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Plant calli, a perpetually undifferentiated cell culture, have defects in maintaining their genetic fidelity during prolonged tissue culture. Cryopreservation using ice-binding proteins (IBP) is a potential solution. Despite a few studies on cryopreservation using IBPs in plant calli, detailed insights into the intracellular metabolism during freezing, thawing, and re-induction remain sparse. This study investigated and employed IBP from polar yeast Leucosporidium sp. (LeIBP) in the cryopreservation process across diverse taxa, including gymnosperms, monocots, dicots, and woody plants. Molecular-level analyses encompassing reactive oxygen species levels, mitochondrial function, and ATP and lipophilic compounds content were conducted. The results across nine plant species revealed the effects of LeIBP on callus competency post-thawing, along with enhanced survival rates, reactive oxygen species reduction, and restored metabolic activities to the level of those of fresh calli. Moreover, species-specific survival optimization with LeIBP treatments and morphological assessments revealed intriguing extracellular matrix structural changes post-cryopreservation, suggesting a morphological strategy for maintaining the original cellular states and paracrine signaling. This study pioneered the comprehensive application of LeIBP in plant callus cryopreservation, alleviating cellular stress and enhancing competence. Therefore, our findings provide new insights into the identification of optimal LeIBP concentrations, confirmation of genetic conformity post-thawing, and the intracellular metabolic mechanisms of cryopreservation advancements in plant research, thereby addressing the challenges associated with long-term preservation and reducing labor-intensive cultivation processes. This study urges a shift towards molecular-level assessments in cryopreservation protocols for plant calli, advocating a deeper understanding of callus re-induction mechanisms and genetic fidelity post-thawing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

The blood-brain barrier (BBB) and blood-retinal barrier (BRB) constitute critical physiochemical interfaces, precisely orchestrating the bidirectional communication between the brain/retina and blood. Increased permeability or leakage of these barriers has been demonstrably linked to age-related vascular and parenchymal damage. While it has been suggested that the gradual aging process may coincide with disruptions in these barriers, this phenomenon is significantly exacerbated in individuals with age-related neurodegenerative disorders (ARND). This review focuses on the microvascular endothelium, a key constituent of BBB and BRB, highlighting the impact of endothelial senescence on barrier dysfunction and exploring recent discoveries regarding core pathways implicated in its breakdown. Subsequently, we address the "vascular senescence hypothesis" for ARND, with a particular emphasis on Alzheimer's disease and age-related macular degeneration, centered on endothelial senescence. Finally, we discuss potential senotherapeutic strategies targeting barrier dysfunction., Competing Interests: Declaration of Competing Interest No competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Muscle atrophy is the waste or loss of muscle mass and is caused by physical inactivity, aging, or diseases such as diabetes, cancer, and heart failure. The number of patients suffering from musculoskeletal disorders is expected to increase in the future. However, intervention for muscle atrophy is limited, so research on treatment for muscle wasting is needed. This study hypothesized that guava leaf (Psidium guajava L. [GL]) would have ameliorative effects on muscle atrophy by regulation of protein degradation pathways in a dexamethasone (DEX)-induced muscle atrophy mice model. Muscle atrophy was induced by DEX injection for 28 days in 7 week-old-male ICR mice. Then, low-dose GL (LGL, 200 mg/kg) or high-dose GL (HGL, 500 mg/kg) extract (GLE) was supplemented by oral gavage for 21 days. Muscle strength, calf thickness, and body composition were analyzed. Histopathological changes in the gastrocnemius muscle were examined using hematoxylin and eosin staining, and molecular pathways related to muscle degradation were analyzed by western blots. GLE treatment regardless of dose increased muscle strength in mice with muscle atrophy accompanied by attenuating autophagy related pathway in the DEX-induced muscle atrophy mice. Moreover, a high dose of GLE treatment ameliorated ubiquitin proteasome system and apoptosis in the DEX-induced muscle atrophy mice. This study suggested that GLE could be helpful to improve muscle health and alleviate proteolysis by regulation of the ubiquitin-proteasome system, autophagy, and apoptosis, which are involved in muscle degradation. In conclusion, GLE could be a potential nutraceutical to prevent muscle atrophy., Competing Interests: Declaration of competing interest All authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective/background: Insomnia is common in children with autism spectrum disorder (ASD). We recently developed and validated the 21-item Pediatric Autism Insomnia Rating Scale (PAIRS). This report explores the associations and agreements between actigraphy and PAIRS., Participants Methods: Children with ASD, with and without sleep problems, were assessed with a battery of parent-rated and clinician measures (N = 134). In a subset (n = 70), a wrist-worn actigraph measured sleep for five consecutive nights. Parents completed logs for scoring sleep intervals. Spearman correlations evaluated associations with the PAIRS and actigraphy indices (sleep onset latency = SOL, wake after sleep onset = WASO, total sleep time = TST, sleep efficiency = SE%). Agreements on "poor sleepers" based on PAIRS total score (≥33) and conventional thresholds for TST and SE% were evaluated with Cohen's Kappa and McNemar's test., Results: Actigraphy data were averaged over 4.64 ± 0.68 nights in 70 children (mean age = 7.3 ± 2.9, 74.3 % male). There were no significant correlations between PAIRS and any actigraphy indices. On TST, 48.6 % (n = 34) and on SE% 52.9 % (n = 37) were classified as "poor sleepers" compared to 32.9 % (n = 23) on PAIRS (kappa = 0.11 for TST and 0.27 for SE%). P-values on McNemar's Chi square test for PAIRS with TST and with SE% were 0.072 and 0.011, respectfully., Conclusions: These results suggest that actigraphy and PAIRS do not agree. Actigraphy TST captures movement and an estimate of specific sleep parameters. PAIRS is a broader measure that incorporates sleep disturbance and sleep-related impairment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Dr. Scahill has served as a consultant to Yamo Pharmaceuticals and Cogstate. He receives book royalties from Oxford, Guilford and American Psychological Association and license fees from Yamo, Roche and Abbvie. Dr. Lecavalier receives book royalties from Oxford and license fees from Yamo, Roche and Abbvie. Dr. Johnson receives book royalties from Oxford and American Psychological Association. The authors have no other financial interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

The skin acts as a vital barrier, shielding the body from external threats that can trigger dryness, itching, and inflammation. Pilea mongolica, a traditional Chinese medicinal herb, holds promise for various ailments, yet its anti-inflammatory properties remain understudied. This study aimed to explore the potential anti-inflammatory effects of the methanol extract of P. mongolica (MEPM) and its underlying molecular mechanisms and active compounds in LPS-stimulated human keratinocytes. MEPM treatment, at concentrations without cytotoxicity, significantly decreased NO productions and the iNOS, IL-6, IL-1β, and TNF-α levels in LPS-induced HaCaT cells. Moreover, MEPM suppressed IRAK4 expression and phosphorylation of JNK, ERK, p38, p65, and c-Jun, suggesting that the anti-inflammatory effects of MEPM result from the inhibition of IRAK4/MAPK/NF-κB/AP-1 signaling pathway. Through LC/MS/MS analysis, 30 compounds and 24 compounds were estimated in negative and positive modes, respectively, including various anti-inflammatory compounds, such as corilagin and geraniin. Through HPLC analysis, geraniin was found to be present in MEPM at a concentration of 18.87 mg/g. Similar to MEPM, geraniin reduced iNOS mRNA expression and inhibited NO synthesis. It also decreased mRNA and protein levels of inflammatory cytokines, including IL-6 and TNF-α, and inhibited IRAK4 expression and the phosphorylation of MAPKs, NF-κB, and AP-1 pathways. Therefore, it can be inferred that the anti-inflammatory effects of MEPM are attributable to geraniin. Thus, MEPM and its active compound geraniin are potential candidates for use in natural functional cosmetics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. S. was supported by the World Health Organization for this work. A. N. S. was financially supported by the World Health Organization for this work, and is additionally supported by the Bill & Melinda Gates Foundation, Gavi, the Vaccine Alliance, and the National Institutes of Health. A. B. H. was supported by the Australian National Health and Medical Research Council for this work, is additionally supported by PATH, the World Health Organization, and Gavi, the Vaccine Alliance, and has received consulting fees from the Australian NSW Ministry of Health, WHO Europe and Asian Development Bank. W. J. M. is supported by the National institutes of Health. A. P. is supported by Imperial College London, the Bill & Melinda Gates Foundation, the World Health Organization, and the University of Oslo. X. W. has served as a Data Safety Monitoring Board member for several China-made COVID-19 vaccines. S. S., A. N. S., and A. B. H. report travel related support from the World Health Organization to attend previous IVIR-AC meetings. All other authors have no declarations., (Copyright © 2024. Published by Elsevier Ltd.)

