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Geminal bromofluoroalkenes are an important subclass of versatile organic interhalide, which can serve as useful synthetic precursors to monofluoroalkenes that are valuable amide group isosteres. Nonetheless, despite the vast advancement of olefination methodologies, the broadly applicable stereoselective synthesis remained elusive for geminal bromofluoroalkenes before our work. In particular, the seemingly straightforward Wittig-type approach with interhalogenated phosphorus ylide has been unsuccessful because of the difficulty in the diastereoselective oxaphosphetane formation. Here, we describe a conceptually distinctive strategy, by which the stereoselectivity is gained via the selective decomposition of the oxaphosphetane intermediates. The suitably identified phosphorus(III) reagent and reaction medium enabled efficient kinetic differentiation, which was supported by nuclear magnetic resonance analysis and density functional theory calculation. Through our method, the highly diastereoselective synthesis of geminal E -bromofluoroalkenes was accomplished in one step. Furthermore, the generality was demonstrated by accommodating a wide range of readily available carbonyl compounds, including ketones and pharmaceutical substrates.

Acute lung injury (ALI) is the pathophysiological precursor of acute respiratory distress syndrome. It is characterized by increased oxidative stress and exaggerated inflammatory response that disrupts redox reactions and immune homeostasis in the lungs, thereby posing significant clinical challenges. In this study, an internally functionalized thioether-enriched dendrimer Sr-G4-PEG is developed, to scavenge both proinflammatory cytokines and reactive oxygen species (ROS) and restore homeostasis during ALI treatment. The dendrimers are synthesized using an efficient and orthogonal thiol-ene "click" chemistry approach that involves incorporating thioether moieties within the dendritic architectures to neutralize the ROS. The ROS scavenging of Sr-G4-PEG manifests in its capacity to sequester proinflammatory cytokines. The synergistic effects of scavenging ROS and sequestering inflammatory cytokines by Sr-G4-PEG contribute to redox remodeling and immune homeostasis, along with the modulation of the NLRP3-pyroptosis pathway. Treatment with Sr-G4-PEG enhances the therapeutic efficacy of ALIs by alleviating alveolar bleeding, reducing inflammatory cell infiltration, and suppressing the release of inflammatory cytokines. These results suggest that Sr-G4-PEG is a potent nanotechnological candidate for remodeling redox and immune homeostasis in the treatment of ALIs, demonstrating the great potential of dendrimer-based nanomedicine for the treatment of respiratory pathologies., (© 2024 Wiley‐VCH GmbH.)

Depression and metabolic syndrome could exacerbate the risks of the other, leading to a series of severe coexisting conditions. One notable comorbidity that must be mentioned is obstructive sleep apnea (OSA). Current studies suggested that depression increases susceptibility to OSA. As the prevalence of depression rises, it becomes critical to prevent and manage its complications or comorbidities, including OSA. Predictive models, non-invasive electroencephalogram monitoring, genetic research, and other promising technologies are being applied to the prevention, diagnosis, and personalized treatment of depression and OSA., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Medication-Related Osteonecrosis of the Jaw (MRONJ) is characterized by bone exposure in the oral and maxillofacial region for more than eight weeks in patients treated with anti-resorptive agents, immunosuppressants, or anti-angiogenic agents, without prior radiation therapy or metastatic disease to the jaws. Conservative treatments can control infection in mild cases, but surgical intervention is necessary for patients with severe symptoms. A 78-year-old female with a history of bisphosphonate treatment for osteoporosis presented with persistent pain, swelling, and malodor following implant placement in the upper right maxilla. SPECT/CT imaging revealed a high-risk hot spot in the right maxillary region. BIS-guided surgery using the Qray pen-C was performed, selectively removing red fluorescent bone tissue. The defect was grafted with HuBT incorporated with rhBMP-2. Postoperative follow-ups at 4, 7, and 14 months showed successful bone healing, transforming into a corticocancellous complex, and implant placement without MRONJ recurrence. Allogeneic demineralized dentin matrix (DDM) incorporated with rhBMP-2 demonstrates effective bone healing and implant placement following BIS-guided MRONJ surgery. This case supports the use of DDM/rhBMP-2 for tissue regeneration in MRONJ treatment, enabling successful prosthetic restoration without recurrence.

