri Lopatin reports being a former employee and holding stock interest in Assembly Biosciences. Richard Colonno reports being an employee of and holding stock interest in Assembly Biosciences. Julie Ma reports being an employee of and holding stock interest in Assembly Biosciences. Steven J. Knox reports being an employee of and holding stock interest in Assembly Biosciences. Luisa M. Stamm reports being an employee of and holding stock interest in Assembly Biosciences. Maurizio Bonacini reports being a member of the speaking bureau for Intercept Pharmaceuticals, Gilead Sciences, and AbbVie and has received research support from Assembly Biosciences, Intercept Pharmaceuticals, Viking Therapeutics, and Boehringer Ingelheim. Ira M. Jacobson reports being a consultant or on advisory boards for AbbVie, Aligos Therapeutics, Arbutus Biopharma, Gilead Sciences, Janssen, Madrigal and Virion; having conducted research (all payments to institution) for Assembly Biosciences, Bristol-Myers Squib, Eli Lilly, Enanta Pharmaceuticals, Gilead Sciences, Janssen, Merck, and Novo Nordisk; receiving payment from the Chronic Liver Disease Foundation for manuscript preparation; and reports participation on a Data Safety Monitoring Board for GSK, Redhill, Galmed, NeuroBo, and Arrowhead Pharmaceuticals. Walid S. Ayoub reports being a member of the speaking bureau for both Gilead Sciences and Intercept Pharmaceuticals and has conducted research for Assembly Biosciences, Intercept Pharmaceuticals, Enanta Pharmaceuticals, and Gilead Sciences. Frank Weilert reports being a study investigator for AbbVie. Natarajan Ravendhran reports advising, being on the speakers’ bureau for, and receiving grants from Gilead Sciences and AbbVie; being on the speakers' bureau for Salix and Onyx; and having received grants from Bristol-Myers Squibb and Merck. Alnoor Ramji reports receiving grant support, lecture fees, and advisory board fees from AbbVie, Celgene, Gilead Sciences, Intercept Pharmaceuticals, Novartis, and Merck. Paul Yien Kwo reports being an advisor/consultant for AbbVie, Aligos Therapeutics, Antios Therapeutics, Enanta Pharmaceuticals, Gilead Sciences, Janssen, and receives grant/research support from Assembly Biosciences, Arrowhead Pharmaceuticals, Eiger Biopharmaceuticals, Bristol Myer Squibb, Altimmune, and Target Registries. Magdy Elkhashab reports receiving grants from AbbVie, Bristol-Myers Squibb, Eisai, Gilead Sciences, and Roche; and serving on advisory boards for AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. Tarek Hassanein reports being on the advisory committee, review panel, or consulting for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Mallinckrodt Pharmaceuticals, Merck, and Organovo and receiving research support from AbbVie, Allergan, Cytodyn, Assembly Biosciences, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CARA, DURECT Corporation, Enanta Pharmaceuticals, Galectin Therapeutics, Gilead Sciences, Grifols, Intercept Pharmaceuticals, Janssen, Merck, Mirum, Novartis, Novo Nordisk, Nucorion Pharmaceuticals, Pfizer, Salix Pharmaceuticals, Sonic Incytes, Terns Pharmaceuticals, and Valeant. Ho S. Bae reports having consultancy agreements with and receiving research support from Bristol-Myers-Squibb and Gilead Sciences. Jacob P. Lalezari reports having no conflicts of interest. Scott K. Fung reports receiving fees for speaking & teaching and/or serving on advisory committees for AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and Springbank Pharma. Mark S. Sulkowski reports receiving grants from AbbVie, Assembly Biosciences, Gilead Sciences, Janssen, and the National Institutes of Health; and receiving personal fees from AbbVie, Antios Therapeutics, Arbutus Biopharma, Atea Pharmaceuticals, Gilead Sciences, FH360, and Immunocore. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