Evaluating vaccine-related research is critical to maximize the potential of vaccination programmes. The WHO Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) provides an independent review of research that estimates the performance, impact and value of vaccines, with a particular focus on transmission and economic modelling. On 11-13 September 2023, IVIR-AC was convened for a bi-annual meeting where the committee reviewed research and presentations across eight different sessions. This report summarizes the background information, proceedings and recommendations from that meeting. Sessions ranged in topic from timing of measles supplementary immunization activities, analyses of conditions necessary to meet measles elimination in the South-East Asia region, translating modelled evidence into policy, a risk-benefit analysis of dengue vaccine, COVID-19 scenario modelling in the African region, therapeutic vaccination against human papilloma virus, the Vaccine Impact Modelling Consortium, and the Immunization Agenda 2030 vaccine impact estimates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

In this study, we investigated the protective effects of SM on skeletal muscle and brain damage by regulation of BDNF/PGC1α/irisin pathway via brain function related myokines in high-fat diet-induced OB mice. OB was induced by high-fat diet for 6 weeks. SM extract (SME) was administered with 200 mg/kg BW (LSM) and 500 mg/kg BW (HSM) by oral gavage every day for 12 weeks. Behavior tests such as grip strength, Y-maze, and passive avoidance test were conducted to analyze muscle and cognitive function. Histopathological changes in skeletal muscle and brain were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to oxidative stress, inflammation, protein degradation, neuro-plasticity, and cell cycling were measured by western blot. SME regulated morphological changes (muscle cross-sectional area: 1.23%, 1.40%; density of neurons in hippocampus:1.74%, 1.73%) in T2DM mice. Importantly, SME supplementation significantly increased several muscle-derived myokines which might influence the expression of neuronal markers in OB mice (FGF21: 1.27%, 1.34%; PGC1α: 1.0%, 1.32%; IRISIN: 1.9%, 1.08%; BDNF: 1.35%, 1.23%). Accordingly, SME activated hippocampal neurotrophic factors including BDNF (1.0%, 1.2%) and its associated PGC1α/irisin pathway (PGC1α :1.1%, 1.1%; IRISIN:1.1%, 0.9%) significantly. This study demonstrated the possibliy that protective myokines increased by SME supplementation may contribute to neuro-protection in OB mice. Taken together, the current study suggests that SME can be used to prevent skeletal muscle and brain damage in OB by protecting against oxidative stress and inflammatin via modulation of the BDNF/PGC1α/irisin pathway in the therapeutic approach of obese patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Sialocele that develops after parotid surgery often prolongs the treatment period and stresses both the surgeon and patient. The extent of surgery and tumor size are known to be associated with sialocele occurrence. We investigated the incidence of post-parotidectomy sialocele and the associated risk factors, with a focus on tumor size., Methods: We retrospectively reviewed the medical records of 172 patients who underwent parotidectomy between January 2013 and May 2020 at Haeundae Paik Hospital, Inje University of Korea. We stratified patients into those with and without sialocele (fluid collection in the operative bed). We compared clinical data, patient demographics, and surgical details; we identified risk factors for sialocele development after parotid surgery., Results: Seventeen patients were diagnosed with post-parotidectomy sialocele (9.88%; 17/172). Univariate logistic regression revealed that the male sex, deep lobe tumor location, and large tumor size were significantly associated with postoperative sialocele (p = 0.015, 0.009, and 0.016, respectively). We subjected these parameters to multivariate analyses; the odds ratios were 3.70, 3.58, and 2.34, respectively. Receiver operating characteristic curve analyses showed that a tumor size > 2.50 cm was the optimal cutoff in terms of predicting post-parotidectomy sialocele., Conclusion: Male sex, a tumor in the deep lobe, and large tumor size were strongly associated with increased risk for sialocele after parotidectomy. Tumor size > 2.50 cm serves as the cutoff identifying patients likely to experience sialocele after parotid surgery., Competing Interests: Declaration of Competing Interest The Authors declares that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Hydrangenol, a dihydroisocoumarin, isolated from the leaves of Hydrangea serrata, possesses anti-inflammatory, anti-obesity, and anti-photoaging activities. In this study, we investigated the protective effects of hydrangenol (HG) against lipopolysaccharide (LPS)-induced endotoxemia and elucidated the underlying molecular mechanisms of action in C57BL/6 mice. Oral administration of HG (20 or 40 mg/kg) significantly restored the survival rate and population of macrophages, T helper cells (CD3 + /CD4 + ), and Th17 cells (CD3 + /CD4 + /CCR6 + ) in the spleens of mice with LPS-induced endotoxemia. HG suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, and Interferon (IFN)-γ and the mRNA and protein expressions of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in the intestine and lung of LPS-treated mice. Molecular data showed that HG ameliorated the activation of nuclear factor kappa B (NF-κB) p65, signal transducers and activators of transcription 3 (STAT3), and c-Fos and c-Jun (AP-1 subunits) via the myeloid differentiation primary response 88 (MyD88) dependent toll-like receptor 4 (TLR4) signaling pathway in the LPS-treated mouse intestines. HG treatment caused the recovery of LPS-induced impaired tight junction (occludin and claudin-2) protein and mRNA expressions. Furthermore, HG improved LPS-induced gut dysbiosis in mice. Taken together, our results suggest that HG protects against LPS-induced endotoxemia by restoring immune cells and the capacity of the intestinal barrier, reducing intestinal inflammation, and improving the composition of the gut microbiota., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Whilst a number of studies have demonstrated that low-intensity pulsed ultrasound (LIPUS) is a promising therapeutic ultrasound technique that can be used for delivering mild mechanical stimuli to target tissue non-invasively, the underlying biophysical mechanisms still remain unclear. Most mechanism studies have focused explicitly on the effects of LIPUS on the cell membrane and mechanosensitive receptors. In the present study, we propose an additional mechanism by which LIPUS propagation through living cells may directly impact intracellular dynamics, particularly the diffusion transport of biomolecules. To support our hypothesis, human epithelial-like cells (SaOS-2 and HeLa) seeded on a confocal dish placed on a microscope stage were exposed to LIPUS with various exposure conditions (ultrasound frequencies of 0.5, 1 and 3 MHz, peak acoustic pressure of 200 and 400 kPa, a pulse repetition frequency of 1 kHz and a 20 % duty cycle), and the diffusivities of various sizes of biomolecules in the cytoplasm area were measured using fluorescence recovery after photobleaching (FRAP). Furthermore, giant unilamellar vesicles (GUVs) filled with macromolecules were used to examine the physical causal relationship between LIPUS and molecular diffusion changes. Nucleocytoplasmic transport coefficients were also measured by modified FRAP that bleaches the whole cell nuclear region. Extracellular signal-regulated kinases (ERK) activity (the phosphorylation dynamics) was monitored using fluorescence resonance energy transfer (FRET) microscopy. All the measurements were taken during, before and after the LIPUS exposure. Our experimental results clearly showed that the diffusion coefficients of macromolecules within the cell increased with acoustic pressure by 12.1 to 33.5 % during the sonication, and the increments were proportional to their molecular sizes regardless of the ultrasound frequency used. This observation in living cells was consistent with the GUVs exposed to the LIPUS, which indicated that the diffusivity increase was a passive physical response to the acoustic energy of LIPUS. Under the 1 MHz LIPUS exposure with 400 kPa, the passive nucleocytoplasmic transport of enhanced green fluorescent protein (EGFP) was accelerated by 21.4 %. With the same LIPUS exposure condition, both the diffusivity and phosphorylation of ERK induced by EGF treatment were significantly elevated simultaneously, which implied that LIPUS could also modify the kinase kinetics in the signal transduction process. Taken together, this study is the first attempt to uncover the physical link between LIPUS and the dynamics of intracellular macromolecules and related biological processes that LIPUS can possibly increase the diffusivity of intracellular macromolecules, leading to the changes in the basic cellular processes: passive nucleocytoplasmic transport and ERK. Our findings can provide a novel perspective that the mechanotransduction process that the intracellular region, in addition to the cell membrane, can convert the acoustic stimuli of LIPUS to biochemical signals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vaccination procedures can be stressful for fish and can bring severe side effects. Therefore, vaccines that can minimize the number of administrations and maximize cross-protection against multiple serotypes, genotypes, or even different species would be highly advantageous. In the present study, we investigated the cross-protective ability of two types of vaccines - viral hemorrhagic