The Moving Protecting-Qi ( Wei Qi Xing ), in Lingshu , one of the volumes of the Inner Cannon of Huangdi , records two types of circulatory routes which were believed to link man and nature (a traditional Chinese medicine theory that argues man is an integral part of nature). The first type of circulatory route matched the Sun and twenty-eight lunar mansions because it was believed that the Protecting-Qi circulates through different body parts of human during the day and night. This indicates that the Protecting-Qi passes through the meridians at day time and washes the five viscera at night. The second type matched the hourglass. This means it does twenty-five cycles circulation through three Yang and one Yin in the human body on a centigrade scale. The Protecting-Qi in Lingshu attempted to unify the two circulatory routes numerically by equating the two different time measures-the sun moving and the hourglass. Additionally, it implicitly took an ambiguous concept of 'Yin Fen' to replace the different parts of the five viscera, attempting to unify the two circulatory routes together. However, because of the intrinsic differences between the two circulatory routes, this effort does not make sense. It was found that the first circulatory route is mostly used in clinical practice to explain and treat disorders associated with yawning and insomnia, yet there exists a subtle difference in theoretical explanation.

Depression is a common occurrence among cancer patients, and it significantly impacts their clinical outcomes and quality of life, with a high incidence during anti-tumor treatment or after surgery. The association between surgery and depression is the result of the interaction of various factors, including physiological, psychological, and social factors, all of which are intertwined and make patients susceptible to depression after surgical treatment. Postoperative depression has a significant negative impact on many aspects of cancer patients, and it requires timely identification and intervention to improve the overall outcome., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interests., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: To evaluate the diagnostic efficiency among the clinical model, the radiomics model and the nomogram that combined radiomics features, frozen section (FS) analysis and clinical characteristics for the prediction of lymph node (LN) metastasis in patients with papillary thyroid cancer (PTC)., Methods: A total of 208 patients were randomly divided into two groups randomly with a proportion of 7:3 for the training groups (n = 146) and the validation groups (n = 62). The Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for the selection of radiomics features extracted from ultrasound (US) images. Univariate and multivariate logistic analyses were used to select predictors associated with the status of LN. The clinical model, radiomics model and nomogram were subsequently established by logistic regression machine learning. The area under the curve (AUC), sensitivity and specificity were used to evaluate the diagnostic performance of the different models. The Delong test was used to compare the AUC of the three models., Results: Multivariate analysis indicated that age, size group, Adler grade, ACR score and the psammoma body group were independent predictors of lymph node metastasis (LNM). The results showed that in both the training and validation groups, the nomogram showed better performance than the clinical model, albeit not statistically significant (p > .05), and significantly outperformed the radiomics model (p < .05). However, the nomogram exhibits a slight improvement in sensitivity that could reduce the incidence of false negatives., Conclusion: We propose that the nomogram holds substantial promise as an effective tool for predicting LNM in patients with PTC., (© 2024 John Wiley & Sons Ltd.)

In this paper, we consider the problem of asynchronous estimation in the presence of packet losses for the randomly sampling nonlinear system. Packet losses occur at the control input and at the measurement side. Firstly, the synchronization of the asynchronous sampling system is realized by weighting the state of the adjacent state update points. Secondly, the projection theorem is used to estimate the system state at the sampling time. Due to modeling errors and unmodeled dynamics, obtaining an accurate dynamic model is challenging. Therefore, observation inference based on interpolation techniques is proposed to solve the asynchronous estimation problem. Furthermore, the algorithm is extended to multi-sensor systems to obtain a distributed fusion estimator. Finally, simulation experiments are conducted to validate the effectiveness of the algorithm.