The Kohn-Sham density functional theory (KS-DFT) with the long-range corrected (LC) functional is applied to the benchmark dataset of 401 valence ionization potentials (IPs) of 63 small molecules of Chong, Gritsenko and Baerends (the CGB set). The vertical IP of the CGB set are estimated as negative orbital energies within the context of the Koopmans' prediction using the LCgau-core range-separation scheme in combination with PW86-PW91 exchange-correlation functional. The range separation parameter μ of the functional is tuned to minimize the error of the negative HOMO orbital energy from experimental IP. The results are compared with literature data, including ab initio IP variant of the equation-of-motion coupled cluster theory with singles and doubles (IP-EOM-CCSD), the negative orbital energies calculated by KS-DFT with the statistical averaging of orbital potential, and those with the QTP family of functionals. The optimally tuned LC functional performs better than other functionals for the estimation of valence level IP. The mean absolute deviations (MAD) from experiment and from IP-EOM-CCSD are 0.31 eV (1.77%) and 0.25 eV (1.46%), respectively. LCgau-core performs quite well even with fixed μ (not system-dependent). A μ value around 0.36 bohr -1 gives MAD of 0.40 eV (2.42%) and 0.33 eV (1.96%) relative to experiment and IP-EOM-CCSD, respectively. The LCgau-core-PW86-PW91 functional is an efficient alternative to IP-EOM-CCSD and it is reasonably accurate for outer valence orbitals. We have also examined its application to core ionization energies of C(1s), N(1s), O(1s) and F(1s). The C(1s) core ionization energies are reproduced reasonably [MAD of 46 cases is 0.76 eV (0.26%)] but N(1s), O(1s) and F(1s) core ionization energies are predicted less accurately., (© 2022 IOP Publishing Ltd.)

Acoustic Doppler current profilers (ADCPs) were developed to acquire water current velocities, as well as depth-dependent echo intensities. As the backscattering strength of an underwater object can be estimated from the measured echo intensity, the ADCP can be used to estimate plankton populations and distributions. In this study, the backscattering strength of bubble clusters in a water tank was estimated using the commercial ADCP as a proof-of-concept. Specifically, the temporal variations in the backscattering strength and the duration of bubble existence were quantitatively evaluated. Additionally, the PDSL (population density spectrum level) and VF (void fraction) of the artificial bubbles were characterized based on the obtained distribution characteristics using a PDPA (phase Doppler particle analyzer).

Huntington's disease (HD) is a severe inherited neurological disorder caused by a CAG repeat expansion in the huntingtin gene (HTT), leading to the accumulation of mutant huntingtin with polyglutamine repeats. Despite its severity, there is no cure for this debilitating disease. HTT lowering strategies, including antisense oligonucleotides (ASO) showed promising results very recently. Attempts to develop stem cell-based therapeutics have shown efficacy in preclinical HD models. Using an HD patient's autologous cells, which have genetic defects, may hamper therapeutic efficacy due to mutant HTT. Pretreating these cells to reduce mutant HTT expression and transcription may improve the transplanted cells' therapeutic efficacy. To investigate this, we targeted the SUPT4H1 gene that selectively supports the transcription of long trinucleotide repeats. Transplanting SUPT4H1-edited HD-induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) into the YAC128 HD transgenic mouse model improved motor function compared to unedited HD iPSC-NPCs. Immunohistochemical analysis revealed reduced mutant HTT expression without compensating wild-type HTT expression. Further, SUPT4H1 editing increased neuronal and decreased reactive astrocyte differentiation in HD iPSC-NPCs compared to the unedited HD iPSC-NPCs. This suggests that ex vivo editing of SUPT4H1 can reduce mutant HTT expression and provide a therapeutic gene editing strategy for autologous stem cell transplantation in HD., (© 2022. The Author(s).)