septicemia virus (VHSV) G protein-expressing DNA vaccine and G gene-deleted single-cycle VHSV genotype IVa (rVHSV-ΔG) vaccine - against both VHSV genotype Ia and infectious hematopoietic necrosis virus (IHNV) in rainbow trout (Oncorhynchus mykiss). The results showed that rainbow trout immunized with VHSV genotype Ia G gene- or IVa G gene-expressing DNA vaccine were significantly protected against VHSV genotype Ia, but were not protected against IHNV. In contrast to the DNA vaccine, the single-cycle VHSV IVa vaccine induced significant protection against not only VHSV Ia but also IHNV. Considering no significant increase in ELISA titer and serum neutralization activity against IHNV in fish immunized with single-cycle VHSV IVa, the protection might be independent of humoral adaptive immunity. The scarcity of cytotoxic T cell epitopes between VHSV and IHNV suggested that the possibility of involvement of cytotoxic T cell-mediated cellular adaptive immunity would be low. The role of trained immunity (innate immune memory) in cross-protection should be further investigated., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ki Hong Kim reports financial support was provided by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The use of appropriately designed immunotherapeutic bacteria is an appealing approach to tumor therapy because the bacteria specifically target tumor tissue and deliver therapeutic payloads. The present study describes the engineering of an attenuated strain of Salmonella typhimurium deficient in ppGpp biosynthesis (SAM) that could secrete Vibrio vulnificus flagellin B (FlaB) conjugated to human (hIL15/FlaB) and mouse (mIL15/FlaB) interleukin-15 proteins in the presence of L-arabinose (L-ara). These strains, named SAMphIF and SAMpmIF, respectively, secreted fusion proteins that retained bioactivity of both FlaB and IL15. SAMphIF and SAMpmIF inhibited the growth of MC38 and CT26 subcutaneous (sc) tumors in mice and increased mouse survival rate more efficiently than SAM expressing FlaB alone (SAMpFlaB) or IL15 alone (SAMpmIL15 and SAMphIL15), although SAMpmIF had slightly greater antitumor activity than SAMphIF. The mice treated with these bacteria showed enhanced macrophage phenotype shift, from M2-like to M1-like, as well as greater proliferation and activation of CD4 + T, CD8 + T, NK, and NKT cells in tumor tissues. After tumor eradication by these bacteria, ≥50% of the mice show no evidence of tumor recurrence upon rechallenge with the same tumor cells, indicating that they had acquired long-term immune memory. Treatment of mice of 4T1 and B16F10 highly malignant sc tumors with a combination of these bacteria and an immune checkpoint inhibitor, anti-PD-L1 antibody, significantly suppressed tumor metastasis and increased mouse survival rate. Taken together, these findings suggest that SAM secreting IL15/FlaB is a novel therapeutic candidate for bacterial-mediated cancer immunotherapy and that its antitumor activity is enhanced by combination with anti-PD-L1 antibody., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Nicotinamide riboside (NR) is considered a super-supplement that prevents obesity and diabetes. While NR has been investigated for various effects depending on nutritional conditions, metabolic research on women and pregnant women has rarely been discussed. In this study, we focused on the glycemic control of NR in females and found the protective role of NR in pregnant animals under hypoglycemic conditions. Metabolic-tolerance tests were performed in vivo under progesterone (P4) exposure after ovariectomy (OVX). NR enhanced resistance to energy deprivation and showed a slight increase in gluconeogenesis in naïve control mice. However, NR reduced hyperglycemia and significantly induced gluconeogenesis in OVX mice. While NR reduced hyperglycemia in the P4-treated OVX mice, it reduced insulin response and substantially increased gluconeogenesis. Similar to animal experiments, NR increased gluconeogenesis and mitochondrial respiration in Hep3B cells. The gluconeogenic function of NR is mediated by tricarboxylic acid cycle (TCA) cycle enrichment, as residual pyruvate could induce gluconeogenesis. NR recovered fetal growth by increasing blood glucose levels when hypoglycemia was induced by diet-restriction during pregnancy. Our study revealed the glucose-metabolic function of NR in hypoglycemic pregnant animals, suggesting NR as a dietary supplement to improve fetal growth. Because diabetic women suffer from hypoglycemia due to insulin therapy, NR has therapeutic potential for use as a glycemic control pill., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

L-Asparaginase (L-ASNase), a bacterial enzyme that degrades asparagine, has been commonly used in combination with several chemical drugs to treat malignant hematopoietic cancers such as acute lymphoblastic leukemia (ALL). In contrast, the enzyme was known to inhibit the growth of solid tumor cells in vitro, but not to be effective in vivo. We previously reported that two novel monobodies (CRT3 and CRT4) bound specifically with calreticulin (CRT) exposed on tumor cells and tissues during immunogenic cell death (ICD). Here, we engineered L-ASNases conjugated with monobodies at the N-termini and PAS200 tags at the C-termini (CRT3LP and CRT4LP). These proteins were expected to possess four monobody and PAS200 tag moieties, which did not disrupt the L-ASNase conformation. These proteins were expressed 3.8-fold more highly in E. coli than those without PASylation. The purified proteins were highly soluble, with much greater apparent molecular weights than expected ones. Their affinity (Kd) against CRT was about 2 nM, 4-fold higher than that of monobodies. Their enzyme activity (∼6.5 IU/nmol) was similar to that of L-ASNase (∼7.2 IU/nmol), and their thermal stability was significantly increased at 55 °C. Their half-life times were > 9 h in mouse sera, about 5-fold longer than that of L-ASNase (∼1.8 h). Moreover, CRT3LP and CRT4LP bound specifically with CRT exposed on tumor cells in vitro, and additively suppressed the tumor growth in CT-26 and MC-38 tumor-bearing mice treated with ICD-inducing drugs (doxorubicin and mitoxantrone) but not with a non-ICD-inducing drug (gemcitabine). All data indicated that PASylated CRT-targeted L-ASNases enhanced the anticancer efficacy of ICD-inducing chemotherapy. Taken together, L-ASNase would be a potential anticancer drug for treating solid tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Owing to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, the development of effective and safe vaccines has become a priority. The measles virus (MeV) vaccine is an attractive vaccine platform as it has been administered to children for more than 40 years in over 100 countries. In this study, we developed a recombinant MeV expressing the full-length SARS-CoV-2 spike protein (rMeV-S) and tested its efficacy using mouse and hamster models. In hCD46Tg mice, two-dose rMeV-S vaccination induced higher Th1 secretion and humoral responses than one-dose vaccination. Interestingly, neutralizing antibodies induced by one-dose and two-dose rMeV-S immunization effectively blocked the entry of the α, β, γ, and δ variants of SARS-CoV-2. Furthermore, two-dose rMeV-S immunization provided complete protection against SARS-CoV-2 in the hamster model. These results suggest the potential of rMeV-S as a vaccine candidate for targeting SARS-CoV-2 and its variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The matrix (M) protein of rhabdoviruses locates between the inner line of the viral envelope and the nucleocapsids core and plays an important role in viral replication. In the present study, we aimed to rescue a mutant of VHSV genotype IVa that has artificial mutations in the M protein (M-D62A E181A). However, most rescued recombinant viruses unexpectedly showed non-targeted secondary mutations in the M protein. Therefore, this study was conducted to know whether the targeted artificial mutation can lead to specific non-targeted secondary mutations in the M protein and whether the secondary mutations are compensatory for the targeted artificial mutations. Experiments were conducted to rescue three kinds of M protein mutants (rVHSV-M-D62A, -E181A, and -D62A E181A), and rVHSV-M-E181A and rVHSV-M-D62A E181A without the secondary mutations were rescued only from IRF-9 gene-knockout EPC cells. Recombinant VHSVs having only targeted mutation(s) (rVHSV-M-D62A, -E181A, and -D62A E181A) showed slower CPE progression and retarded growth compared to rVHSV-wild. Although the sites of secondary mutations were changed in every transfection experiment to generate recombinant VHSVs, the positions of the secondary mutations were not random. Some amino acid residues in the M protein showed more frequent mutations than others, and the changed amino acid residues were always the same. EPC cells infected with rVHSV-M-D62A E181A showed significantly higher type I interferon response and NF-κB activity, and the inhibitory activity against type I interferon response and NF-κB activity in other recombinant VHSVs having secondary mutations in M gene were similar to those of rVHSV-wild. In conclusion, the present results showed that VHSV actively responded to the artificial mutation of M protein through the secondary mutations, and those secondary mutations occurred when the artificial mutations were deleterious to viral replication and protein stability. Furthermore, most secondary mutations in recombinant viruses compensated for the deleterious effect of the engineered mutations., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