Purpose: Asthma can not be eradicated till now and its control primarily relies on the application of corticosteroids. Recently, glycolytic reprogramming has been reportedly contributed to asthma, this study aimed to reveal whether the effect of corticosteroids on asthma control is related to their regulation of glycolysis and glycolysis-dependent protein lactylation., Methods: Ovalbumin (OVA) aeroallergen was used to challenge mice and stimulate human macrophage cell line THP-1 following dexamethasone (DEX) treatment. Airway hyperresponsiveness, airway inflammation, the expressions of key glycolytic enzymes and pyroptosis markers, the level of lactic acid, real-time glycolysis and oxidative phosphorylation (OXPHOS), and protein lactylation were analyzed., Results: DEX significantly attenuated OVA-induced eosinophilic airway inflammation, including airway hyperresponsiveness, leukocyte infiltration, goblet cell hyperplasia, Th2 cytokines production and pyroptosis markers expression. Meanwhile, OVA-induced Hif-1α-glycolysis axis was substantially downregulated by DEX, which resulted in low level of lactic acid. Besides, key glycolytic enzymes in the lungs of asthmatic mice were notably co-localized with F4/80-positive macrophages, indicating metabolic shift to glycolysis in lung macrophages during asthma. This was confirmed in OVA-stimulated THP-1 cells that DEX treatment resulted in reductions in pyroptosis, glycolysis and lactic acid level. Finally, protein lactylation was found significantly increased in the lungs of asthmatic mice and OVA-stimulated THP-1 cells, which were both inhibited by DEX., Conclusion: Our present study revealed that the effect of DEX on asthma control was associated with its suppressing of Hif-1α-glycolysis-lactateaxis and subsequent protein lactylation, which may open new avenues for the therapy of eosinophilic asthma., 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.)

Asthma demonstrates a strong circadian rhythm with disrupted molecular clock. Melatonin which can directly regulate circadian rhythm has been reported to alleviate asthma, but whether this effect is related to its regulation on circadian clock has not yet been known. Here, female C57BL/6 mice were challenged with ovalbumin (OVA) to establish allergic airway inflammation, and were treated with melatonin or Luzindole to investigate whether the expressions of circadian clock proteins were changed in response to OVA and were affected by exogenous/endogenous melatonin. Airway inflammation, mucus secretion, protein expressions of circadian proteins (Bmal1, Per1, Clock, Timeless, Cry1 and Cry2), melatonin biosynthetase (ASMT, AANAT) and melatonin receptor (Mel-1A/B-R) were analyzed accordingly. The results showed that in the successfully established allergic airway inflammation model, inflammatory cells infiltration, expressions of circadian clock proteins in the lung tissues of OVA-challenged mice were all notably up-regulated as compared to that of the vehicle mice. Meanwhile, the protein expression of ASMT and the level of melatonin in the lung tissues were reduced in allergic mice, while the expression of melatonin receptor Mel-1A/B-R was markedly increased. After addition of exogenous melatonin, the OVA-induced airway inflammation was pronouncedly ameliorated, while simultaneously the OVA-induced expressions of Per1 and Clock were further increased. However, a melatonin receptor antagonist Luzindole further augmented the OVA-induced airway inflammation, accompanied with remarkably decreased expressions of Per1, Bmal1, Cry1 and Cry2 but notably increased expression of Timeless. Collectively, our results demonstrated that the expression of circadian clock proteins was increased in the lungs during allergic airway inflammation, and Per1 was a clock protein that can be regulated by both exogenous and endogenous melatonin, suggesting Per1 may be an important potential circadian clock target for melatonin as a negative regulatory factor against Th2-type airway inflammation., Competing Interests: 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., (© 2024 The Authors.)