Silicon is an attractive anode material for lithium-ion batteries (LIBs) because of its natural abundance and excellent theoretical energy density. However, Si-based electrodes are difficult to commercialize because of their significant volume changes during lithiation that can result in mechanical damage. To overcome this limitation, we synthesized an eco-friendly water-soluble polyimide (W-PI) precursor, poly(amic acid) salt (W-PAmAS), as a binder for Si anodes via a simple one-step process using water as a solvent. Using the W-PAmAS binder, a composite Si electrode was achieved by low-temperature processing at 150 °C. The adhesion between the electrode components was further enhanced by introducing 3,5-diaminobenzoic acid, which contains free carboxylic acid (-COOH) groups in the W-PAmAS backbone. The -COOH of the W-PI binder chemically interacts with the surface of Si nanoparticles (SiNPs) by forming ester bonds, which efficiently bond the SiNPs, even during severe volume changes. The Si anode with W-PI binder showed improved electrochemical performance with a high capacity of 2061 mAh g -1 and excellent cyclability of 1883 mAh g -1 after 200 cycles at 1200 mA g -1 . Therefore, W-PI can be used as a highly effective polymeric binder in Si-based high-capacity LIBs.

Subterranean estuaries (STEs), the zones in which seawater and subsurface groundwater mix, are recognized as hotspots for biogeochemical reactions; however, little is known of the microbial communities that control many of those reactions. This study investigated the potential functions of microbes inhabiting a cenote and an offshore submarine spring (Pargos) in the near-coastal waters of the Yucatan Peninsula, Mexico. The inland cenote (Cenote Siete Bocas; C7B) is characterized by a chemocline that is host to an array of physicochemical gradients associated with microbial activities. The chemocline includes an increasing gradient in sulfide concentrations with depth and a decreasing gradient in nitrate concentrations. The microbial community within the chemocline was dominated by Sulfurimonas and Sulfurovum of the Campylobacteria, which are likely responsible for sulfide oxidation coupled with nitrate reduction. Although C7B has not been directly connected with Pargos Spring, water discharging from the spring has physicochemical characteristics and microbial community structures similar to C7B, strongly suggesting biogeochemical processing in the STE impacts groundwater composition prior to discharge. This work yields insight into the microbial communities and biogeochemical reactions in STEs in karstic aquifers and provides evidence for the importance of Campylobacteria in controlling nitrate concentrations exported to marine springs., (© 2021 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background: Elastic ear cartilage is a good source of tissue for support or augmentation in plastic and reconstructive surgery. However, the amount of ear cartilage is limited and excessive use of cartilage can cause deformation of the auricular framework. This animal study investigated the potential of periosteal chondrogenesis in an ear cartilage defect model., Methods: Twelve New Zealand white rabbits were used in the present study. Four ear cartilage defects were created in both ears of each rabbit, between the central artery and marginal veins. The defects were covered with perichondrium (group 1), periosteum taken from the calvarium (group 2), or periosteum taken from the tibia (group 3). No coverage was performed in a control group (group 4). All animals were sacrificed 6 weeks later, and the ratio of neo-cartilage to defect size was measured., Results: Significant chondrogenesis occurred only in group 1 (cartilage regeneration ratio: mean± standard deviation, 0.97± 0.60), whereas the cartilage regeneration ratio was substantially lower in group 2 (0.10± 0.11), group 3 (0.08± 0.09), and group 4 (0.08± 0.14) (p= 0.004). Instead of chondrogenesis, osteogenesis was observed in the periosteal graft groups. No statistically significant differences were found in the amount of osteogenesis or chondrogenesis between groups 2 and 3. Group 4 showed fibrous tissue accumulation in the defect area., Conclusion: Periosteal grafts showed weak chondrogenic potential in an ear cartilage defect model of rabbits; instead, they exhibited osteogenesis, irrespective of their embryological origin.