Oncogene-induced senescence (OIS) is highly heterogeneous, varying by oncogenic signals and cellular context. While its dual role, in the initial inhibition potentially later leading to promotion of tumors through the senescence-associated secretory phenotype, is still a matter of debate, it is undeniable that OIS is critical to understanding tumorigenesis. A major obstacle to OIS research is the absence of a universally accepted marker. Here, we present a robust OIS-specific transcriptomic secretory phenotype, termed oncogene-induced senescence secretory phenotype (OIS-SP), which can identify OIS across multiple biological contexts from in vitro datasets to in vivo human samples. We apply a meta-analytic machine learning pipeline to harmonize a deliberately varied selection of Ras-Raf-MEK-induced senescence datasets of differing origins, oncogenic signals and cell types. Finally we make use of bypass data to identify key genes and eliminate genes associated with quiescence, so identifying 40 OIS-SP genes. Within this set, we determined a robust core of five OIS-SP genes (FBLN1, CXCL12, EREG, CST1 and MMP10). Importantly, these 5 OIS-SP genes showed clear, consistent regulation patterns across various human Ras-Raf-MEK-mutated tumor tissues, which suggests that OIS-SP may be a novel cancer driver phenotype with an unexpectedly critical role in tumorigenesis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Lespedeza bicolor (LB) is known to have antidiabetic activities; however, the underlying molecular mechanisms of LB in hyperglycemia-induced skeletal muscle damage is unclear. Inflammation and oxidative stress caused by type 2 diabetes mellitus (T2DM) not only contributes to insulin resistance, but also promotes muscle atrophy via decreased muscle protein synthesis and increased protein degradation, leading to frailty and sarcopenia. In this study, we hypothesized that LB extract (LBE) supplementatin has an ameliorative effect on hyperglycemia-induced skeletal muscle damage by activation of 5' adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)/proliferator-activated receptor γ coactivator 1α (PGC1α)-associated energy metabolism in mice with T2DM. Diabetes was induced by a high-fat diet with a 2-time streptozotoxin injection (30 mg/kg body weight) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose level ≥140 mg/dL), the mice were administered with LBE at a low dose (100 mg/kg/d) or high dose (250 mg/kg/d) by gavage for 12 weeks. LBE supplementation ameliorated glucose tolerance and hemoglobin A1c (%) in mice with T2DM. Moreover, LBE supplementation upregulated protein levels of insulin receptor subunit-1 and Akt accompanied by increased translocation of glucose transporter 4 in mice with T2DM. Furthermore, LBE increased mitochondrial biogenesis by activating SIRT1, SIRT3, SIRT4, and peroxisome PGC1α in diabetic skeletal muscle. Meanwhile, LBE supplementation reduced oxidative stress and inflammation in mice with T2DM. Taken together, the current study suggested that LBE could be a potential therapeutic to prevent skeletal muscle damage by regulation AMPK/SIRT/PGC1α-related energy metabolism in T2DM., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To evaluate plasma antiretinal autoantibody (ARA) profiling and diagnostic efficacy for autoimmune retinopathy (AIR)., Design: A multicenter, diagnostic evaluation study., Methods: Forty-nine patients with a clinical diagnosis of AIR, disease controls including 20 patients with retinitis pigmentosa (RP), and 30 normal controls were included. Plasma samples from patients were analyzed for the presence of 6 ARAs, including recoverin, α-enolase, carbonic anhydrase II, heat shock protein 60, aldolase C, and cone-rod homeobox/cone-rod retinal dystrophy 2 using western blotting., Results: Autoantibody detection rates against cone-rod homeobox/cone-rod retinal dystrophy 2, heat shock protein 60, and aldolase C in AIR were 67.3%, 40.8%, and 42.9%, respectively, which were higher than those in RP and normal controls (P < .001, P < .001, and P = .007, respectively), but recoverin, α-enolase, and carbonic anhydrase II were not different from other control groups (P = .117, P = .774, and P = .467, respectively). Among ARAs, antirecoverin antibody was the most specific, as it was found in 3 (6.1%) patients with AIR and none of the control groups. As the number of detected ARAs increased, the probability of AIR increased (odds ratio: 1.913; P < .001; 95% confidence interval: 1.456-2.785). The positive number of ARAs was significantly higher when photoreceptor disruption was observed on optical coherence tomography, or severe dysfunction was observed in electroretinography (P = .022 and P = .029, respectively)., Conclusions: The profiles of ARAs in the AIR group were different from those in the RP and normal controls. The higher number of positive ARAs suggests a higher possibility of AIR diagnosis. ARAs should be used as adjunct tools for the clinical diagnosis of AIR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Drilling mud is a multi-phase fluid that is used in the petroleum drilling process. Bentonite is the most important constituent of drilling mud; it endows the drilling mud with its rheological behaviors, such as viscosity, yield stress, and shear thinning. The process of manufacturing microscale bentonite at the nanoscale level is very promising for commercializing nano-based drilling mud. In contrast to the conventional method using the impeller, bentonite was manufactured in its nanoparticle state in the present work through ultrasonic and homogenizer processes in the solution state. In case of the ultrasonic process, the viscosity increase in the low shear rate region before and after processing of the 5 wt% bentonite-based mud and the rheological properties in the presence of polymer additive were compared. In case of the homogenizer process, the rheological properties of 3 wt% bentonite-based mud employed through the homogenizer process and 5 wt% mud prepared generally were compared. Both processes reported improvement of rheological properties, in which shear thinning behavior strongly occurred when particle size decreased through FE-SEM, TEM image analysis, and particle size analyzer. A regularized Herschel-Bulkley model suitable for rheological quantitative explanation of drilling mud including yield stress was selected. The homogenizer process has the potential to be applied in the petroleum drilling industry for large-scale production, and the mechanism was confirmed by numerical analyses. In conclusion, we presented a simple and easy-to-apply process to rapidly produce nano-based drilling mud., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Little is known about the effect of air pollution on Alzheimer's disease (AD)-specific brain structural pathologies. There is also a lack of evidence on whether this effect leads to poorer cognitive function. We investigated whether, and the extent to which, AD-like cortical atrophy mediated the association between air pollution exposures and cognitive function in dementia-free adults. We used cross-sectional data from 640 participants who underwent brain magnetic resonance imaging and the Montreal Cognitive Assessment (MoCA). Mean cortical thickness (as the measure of global cortical atrophy) and machine learning-based AD-like cortical atrophy score were estimated from brain images. Concentrations of particulate matter with diameters ≤ 10 μm (PM 10 ) and ≤ 2.5 μm (PM 2.5 ) and nitrogen dioxide (NO 2 ) were estimated based on each participant's residential address. Following the product method, a mediation effect was tested by conducting a series of three regression analyses (exposure to outcome; exposure to mediator; and exposure and mediator to outcome). A 10 μg/m 3 increase in PM 10 (β = -1.13; 95 % CI, -1.73 to -0.53) and a 10 ppb increase in NO 2 (β = -1.09; 95 % CI, -1.40 to -0.78) were significantly associated with a lower MoCA score. PM 10 (β = 0.27; 95 % CI, 0.06 to 0.48) and NO 2 (β = 0.35; 95 % CI, 0.25 to 0.45) were significantly associated with an increased AD-like cortical atrophy score. Effects of PM 10 and NO 2 on MoCA scores were significantly mediated by mean cortical thickness (proportions mediated: 25 %-28 %) and AD-like cortical atrophy scores (13 %-16 %). The findings suggest that air pollution exposures may induce AD-like cortical atrophy, and that this effect may lead to poorer cognitive function in dementia-free adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Large elastic arteries, such as the aorta, contain concentric layers of elastic laminae composed mainly of the extracellular matrix protein elastin. The structure of the elastic laminae could affect transmural mass transport and contribute to aortic disease progression. We studied the effects of a genetic mutation (Lox M292R/+ , referred to as MU) in mice associated with ascending thoracic aortic aneurysm (TAA) on the mass transport and elastic laminae structure. Solute absent fluid flux and hydraulic conductance through the ascending aortic wall were not significantly different between groups, however solute present fluid flux, hydraulic conductance, solute flux, and solute permeability of 4 kDa FITC-dextran were significantly increased in the MU group, indicating that movement of small molecules into the aortic wall is facilitated in MU mice. Quantification from light microscopy images of the ascending aorta showed no significant differences in wall thickness, or inner elastic lamina fenestration size and density, but an increase in the number of elastic laminae breaks in the MU group. Ultrastructural comparisons from transmission electron micrographs suggest less dense and disorganized elastic laminae in MU aorta that may also contribute to the transport differences. Our results provide an initial investigation into the connections between mass transport and elastic laminae structure, specifically in a genetic mouse aneurysm model, which can be further used to understand TAA pathology and develop treatment strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