Purpose: To analyze occurrence and risk factors for macular edema (ME) in juvenile idiopathic arthritis-associated uveitis (JIA-U)., Methods: Retrospective analysis of patients with JIA-U at a tertiary referral uveitis center between 2000 and 2019. Epidemiological data and clinical findings before ME onset were evaluated., Results: Out of 245 patients, ME developed in 41 (18%) of the 228 JIA-U patients for whom data documentation was complete during the follow-up (mean 4.0 ± 3.8 years). Risk factors (univariable logistic regression analysis) at baseline for subsequent ME onset included older age at initial documentation at institution (hazard ratio, HR 1.19, p < 0.0001), longer duration of uveitis at initial documentation (HR 1.17, p < 0.0001), worse best-corrected visual acuity (BCVA; HR 2.49, p < 0.0001), lower intraocular pressure (IOP; HR 0.88, p < 0.01), band keratopathy (HR 2.29, p < 0.01), posterior synechiae (HR 2.55, p < 0.01), epiretinal membrane formation (HR 6.19, p < 0.0001), optic disc swelling (HR 2.81, p < 0.01), and cataract (HR 4.24, p < 0.0001). Older age at initial documentation at institution (HR 1.55, p < 0.001), worse BCVA (HR 28.56, p < 0.001), and higher laser-flare photometry (LFM) values (HR 1.003, p = 0.01) were independent risk factors for ME manifestation. Patients with ME revealed significant changes in BCVA, LFM, and IOP and new optic disc swelling at 6 and 3 months before ME onset compared to timepoint of ME occurrence ( p < 0.05, each)., Conclusion: ME is a common complication of JIA-U. Demographic risk factors and courses of IOP, BCVA, and LFM may indicate patients at risk for ME onset.

Pediatric myopia is increasing globally and has become a major public health issue. However, the mechanism of pediatric myopia is still poorly understood, and there is no effective treatment to prevent its progression. Based on results from animal and clinical studies, certain neuronal-humoral factors (NHFs), such as IGF-1, dopamine, and cortisol may be involved in the progression of pediatric myopia. Digital therapeutics uses evidence-based software as therapeutic interventions and it has the potential to offer innovative treatment strategies for pediatric myopia beyond conventional treatment methods. In this perspective article, we introduce digital therapeutics SAT-001, a software algorithm that modulates the level of NHFs to reduce the progression of pediatric myopia. The proposed mechanism is based on a theoretical hypothesis derived from scientific research and clinical studies and will be further confirmed by evidence generated from clinical studies involving pediatric myopia., Competing Interests: YL, SC, and MK are stockholders of S-Alpha Therapeutics. YL, SC, and JH are employed by S-Alpha Therapeutics. HB is employed by Black Kactus, LLC. HB received consulting fees from S-Alpha Therapeutics. The remaining authors declare that there is no commercial or financial relationship in the research conducted that could be constructed as a potential conflict of interest., (Copyright © 2021 Lee, Choi, Hahm, Kim, Bae, Yi, Lim and Hyon.)

Spread of biosolids-borne antibiotic resistance is a growing public and environmental health concern. Herein, we conducted incubation experiments involving biosolids, which are byproducts of sewage treatment processes, and biosolids-amended soil. Quantitative reverse transcription-PCR (RT-qPCR) was employed to assess responses of select antibiotic resistance genes (ARGs) and mobile elements to environmentally relevant concentrations of two biosolids-borne antibiotics, azithromycin (AZ) and ciprofloxacin (CIP). Additionally, we examined sequence distribution of gyrA (encoding DNA gyrase; site of action of CIP) to assess potential shifts in genotype. Increasing antibiotic concentrations generally increased the transcriptional activities of qnrS (encoding CIP resistance) and ermB and mefE (encoding AZ resistance). The transcriptional activity of intl1 , a marker of class 1 integrons, was unaffected by CIP or AZ concentrations, but biosolids amendment increased intl1 activity in the soil by 4 to 5 times, which persisted throughout incubation. While the dominant gyrA sequences found herein were unrelated to known CIP-resistant genotypes, the increasing CIP concentrations significantly decreased the diversity of genes encoding the DNA gyrase A subunit, suggesting changes in microbial community structures. This study suggests that biosolids harbor transcriptionally active ARGs and mobile elements that could survive and spread in biosolids-amended soils. However, more research is warranted to investigate these trends under field conditions. IMPORTANCE Although previous studies have indicated that biosolids may be important spreaders of antibiotics and antibiotic resistance genes (ARGs) in environments, the potential activities of ARGs or their responses to environmental parameters have been understudied. This study highlights that certain biosolids-borne antibiotics can induce transcriptional activities of ARGs and mobile genetic elements in biosolids and biosolids-amended soil, even when present at environmentally relevant concentrations. Furthermore, these antibiotics can alter the structure of microbial populations expressing ARGs. Our findings indicate the bioavailability of the antibiotics in biosolids and provide evidence that biosolids can promote the activities and dissemination of ARGs and mobile genes in biosolids and soils that receive contaminated biosolids, thus, underscoring the importance of investigating anthropogenically induced antibiotic resistance in the environment under real-world scenarios.

Li metal thickness has been considered a key factor in determining the electrochemical performance of Li metal anodes. The use of thin Li metal anodes is a prerequisite for increasing the energy density of Li secondary batteries intended for emerging large-scale electrical applications, such as electric vehicles and energy storage systems. To utilize thin (20 μm thick) Li metal anodes in Li metal secondary batteries, we investigated the synergistic effect of a functional additive (Li nitrate, LiNO 3 ) and a dual-salt electrolyte (DSE) system composed of Li bis(fluorosulfonyl)imide (LiTFSI) and Li bis(oxalate)borate (LiBOB). By controlling the amount of LiNO 3 in DSE, we found that DSE containing 0.05 M LiNO 3 (DSE-0.05 M LiNO 3 ) significantly improved the electrochemical performance of Li metal anodes. DSE-0.05 M LiNO 3 increased the cycling performance by 146.3% [under the conditions of a 1C rate (2.0 mA cm -2 ), DSE alone maintained 80% of the initial discharge capacity up to the 205th cycle, whereas DSE-0.05 M LiNO 3 maintained 80% up to the 300th cycle] and increased the rate capability by 128.2% compared with DSE alone [the rate capability of DSE-0.05 M LiNO 3 = 50.4 mAh g -1 , and DSE = 39.3 mAh g -1 under 7C rate conditions (14.0 mA cm -2 )]. After analyzing the Li metal surface using scanning electron microscopy and X-ray photoelectron spectroscopy, we were able to infer that the stabilized solid electrolyte interphase layer formed by the combination of LiNO 3 and the dual salt resulted in a uniform Li deposition during repeated Li plating/stripping processes.

In the present study, we have investigated the applicability of long-range-corrected (LC) functionals to a Kohn-Sham (KS) Koopmans'-type theorem. Specifically, we have examined the performance of optimally tuned LCgau-core functionals (in combination with BOP and PW86-PW91 exchange-correlation functionals) by calculating the ionization potential (IP) within the context of Koopmans' prediction. In the LC scheme, the electron repulsion operator, 1/ r 12 , is divided into short-range and long-range components using a standard error function, with a range separation parameter μ determining the weight of the two ranges. For each system that we have examined (H 2 O, CO, benzene, N 2 , HF, H 2 CO, C 2 H 4 , and five-membered ring compounds cyclo-C 4 H 4 X, with X = CH 2 , NH, O, and S, and pyridine), the value of μ is optimized to minimize the deviation of the negative HOMO energy from the experimental IP. Our results demonstrate the utility of optimally tuned LC functionals in predicting the IP of outer valence levels. The accuracy is comparable to that of highly accurate ab initio theory. However, our Koopmans' method is less accurate for the inner valence and core levels. Overall, our results support the notion that orbitals in KS-DFT, when obtained with the LC functional, provide an accurate one-electron energy spectrum. This method represents a one-electron orbital theory that is attractive in its simple formulation and effective in its practical application.