While conventional approaches for PTEN-loss cancers mainly focus on turning off growth promoting process through modulation of PI3K/AKT pathways, no effective therapeutic treatments that target PTEN-loss cancer cells have yielded results. Moreover, conventional targeted therapies, which are potent against only a subset of cancer cells with limited specificity, bring on temporary response. Here, we report the development of albumin-binding caspase-3 cleavable peptide-drug conjugate (PDC), which utilizes the enhanced albumin metabolism pathway in PTEN-loss cancer cells to enhance the intracellular delivery of chemotherapeutic payload that could exert a bystander killing effect. Albumin metabolism-mediated apoptosis triggered expression of caspase-3 allows the continuous activation of the PDC, accumulation of payloads, sustained upregulation of tumoral caspase-3, and intensified in-situ apoptosis. Importantly, PDC strategy exerts potent therapeutic efficacy against PTEN-loss metastatic triple-negative breast cancer, the highly aggressive and heterogenous nature of which remains a challenge conventional targeted therapies need to overcome. This study thus presents a conceptually novel approach to treat PTEN-loss cancer and creates new translational perspectives of exploiting PTEN-loss for providing an avenue to advance current targeted therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diet is a critical risk factor for gastric cancer, and Koreans consume significantly high amounts of carbohydrates. This study examined the association between carbohydrate intake, glycemic index, and glycemic load and the risk of gastric cancer and whether the association varied based on the general risk factors for gastric cancer. We hypothesized that carbohydrate intake, glycemic index, and glycemic load elevated gastric cancer risk and the relationship differed by the gastric cancer risk factors. This was a case-control study with a total of 307 matched pairs aged 20 to 79 years. Data collection was completed at two hospitals from December 2002 to September 2006. A food frequency questionnaire was applied for dietary assessment. Carbohydrate intake was not related to gastric cancer risk. However, a high glycemic index (odds ratio [OR], 1.88; 95% confidence interval (95% CI), 1.18-2.97) and glycemic load (OR, 2.51; 95% CI, 1.53-4.12) were significantly associated with the elevated risk of gastric cancer. When the relationship between glycemic load and gastric cancer risk was stratified by risk factors for gastric cancer, the gastric cancer risk especially increased among men, ≥65 years, smokers, drinkers, and people with Helicobacter pylori infection. Although there was no association between carbohydrate consumption and gastric cancer, high glycemic index and glycemic load were associated with the increased gastric cancer risk., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Prior research suggests a link between obstructive sleep apnea (OSA) and the likelihood of developing a variety of solid tumors; however, there are no studies assessing OSA and leukemia. This study is the first to identify a potential association between OSA and leukemia using data from the Korea National Health Insurance Service database., Methods: A total of 162,646 patients (≥20 years of age and without any cancer history) newly diagnosed with OSA between 2011 and 2017 were included. A control group of 813,230 subjects was selected using propensity score matching based on age and sex. The mean follow-up time was 4.4 ± 2.0 years. The primary endpoint was newly diagnosed leukemia of any type. The leukemia hazard ratio (95% confidence interval [CI]) was calculated for patients with OSA and compared with that of patients in the control group., Results: The incidence of leukemia among patients with OSA was significantly higher than that in the controls (1.35 [1.05-1.74]). The hazard ratio was the highest, 1.74 in those under 40 years, and gradually decreased with age, to 1.38 in those aged 40-65 years and 0.96 in those over 65. In particular, the incidence of lymphoid leukemia (2.06 [1.18-3.60]) was higher than that of myeloid (1.34 [1.00-1.81]) or unspecified leukemia (0.60 [0.20-1.58])., Conclusion: OSA is associated with an increased incidence of leukemia, particularly in patients younger than 40 years of age., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Quamoclit angulata (QA) is a species of the Convolvulaceae family and has a regulatory effect on glucose homeostasis. However, the effects of QA on hyperglycemia-induced hepatic damage has not been elucidated. We hypothesized that QA extract (QAE) would alleviate hepatic damage through regulation of hepatic lipid accumulation in type 2 diabetes mellitus (T2DM). T2DM was induced by streptozotocin-high-fat diet in C57BL6 male mice for 8 weeks. The diabetic mice were supplemented with QAE at low dose (5 mg/kg) or high dose (HQ, 10 mg/kg) by oral gavage every day for 12 weeks. Histopathological changes in hepatic tissue were examined using hematoxylin and eosin staining, and the protein levels of biomarkers related to AMP-activation kinase (AMPK)/sirtuin-1 (SIRT1)-associated lipid metabolism were measured using Western blotting. QAE supplementation ameliorated plasma insulin and glycated hemoglobin in diabetic mice. Furthermore, QAE decreased hepatic lipid accumulation demonstrated by hepatic triglyceride and cholesterol levels. QAE supplementation induced hepatic AMPK, which activates SIRT1 accompanied by reduced lipogenesis in the HQ group. These changes were partially explained by the amelioration of advanced glycation end product, hepatic oxidative stress, inflammation, and fibrosis in diabetic mice. Altogether, QAE would be a potential nutraceutical to prevent hepatic damage by regulation of AMPK/SIRT1-associated lipid metabolism through oxidative stress, inflammation, and fibrosis in T2DM., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate the mediating effects of working hours, sleep duration, and depressive mood on the association between shift work and the risk of suicidal ideation in Korean workers., Methods: Data from 33,047 workers were obtained from the nationwide cross-sectional Korea National Health and Nutrition Examination Surveys conducted in 2007-2018. Healthy workers without depressive disorders and chronic medical illnesses were included in the current study. Shift work patterns, sleep duration, working hours, depressive mood, and suicidal ideation were assessed using self-reported questionnaires. Multivariate logistic regressions were used to examine the association between shift work and the risk of suicidal ideation. Additionally, mediating studies were conducted to identify the roles of working hours and sleep durations on the association., Results: Compared with daytime workers, shift workers had 1.33 times greater risk of suicidal ideation (OR = 1.33, 95% Cl = 1.17-1.52, p < 0.001). Specifically, among shift work patterns, fixed-night shift, 24-h rotating shift and irregular rotating shift were associated with the risk of suicidal ideation when compared with daytime workers (irregular rotating shift: OR = 1.92, 95% Cl = 1.29-2.86, p = 0.001; fixed-night shift: OR = 1.75, 95% Cl = 1.32-2.31, p < 0.001; 24-h rotating shift: OR = 1.58, 95% Cl = 1.06-2.36, p = 0.024). In the mediating study, working hours, sleep duration and depressive mood significantly mediated the relationship between shift work and suicidal ideation (direct effect: β = 0.019, p = 0.001; indirect effect: β = 0.004, p = 0.031; total effect: β = 0.023, p < 0.001)., Conclusion: This study revealed that shift workers had a greater risk of suicidal ideation. The patterns significantly associated with suicidal ideation were irregular rotating, fixed-night, and 24-h rotating shifts. The pathway analysis revealed serial mediating effects of working hours, sleep duration, and depressive mood on the association between shift work and suicidal ideation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Alcohol use disorder (AUD) is a major risk factor for numerous social concerns worldwide. In the Republic of Korea, the court imposes compulsory medication treatment on criminals diagnosed with AUD who are on probation. The purpose of the treatment is to reduce the number of repeat offenses committed by AUD-afflicted criminals. In this study, a method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine ethyl glucuronide (EtG), acamprosate (ACAM), naltrexone (NTX), and 6β-naltrexol (6BNT) in urine was developed and validated to monitor the medication compliance and alcohol use of probationers diagnosed with AUD. A zirconia-based hybrid solid-phase extraction technique was introduced to increase the sensitivity toward target analytes having significantly differing pKa values while minimizing the matrix effect of the urine sample. The pretreated urine samples were analyzed by LC-MS/MS performed in a polarity-switching electrospray ionization mode via a three-period multiple-reaction monitoring method. All the target analytes were separated and detected within 6.5 min with an Xselect HSS T3 column and gradient elution using water containing 0.02% formic acid and methanol as the mobile phase. The lower limits of quantification of EtG, ACAM, NTX, and 6BNT were 10.0, 4.0, 0.4, and 0.2 ng mL -1 , respectively. The determination coefficients of each calibration curve were greater than 0.9989. The intra-day accuracy ranged from -5.5-5.3% and the precision was ≤ 5.7%, whereas the inter-day accuracy ranged from -5.3-4.6% and the