Background and Aim: Tenofovir disoproxil fumarate (TDF) has been efficacious in treating chronic hepatitis B (CHB), but long-term use is accompanied by a decline in renal function and bone mineral density (BMD). Tenofovir alefanamide (TAF) is a prodrug of tenofovir, with similar efficacy in CHB but with fewer side effects than TDF. Recent studies on patients who underwent the switch from TDF to TAF have shown improved bone and renal profiles from 24 to 48 weeks of follow-up., Methods: This study provides follow-up at 72 weeks in a real-world cohort of 61 Asian CHB patients who were switched from TDF to TAF. All patients had been treated with TDF for at least 12 months with hepatitis B virus DNA <21 IU/mL prior to switch., Results: Improvements in proximal tubular function, measured by urine beta-2-microglobulin to creatinine and retinol-binding protein to creatinine ratios, were sustained at 72 weeks ( P < 0.01). Renal function showed decline at 72 weeks compared to baseline (GFR CG 90.9 vs 96.3 mL/min, P < 0.01). Improvement in hip BMD was sustained at 72 weeks (mean % change of 17.7% from baseline, P < 0.01). However, spine BMD showed discordance, with initial improvement at 24 weeks (3.3% from week 0, P < 0.01) but regression at 72 weeks (-0.6% from week 0, P = NS). Interestingly, there was a slight increase in weight and BMI after 72 weeks ( P < 0.01)., Conclusions: CHB patients who switch from long-term TDF to TAF therapy show sustained improvement in proximal tubular function and hip BMD. Weight gain was noted, and long-term studies are needed to evaluate its effect on patient outcomes., (© 2020 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The core electron binding energies (CEBEs) and core-level excitation energies of thymine, adenine, cytosine, and uracil are studied by the Kohn-Sham (KS) method with long-range corrected (LC) functionals. The CEBEs are estimated according to the Koopmans-type theorem for density functional theory. The excitation energies from the core to the valence π* and Rydberg states are calculated as the orbital energy differences between core-level orbitals of a neutral parent/cation and unoccupied π* or Rydberg orbitals of its cation. The model is intuitive, and the spectra can easily be assigned. Core excitation energies from oxygen 1s, nitrogen 1s, and carbon 1s to π* and Rydberg states, and the chemical shifts, agree well with previously reported theoretical and experimental data. The straightforward use of KS orbitals in this scheme carries the advantage that it can be applied efficiently to large systems such as biomolecules and nanomaterials.

In Mycobacterium tuberculosis infection, naïve T cells that encounter mycobacterial antigens through dendritic cells (DCs) induce various CD4 + T-cell responses; therefore, appropriate DC activation is the key for protective immunity against tuberculosis. We previously found that Rv2299c-matured DCs induce Th1 differentiation with bactericidal activity. In this study, to prove that Rv2299c could enhance the protective immunity of other vaccine candidates comprising T-cell-stimulating antigens, Ag85B-ESAT6, a well-known vaccine candidate, was selected as a fusion partner of Rv2299c. Recombinant Rv2299c-Ag85B-ESAT6 protein induced DC maturation and activation. Furthermore, fusion of Rv2299c enhanced the protective efficacy of the Ag85B-ESAT6 vaccine in a mouse model and significantly higher production of TNF-α and IL-2 was detected in the lungs, spleen, and lymph nodes of the group immunized with the Rv2299c-fused protein than with Ag85B-ESAT6. In addition, fusion of Rv2299c enhanced the Ag85B-ESAT6-mediated expansion of multifunctional CD4 + T cells. These data suggested that the DC-activating protein Rv2299c may potentiate the protective immunity of the vaccine candidate comprising T cell antigens.

A method of microalgae-templated spray drying to develop hierarchical porous Fe 3 O 4 /C composite microspheres as anode materials for Li-ion batteries was developed. During the spray-drying process, individual microalgae serve as building blocks of raspberry-like hollow microspheres via self-assembly. In the present study, microalgae-derived carbon matrices, naturally doped heteroatoms, and hierarchical porous structural features synergistically contributed to the high electrochemical performance of the Fe 3 O 4 /C composite microspheres, enabling a discharge capacity of 1375 mA·h·g -1 after 700 cycles at a current density of 1 A/g. Notably, the microalgal frameworks of the Fe 3 O 4 /C composite microspheres were maintained over the course of charge/discharge cycling, thus demonstrating the structural stability of the composite microspheres against pulverization. In contrast, the sample fabricated without microalgal templating showed significant capacity drops (up to ~40% of initial capacity) during the early cycles. Clearly, templating of microalgae endows anode materials with superior cycling stability.