precision was ≤ 4.7%. The recovery, matrix effect, and process efficiency were 99.7-107.9%, 80.7-101.8%, and 80.5-108.1%, respectively. The developed method was successfully applied to analyze 107 urine samples obtained from probationers undergoing medication treatment for AUD and to monitor the probationers' medication compliance and alcohol use. This study also determined the urinary concentrations of EtG, ACAM, NTX, and 6BNT as well as the metabolic ratio of NTX following repeated oral administration of AUD medications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This research investigated variations in alcohol consumption by socioeconomic factors and hypertensive status in South Korean adults, aged ≥19 years. This is a secondary data analysis using the Korea National Health and Nutrition Examination Survey (KNHANES). Alcohol intake by socioeconomic and hypertensive status was examined using data from the 2013 to 2016 KNHANES. Total participants were 19,641 adults, with 8,123 men and 11,518 women. Consumption of alcohol in the Korean population was estimated from a single 24-hour dietary recall. Alcohol intake differed, according to socioeconomic status, and, particularly, by occupation among Korean adults. Women with lower education consumed more alcohol daily than those with a higher education (p = 0.018). Furthermore, adult men with hypertension consumed a greater amount of alcohol daily, 30.9 g, than those with pre-hypertension, 23.7 g, followed by those without hypertension, 15.9 g (p < 0.001). In women, adults with pre-hypertension and hypertension consumed more alcohol daily, 9.4 g and 9.0 g, respectively, than those without, 6.6 g (p < 0.001). In addition, men with hypertension who were unaware of their disease and those who were cognizant consumed a higher amount of alcohol daily, 32.4 g and 28.6 g, respectively, than individuals without hypertension, 19.7 g (p < 0.001). Moreover, men with hypertension who had not been treated for hypertension and those in treatment consumed a greater amount of alcohol daily, 32.6 g and 28.0 g, respectively, than those without hypertension, 19.7 g (p < 0.001). In conclusion, Korean adults consume alcohol differently by socioeconomic status, and alcohol intake was more prevalent among people with hypertension., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Melittin, the main venom component of the European Honeybee, is a cationic linear peptide-amide of 26 amino acid residues with the sequence: GIGAVLKVLTTGLPALISWIKRKRQQ-NH 2 . Melittin binds to lipid bilayer membranes, folds into amphipathic α-helical secondary structure and disrupts the permeability barrier. Since melittin was first described, a remarkable array of activities and potential applications in biology and medicine have been described. Melittin is also a favorite model system for biophysicists to study the structure, folding and function of peptides and proteins in membranes. Melittin has also been used as a template for the evolution of new activities in membranes. Here we overview the rich history of scientific research into the many activities of melittin and outline exciting future applications., (Copyright © 2021. Published by Elsevier Inc.)

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8 + T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of cancer cells using synergistic immunogenic agents targeting the MSS CRC., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although cisplatin is an effective platinum-based anticancer drug against solid cancer, its availability is limited owing to its adverse side effects. Our study aimed to identify the potential relationship within cisplatin-induced multi-organ physiological changes and genetic factors associated with sex differences in nephrotoxicity susceptibility. To investigate this, mice received a single intraperitoneal injection of cisplatin. Cisplatin administration resulted in renal dysfunction, as evidenced by the elevation in serum biomarkers of renal damage (blood urea nitrogen and creatinine) and the degree of histopathological alterations. In particular, along with testicular damage and low testosterone levels, we also observed a decrease in male-specific (CYP3A2) or male-dominant (CYP2B1 and CYP3A1) CYP isoforms in the livers of rats with hepatotoxicity following cisplatin treatment, which may be associated with an imbalance in male hormone regulation caused by renal and testicular injury. Notably, we found that male rats were more susceptible to cisplatin-induced nephrotoxicity, as characterized by histopathological and biochemical analyses. Therefore, RNA sequencing was performed at baseline (pre-treatment) and at 48 h following cisplatin administration (post-treatment) to identify the genes associated with sex differences in nephrotoxicity susceptibility. Gap junctions, which play a role in replenishing damaged cells to maintain tissue homeostasis, and mismatch repair associated with a pathological apoptotic mechanism against cisplatin nephrotoxicity were significantly enriched only in males following cisplatin treatment. Moreover, among the 322 DEGs showing different basal expression patterns between males and females before cisplatin treatment, the male expressed high levels of genes, which are responsible for transmembrane transport and regulation of apoptotic process, pre-cisplatin treatment; additionally, genes involved in the PI3K-Akt signaling pathway and the oxidation-reduction process were significantly lower in males before cisplatin treatment. Collectively, our comprehensive findings provided valuable insight into the potential mechanisms of sex differences in cisplatin-induced nephrotoxicity susceptibility., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: After thyroidectomy, many patients suffer from voice problems and vague neck discomfort. The Thyroidectomy-related Voice and Symptom Questionnaire (TVSQ) is a self-administered questionnaire used to evaluate pre- and post-operative vocal status as well as throat and neck discomfort. We investigated voice conditions in thyroidectomy patients using the TVSQ as well as correlations between TVSQ responses and objective voice parameters. Also, we examined whether any clinicopathologic or surgical factors affect phonetic change after thyroidectomy., Methods: We retrospectively reviewed the records of 242 patients who underwent total thyroidectomy to treat papillary carcinoma between January to December of 2019. Of these, we enrolled 232 who exhibited normal vocal cord mobility after surgery. TVSQ responses and acoustic voice analysis results were examined preoperatively and at 1, 3, and 6 months postoperatively. We subclassified patients into favorable and unfavorable TVSQ groups based on the increase in TVSQ score (△TVSQ ≥20) at 1 month postoperatively. We then investigated the difference of acoustic characteristics between two groups and analyzed the correlations between acoustic parameters and various clinical and surgical factors including pathologic results and lymph node status by subgroup., Result: All acoustic voice parameters except for the noise-to-harmonics ratio were significantly worse at 1 month postoperatively and recovered over time, but the TVSQ score did not recover from the 1-month value until 6 months postoperatively. In the subgroups, among the many clinicopathologic factors examined, advanced N stage (p = 0.002) and high positive total and central-and-lateral-neck lymph node ratios were significantly associated with an increased risk of an unfavorable TVSQ (p = 0.049, 0.027, <0.01, respectively). Among the acoustic parameters, only the changes in TVSQ total score and voice score were correlated with deterioration in jitter and shimmer at 1 month postoperatively. However, the correlations was not statistically significant and had disappeared at 6 months postoperatively., Conclusion: We figured out that TVSQ was able to capture the negative effects of lymph node status and lymph node dissection on vocal outcomes after thyroidectomy. Although there was a weak correlation between worsened perturbation value and TVSQ changes, no other acoustic analysis parameters were statistically significant correlated with the TVSQ score., Competing Interests: Declaration of Competing Interest There is no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