To inhibit Li-dendrite growth on lithium (Li)-metal electrodes, which causes capacity deterioration and safety issues in Li-ion batteries, we prepared a porous polyimide (PI) sponge using a solution-processable high internal-phase emulsion technique with a water-soluble PI precursor solution; the process is not only simple but also environmentally friendly. The prepared PI sponge was processed into porous PI separators and used for Li-metal electrodes. The physical properties (e.g., thermal stability, liquid electrolyte uptake, and ionic conductivity) of the porous PI separators and their effect on the Li-metal anodes (e.g., self-discharge and open-circuit voltage properties after storage, cycle performance, rate capability, and morphological changes) were investigated. Owing to the thermally stable properties of the PI polymer, the porous PI separators demonstrated no dimensional changes up to 180 °C. In comparison with commercialized polyethylene (PE) separators, the porous PI separators exhibited improved wetting ability for liquid electrolytes; thus, the latter improved not only the physical properties (e.g., improved the electrolyte uptake and ionic conductivity) but also the electrochemical properties of Li-metal electrodes (e.g., maintained stable self-discharge capacity and open-circuit voltage features after storage and improved the cycle performance and rate capability) in comparison with PE separators.

Previously proposed theoretical schemes for estimating one-electron excitation energies using Kohn-Sham (KS) solutions with long-range corrected (LC) functionals are applied to the charge-transfer (CT) excitations of the ethylene···tetrafluoroethylene (C 2 H 4 -C 2 F 4 ) system, and the CT complex between an aromatic donor (Ar = benzene, toluene, o -xylene, naphthalene, anthracene, and various meso-substituted anthracenes) and the tetracyanoethylene (TCNE) acceptor. The CT excited state is described well as a single-electron excitation between specific orbitals of donor and acceptor. Thus, CT excitation energies are well approximated by the orbital energies because of the satisfaction of the Koopmans-type theorem and the asymptotic behavior of the LC functional. We have examined three computational schemes: scheme 1 employs the orbital energies for the neutral and cationic systems, scheme 2 utilizes orbital energies of just the cation, and in scheme 3, because the electron affinity of a molecule is the ionization energy of its anion, a scale factor is applied to enforce this identity. The present schemes reproduce the correct asymptotic behavior of CT excitation energy of C 2 H 4 ···C 2 F 4 for the long intermolecular distances and give good agreement with accurate ab initio results. Calculated CT excitation energies for Ar-TCNE are compared with those of TD-DFT and ΔSCF methods. Scheme 1 with the optimal range-separation parameter μ accurately reproduces CT excitation energies for all Ar-TCNE systems and gives good agreement with the best TD-DFT calculations and experiment. Scheme 1, scheme 3, and TD-DFT show similar tendencies with respect to the variation in μ. Scheme 2 and ΔSCF approaches are rather insensitive to changes in μ, but both considerably underestimate the CT excitation energies for these systems. KS orbital energies are physically meaningful and they are practically useful; if the range-separation parameter is tuned, then good results can be obtained.

Autophagy is an intracellular self-degradation process that is essential for tissue development, cell differentiation, and survival. Nevertheless, the role of autophagy in tooth development has not been definitively identified. The goal of this study was to investigate how autophagy is involved in midkine (MK)-mediated odontoblast-like differentiation, mineralization, and tertiary dentin formation in a mouse tooth pulp exposure model. In vitro studies show that MK and LC3 have similar expression patterns during odontoblast-like cell differentiation. Odontoblast-like cell differentiation is promoted through MK-mediated autophagy, which leads to increased mineralized nodule formation. Subcutaneous transplantation of hydroxyapatite/tricalcium phosphate with rMK-treated human dental pulp cells led to dentin pulp-like tissue formation through MK-mediated autophagy. Furthermore, MK-mediated autophagy induces differentiation of dental pulp cells into odontoblast-like cells that form DSP-positive tertiary dentin in vivo. Our findings may provide 1) novel insight into the role of MK in regulating odontoblast-like differentiation and dentin formation in particular via autophagy and 2) potential application of MK in vital pulp therapy.