Objective: This study investigated the association between changes in sleep duration after disaster and post-traumatic stress disorder (PTSD) symptoms and the mediating role of resilience on the association., Methods: Data were collected from 2951 Korean adults who were victims of a natural disaster and did not have any mental or medical illnesses before the event. They completed a long-term survey on changes in life for disaster victims using computer-aided personal interviews. Changes in sleep duration before and one month after experiencing a disaster were assessed using a self-reported questionnaire. Resilience levels and PTSD symptoms were measured using the Brief Resilience Scale and the Impact of Event Scale - Revised, respectively, and more than 33 of the IES-R score items were defined as significant PTSD symptoms. Multivariate logistic regression was used to examine the associations between changes in sleep duration and PTSD symptoms. Additionally, mediating studies were conducted to identify the role of resilience on the association., Results: Compared with participants without significant PTSD symptoms, those with PTSD symptoms were more likely to be older and female (group without significant PTSD symptom: mean age = 56.12 ± 18.70 years, female sex = 49.24%; group with significant PTSD symptoms: mean age = 60.88 ± 15.66 years, female sex = 59.52%). Compared with disaster victims without changes in sleep duration, those who had shorter sleep duration after disaster had a higher risk of significant PTSD symptoms (OR = 2.89, 95% Cl = 2.31-3.62, p < 0.001). In the mediating study, resilience level significantly mediated the relationship between reduced sleep duration and PTSD symptoms (direct effect: β = 0.208, 95% Cl = 0.166-0.250, p < 0.001; indirect effect: β = 0.007, 95% Cl = 0.002-0.011, p < 0.001; total effect: β = 0.215, 95% Cl = 0.173-0.257, p < 0.001)., Conclusion: This study revealed that individuals with reduced sleep duration after disaster had a higher risk of PTSD symptoms, while those with increased sleep duration did not. In addition, mediating effects of resilience level on the relationship between reduced sleep duration and significant PTSD symptoms were observed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Here we used 3D finite element analysis (FEA) to analyze and directly compare stress distribution and crack propagation in identical cracked tooth models after treatment with various materials and designs., Methods: A 3D model of a cracked tooth was generated. We then applied eight restoration models, comprising combinations of three kinds of restoration designs (inlay, onlay, and crown) and four types of restoration materials (direct composite resin, indirect composite resin, ceramic, and gold). A 1000-N occlusal load was applied on the three reference points of the ball-shaped part in the direction of the longitudinal axis, causing crack line separation in the buccolingual direction. Stress distribution was analyzed on the occlusal surface, bottom level of the restoration, and mesiodistal longitudinal section. The stress on the lower margin of the crack surface was measured at 15 points on each model., Results: Ceramic inlay and onlay showed stress concentration at the restoration bottom, and low stress on the lower margin of the crack surface. Direct and indirect resin restorations exhibited low stress on the restoration bottom, and high stress on the proximal end of the lower margin of the crack surface. With a resin-unfilled gold crown, stress was concentrated on the crown bottom and the lower margin of the crack surface. Direct resin filling inside the gold crown yielded significantly decreased stress on both areas., Significance: Our results suggest that inlay and onlay ceramic restorations, and gold crown with resin filling inside, are advantageous methods for preventing further crack propagation., (Copyright © 2021 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

Background: This paper compares cost-effectiveness results from two models of maternal immunization to prevent pertussis in infants in Brazil, one static, one dynamic, to explore when static models are adequate for public health decisions and when the extra effort required by dynamic models is worthwhile., Methods: We defined two scenarios to explore key differences between static and dynamic models, herd immunity and time horizon. Scenario 1 evaluates the incremental cost/DALY of maternal acellular pertussis (aP) immunization as routine infant vaccination coverage ranges from low/moderate up to, and above, the threshold at which herd immunity begins to eliminate pertussis. Scenario 2 compares cost-effectiveness estimates over the models' different time horizons. Maternal vaccine prices of $9.55/dose (base case) and $1/dose were evaluated., Results: The dynamic model shows that maternal immunization could be cost-saving as well as life-saving at low levels of infant vaccination coverage. When infant coverage reaches the threshold range (90-95%), it is expensive: the dynamic model estimates that maternal immunization costs $2 million/DALY at infant coverage > 95% and maternal vaccine price of $9.55/dose; at $1/dose, cost/DALY is $200,000. By contrast, the static model estimates costs/DALY only modestly higher at high than at low infant coverage. When the models' estimates over their different time horizons are compared at infant coverage < 90-95%, their projections fall in the same range., Conclusions: Static models may serve to explore an intervention's cost-effectiveness against infectious disease: the direction and principal drivers of change were the same in both models. When, however, an intervention too small to have significant herd immunity effects itself, such as maternal aP immunization, takes place against a background of vaccination in the rest of the population, a dynamic model is crucial to accurate estimates of cost-effectiveness. This finding is particularly important in the context of widely varying routine infant vaccination rates globally., Clinical Trial Registry: Clinical Trial registry name and registration number: Not applicable., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Sinha was at Rutgers School of Public Health until August 2016, but is currently employed by Merck Research Laboratory, a division of Merck & Co. Dr. Andrade has received lecture fees and travel grants from GlaxoSmithKline and Pfizer. Dr. Minamisava has received travel grants from GlaxoSmithKline. The other authors have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: This study evaluates the cost-effectiveness of maternal acellular pertussis (aP) immunization in low- and middle-income countries using a dynamic transmission model., Methods: We developed a dynamic transmission model to simulate the impact of infant vaccination with whole-cell pertussis (wP) vaccine with and without maternal aP immunization. The model was calibrated to Brazilian surveillance data and then used to project health outcomes and costs under alternative strategies in Brazil, and, after adjusting model parameter values to reflect their conditions, in Nigeria and Bangladesh. The primary measure of cost-effectiveness is incremental cost (2014 USD) per disability-adjusted life-year (DALY)., Results: The dynamic model shows that maternal aP immunization would be cost-effective in Brazil, a middle-income country, under the base-case assumptions, but would be very expensive at infant vaccination coverage in and above the threshold range necessary to eliminate the disease (90-95%). At 2007 infant coverage (DTP1 90%, DTP3 61% at 1 year of age), maternal immunization would cost < $4,000 per DALY averted. At high infant coverage, such as Brazil in 1996 (DTP1 94%, DTP3 74% at 1 year), cost/DALY increases to $1.27 million. When the model's time horizon was extended from 2030 to 2100, cost/DALY increased under both infant coverage levels, but more steeply with high coverage. The results were moderately sensitive to discount rate, maternal vaccine price, and maternal aP coverage and were robust using the 100 best-fitting parameter sets. Scenarios representing low-income countries showed that maternal aP immunization could be cost-saving in countries with low infant coverage, such as Nigeria, but very expensive in countries, such as Bangladesh, with high infant coverage., Conclusion: A dynamic model, which captures the herd immunity benefits of pertussis vaccination, shows that, in low- and middle-income countries, maternal aP immunization is cost-effective when infant vaccination coverage is moderate, even cost-saving when it is low, but not cost-effective when coverage levels pass 90-95%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. [Dr. Sinha is currently an employee at Merck & Co and has stock holdings in that company. She was at Rutgers New Jersey Medical School when this work was conducted. Merck & Co. played no role in study design, collection, analysis, interpretation of data, writing of the report, or in the decision to submit the paper for publication. They accept no responsibility for the contents. Pej Rohani served as a paid consultant on structuring and calibrating the dynamic model.], (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Using dynamic transmission models we evaluated the health and cost outcomes of adding acellular pertussis (aP) vaccination of pregnant women to infant vaccination in three Brazilian states that represent different socioeconomic conditions. The primary objective was to determine whether the same model structure could be used to represent pertussis disease dynamics in differing socioeconomic conditions., Methods: We tested three model structures (SIR, SIRS, SIRSIs) to represent population-level transmission in three socio-demographically distinct Brazilian states: São Paulo, Paraná and Bahia. Two strategies were evaluated: infant wP vaccination alone versus maternal aP immunization plus infant wP vaccination. Model projections for 2014-2029 include outpatient and inpatient pertussis cases, pertussis deaths, years of life lost, disability-adjusted life-years (DALYs) lost, and costs (in 2014 USD) of maternal aP vaccination, infant vaccination, and pertussis medical treatment. Incremental cost per DALY averted is presented from the perspective of the Brazilian National Health System., Results: Based on goodness-of-fit statistics, the SIRSIs model fit best, although it had only a modest improvement in statistical quantitative assessments relative to the SIRS model. For all three Brazilian states, maternal aP immunization led to higher costs but also saved infant lives and averted DALYs. The 2014 USD cost/DALY averted was $3068 in Sao Paulo, $2962 in Parana, and $2022 in Bahia. These results were robust in sensitivity analyses with the incremental cost-effectiveness ratios exceeding per capita gross regional product only when the probability that a pertussis case is reported was assumed higher than base case implying more overt cases and deaths and therefore more medical costs., Conclusions: The same model structure fit all three states best, supporting the idea that the disease behaves similarly across different socioeconomic conditions. We also found that immunization of pregnant women with aP is cost-effective in diverse Brazilian states., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Andrade has received lecture fees and travel grants from GlaxoSmithKline and Pfizer. Dr. Minamisava has received travel grants from GlaxoSmithKline. All other authors have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Lung cancer is one of the leading causes of death in cancer patients. Epithelial-mesenchymal transition (EMT) plays an important role in lung cancer progression. Therefore, for lung cancer treatment, it is crucial to find substances that inhibit EMT. Ethacrynic acid (ECA) is a diuretic that inhibits cellular ion flux and exerts anticancer effects. However, the effects of ECA on EMT in lung cancer remain unclear. We examined the effects of ECA on sphingosylphosphorylcholine (SPC) or TGF-β1-induced EMT process in A549 and H1299 cells via reverse transcription polymerase chain reaction and Western blotting. We found that ECA inhibited SPC-induced EMT and SPC-induced WNT signalling in EMT. We observed that SPC induces the expression of NDP [Norrie disease protein] and WNT-2, whereas ECA suppressed their expression. SPC-induced WNT activation, EMT, migration, and invasion were suppressed by NDP small-interfering RNA (siNDP), but NDP overexpression (pNDP) enhanced these events in A549 and H1299 cells. Accordingly, NDP expression may influence lung cancer prognosis. In summary, our results revealed that ECA inhibited SPC or TGF-β1-induced EMT in A549 and H1299 lung cancer cells by downregulating NDP expression and inhibiting WNT activation. Therefore, ECA might be a new drug candidate for lung cancer treatment., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Research into mechanisms underlying lung injury and subsequent repair responses is currently of paramount importance. There is a paucity of models that bridge the gap between in vitro and in vivo research. Such intermediate models are critical for researchers to decipher the mechanisms that drive repair and to test potential new treatments for lung repair and regeneration. Here we report the establishment of a new tool, the Acid Injury and Repair (AIR) model, that will facilitate studies of lung tissue repair. In this model, injury is applied to a restricted area of a precision-cut lung slice using hydrochloric acid, a clinically relevant driver. The surrounding area remains uninjured, thus mimicking the heterogeneous pattern of injury frequently observed in lung diseases. We show that in response to injury, the percentage of progenitor cells (pro surfactant protein C, proSP-C and TM4SF1 positive) significantly increases in the injured region. Whereas in the uninjured area, the percentage of proSP-C/TM4SF1 cells remains unchanged but proliferating cells (Ki67 positive) increase. These effects are modified in the presence of inhibitors of proliferation (Cytochalasin D) and Wnt secretion (C59) demonstrating that the AIR model is an important new tool for research into lung disease pathogenesis and potential regenerative medicine strategies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Numerous systemic vascular dysfunction that leads to age-related diseases is highly associated with endothelial cell (EC) senescence; thus, identifying consensus features of EC senescence is crucial in understanding the mechanisms and identifying potential therapeutic targets. Here, by utilizing a total of 8 screened studies from different origins of ECs, we have successfully obtained common features in both gene and pathway level via sophisticated machine learning algorithms. A total of 400 differentially expressed genes (DEGs) were newly discovered with meta-analysis when compared to the usage of individual studies. The generated parsimonious model established 36 genes and 57 pathways features with non-zero coefficient, suggesting remarkable association of phosphoglycerate dehydrogenase and serine biosynthesis pathway with endothelial cellular senescence. For the cross-validation process to measure model performance of 36 deduced features, leave-one-study-out cross-validation (LOSOCV) was employed, resulting in an overall area under the receiver operating characteristic (AUROC) of 0.983 (95 % CI, 0.952, 1.000) showing excellent discriminative performance. Moreover, pathway-level analysis was performed by Pathifier algorithm, obtaining a total of 698 pathway deregulation scores from the 10,416 merged genes. In this process, high dimensional data was eventually narrowed down to 57 core pathways with AUROC value of 0.982 (95 % CI, 0.945, 1.000). The robust model with high performance underscores the merit of utilizing sophisticated meta-analysis in finding consensus features of endothelial cell senescence, which may lead to the development of therapeutic targets and advanced understanding of vascular dysfunction pathogenesis with further elucidation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Melanoma, the most severe form of skin cancer, has poor prognosis and is resistant to chemotherapy. Targeting cancer metabolism is a promising approach in cancer therapeutics. Dihydrolipoyl dehydrogenase (DLD) is a mitochondrial enzyme with diaphorase activity. Here we report a pivotal role of DLD in melanoma cell progression and proliferation. Suppression DLD expression by low intensity UVA (125 mJ/cm 2 ) increased intracellular ROS production and decreased mitochondrial membrane potential thereby inducing autophagy cell death which were confirmed by increased LC3BII and decreased p62 expression in melanoma cells. Knockdown of DLD in melanoma cells also showed similar results. More so, suppression of DLD significantly inhibits in vivo melanoma growth and tumor proliferation. In addition, suppression of DLD increased the NAD+/NADH ratio in melanoma cells and also inhibits TCA cycle related metabolites. DLD downregulation markedly increased α-ketoglutarate and decreased succinic acid suggesting that DLD suppression may have decreased TCA cycle downstream metabolites, resulting in the alteration of mitochondrial energy metabolism Thus the downregulation of DLD induced autophagic cell death in melanoma cells and inhibits in vivo tumor growth and proliferation by increasing ROS production and altering energy metabolism. Our findings suggest that DLD plays a pivotal role in melanoma progression and proliferation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Scapular kinematics of breast cancer survivors are most often evaluated during arm elevation. However, known compensations exist during functional task performance. The purpose of this study was to determine if scapular kinematics of breast cancer survivors during arm elevation are related to scapular kinematics during functional task performance., Methods: Scapular kinematics of 25 non-cancer controls and 25 breast cancer survivors (split by presence of impingement pain) during arm elevation in 3 planes and 3 reaching and lifting functional tasks were measured. Scapular upward rotation and scapulohumeral rhythm (SHR) at 30° increments of arm elevation were calculated. Between-group differences of upward rotation during arm elevation were evaluated with one-way ANOVAs (p < 0.05). The association of upward rotation angle and SHR during arm elevation and functional tasks was tested with Pearson correlations (p < 0.05)., Findings: Scapular upward rotation was reduced for the breast cancer survivor with pain at lower levels of arm elevation in each plane by up to 7.1° (p = .014 to 0.049). This is inconsistent with functional task results, in which upward rotation decrements occurred at higher levels of arm elevation. Upward rotation angles and SHR during arm elevation had an overall weak-to-moderate relationship (r = 0.003 to 0.970, p = .001 to 0.048) to values from functional tasks. Arm elevation during sagittal plane elevation demonstrated scapular upward rotation that was most closely associated to upward rotation during functional task performance., Interpretation: Inconsistent relationships suggests that clinical evaluations should adopt basic functional movements for scapular motion assessment to complement simple arm elevations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Changes in perineuronal nets (PNNs) after hearing loss were described in previous studies. The present study aimed to examine how single-sided deafness (SSD) affects the expression of excitatory and inhibitory synaptic transporters and PNNs in the primary auditory cortex (A1). Sprague-Dawley rats (8-week-old females, n = 30) were divided into three groups: (1) the SSD 2-week group (n = 10), (2) the SSD 4-week group (n = 10), and (3) the 4-week control group (n = 10). The expression levels of vesicular glutamate transporter 1 (VGLUT1), VGLUT2, vesicular GABA transporter (VGAT), and genes related to PNNs were measured using quantitative reverse transcription-polymerase chain reaction. The A1 was immunostained for VGLUT1, glutamate acid decarboxylase (GAD) 67, neurocan, aggrecan, brevican, and Wisteria floribunda agglutinin (WFA). The expression levels of VGLUT1, VGLUT2, and VGAT were elevated in the A1 on the ipsilateral side in the SSD groups compared with those in the control groups. Aggrecan expression was elevated in the A1 on the contralateral side in the SSD 2-week group. The SSD groups had elevated expression levels of metalloproteinase (MMP) 9 on the contralateral side. The presynaptic glutamatergic and GABAergic transporters were increased in the A1 on the ipsilateral side after induction of SSD. Changes in the cortical auditory nervous system accompanied changes in the PNNs and their degradation enzymes MMP9 and MMP14., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)