Thyroid hormone (TH) has long been believed to play a minor role in male reproduction. However, evidences from experimental model of thyrotoxicosis or hypothyroidism suggests its role in spermatogenesis. Cellular action of TH requires membrane transport via specific transporters such as monocarboxylate transporter 8 (MCT8). SLC16A2 (encodes for MCT8) inactivating mutation in humans can lead to Allan-Herndon Dudley-syndrome, a X-linked psychomotor and growth retardation. These patients present cryptorchidism which suggests a role of MCT8 during spermatogenesis. In this study, we found that Mct8 is highly expressed during early postnatal development and decreases its expression in the adulthood of testis of wild-type male rats. Histological analysis revealed that spermatogonia largely lacks MCT8 expression while spermatocytes and maturing spermatids highly express MCT8. To further understand the role of Mct8 during spermatogenesis, we generated Slc16a2 (encodes MCT8) knockout rats using CRISPR/Cas9. Serum THs (T3 and T4) level were significantly altered in Slc16a2 knockout rats when compared to wild-type littermates during early to late postnatal development. Unlike Slc16a2 knockout mice, Slc16a2 knockout rats showed growth delay during early to late postnatal development. In adult Slc16a2 knockout rats, we observed reduced sperm motility and viability. Collectively, our data unveil a functional involvement of MCT8 in spermatogenesis, underscoring the importance of TH signaling and action during spermatogenesis.

The Streptococcus pyogenes CRISPR/Cas9 (SpCas9) system is now widely utilized to generate genome engineered mice; however, some studies raised issues related to off-target mutations with this system. Herein, we utilized the Campylobacter jejuni Cas9 (CjCas9) system to generate knockout mice. We designed sgRNAs targeting mouse Tyr or Foxn1 and microinjected into zygotes along with CjCas9 mRNA. We obtained newborn mice from the microinjected embryos and confirmed that 50% (Tyr) and 38.5% (Foxn1) of the newborn mice have biallelic mutation on the intended target sequences, indicating efficient genome targeting by CjCas9. In addition, we analyzed off-target mutations in founder mutant mice by targeted deep sequencing and whole genome sequencing. Both analyses revealed no off-target mutations at potential off-target sites predicted in silico and no unexpected random mutations in analyzed founder animals. In conclusion, the CjCas9 system can be utilized to generate genome edited mice in a precise manner., Competing Interests: JYL, HSB, SJK and OJK are employees of ToolGen Inc, a company develops products based on CRISPR/Cas9 system. SGP is employee of TheragenEtex Bio Inc, a company providing genome sequencing., (© 2020 The Authors.)

Charcot-Marie-Tooth 1A (CMT1A) is the most common inherited neuropathy without a known therapy, which is caused by a 1.4 Mb duplication on human chromosome 17, which includes the gene encoding the peripheral myelin protein of 22 kDa (PMP22). Overexpressed PMP22 protein from its gene duplication is thought to cause demyelination and subsequently axonal degeneration in the peripheral nervous system (PNS). Here, we targeted TATA-box of human PMP22 promoter to normalize overexpressed PMP22 level in C22 mice, a mouse model of CMT1A harboring multiple copies of human PMP22. Direct local intraneural delivery of CRISPR/Cas9 designed to target TATA-box of PMP22 before the onset of disease, downregulates gene expression of PMP22 and preserves both myelin and axons. Notably, the same approach was effective in partial rescue of demyelination even after the onset of disease. Collectively, our data present a proof-of-concept that CRISPR/Cas9-mediated targeting of TATA-box can be utilized to treat CMT1A., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)