Background: Understanding the clinical course and pivotal time points of COVID-19 aggravation is critical for enhancing patient monitoring. This retrospective, multi-center cohort study aims to identify these significant time points and associate them with potential risk factors, leveraging data from a sizable cohort with mild-to-moderate symptoms upon admission., Methods: This study included data from 1,696 COVID-19 patients with mild-to-moderate clinical severity upon admission across multiple hospitals in Daegu-Kyungpook Province (Daegu dataset) between February 18 and early March 2020 and 321 COVID-19 patients at Seoul Boramae Hospital (Boramae dataset) collected from February to July 2020. The approach involved: (1) identifying the optimal time point for aggravation using survival analyses with maximally selected rank statistics; (2) investigating the relationship between comorbidities and time to aggravation; and (3) developing prediction models through machine learning techniques. The models were validated internally among patients from the Daegu dataset and externally among patients from the Boramae dataset., Results: The Daegu dataset showed a mean age of 51.0 ± 19.6 years, with 8 days for aggravation and day 5 being identified as the pivotal point for survival. Contrary to previous findings, specific comorbidities had no notable impact on aggravation patterns. Prediction models utilizing factors including age and chest X-ray infiltration demonstrated promising performance, with the top model achieving an AUC of 0.827 in external validation for 5 days aggravation prediction., Conclusion: Our study highlights the crucial significance of the initial 5 days period post-admission in managing COVID-19 patients. The identification of this pivotal time frame, combined with our robust predictive models, provides valuable insights for early intervention strategies. This research underscores the potential of proactive monitoring and timely interventions in enhancing patient outcomes, particularly for those at risk of rapid aggravation. Our findings offer a meaningful contribution to understanding the COVID-19 clinical course and supporting healthcare providers in optimizing patient care and resource allocation., Competing Interests: The authors 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 © 2024 Moon, Ham, Song, Lee, Goo, Oh, Lee, Kim and Park.)

In this work, a series of 2-(trifluoromethyl)quinolin-4-amine derivatives were designed and synthesized through structural optimization strategy as a microtubule-targeted agents (MTAs) and their cytotoxicity activity against PC3, K562 and HeLa cell lines were evaluated. The half maximal inhibitory concentration (IC 50 ) of 5e, 5f, and 5o suggested that their potency of anti-proliferative activities against HeLa cell lines were better than the combretastatin A-4. Compound 5e showed the higher anti-proliferative activity against PC3, K562 and HeLa in vitro with IC 50 values of 0.49 µM, 0.08 µM and 0.01 µM, respectively. Further mechanism study indicated that the representative compound 5e was new class of tubulin inhibitors by EBI competition assay and tubulin polymerization assays, it is similar to colchicine. Immunofluorescence staining revealed that compound 5e apparently disrupted tubulin network in HeLa cells, and compound 5e arrested HeLa cells at the G2/M phase and induced cells apoptosis in a dose-dependent manner. Molecular docking results illustrated that the hydrogen bonds of represented compounds reinforced the interactions in the pocket of colchicine binding site. Preliminary results suggested that 5e deserves further research as a promising tubulin inhibitor for the development of anticancer agents., 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 Inc. All rights reserved.)

Background: The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity., Methods: From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy., Results: The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n = 47) and 13% (n = 36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P < .001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P = .018], renal amyloidosis [OR 13.039 (4.108-44.041), P < .001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P = .042] were predictors of AKI. MM stages and β-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and β-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, β-2-microglobulin level [OR 1.204 (1.005-1.461), P = .038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P = .016] were associated with higher risk of TLS., Conclusions: Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: The sagittal plane of spine-pelvis morphology of adult patients with lumbar disc herniation (LDH) differs from that of normal people. There is a correlation between abnormal sagittal plane morphology and adult LDH. This study aimed to investigate the relationship between LDH in young people and the Roussouly classification in the sagittal alignment of the spine and pelvis., Methods: A total of 126 patients with LDH hospitalized in our tertiary hospital between January 2020 and January 2021 who met the inclusion and exclusion criteria were retrospectively analyzed in a cross-sectional study. Participants were grouped according to the spinal level of disc herniation (L4/5 group, L5/S1 group, L3/4 group). Pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS) of all cases were measured using standing lateral spinal radiographs. Facet joint angles (FJA) were measured using lumbar computed tomography (CT) horizontal radiographs, and the height of the anterior, middle, and posterior margins of the herniated disc was measured using sagittal radiographs. The classification of Pfirrmann disc degeneration was determined via magnetic resonance imaging (MRI) film of the lumbar region. Roussouly classification was performed according to sagittal plane morphology, and data were analyzed among each group., Results: In all, 126 patients aged from 18 to 40 years, with an average age of 31.04±5.886 years were included. There were 63 cases of L4/5 disc herniation, 59 cases of L5/S1 herniation, and 4 cases of L3/4 herniation. There were 35 cases of epiphyseal separation. The Roussouly classification included 21 cases of type 1, 56 cases of type 2, 32 cases of type 3, 4 cases of type 4, and 13 cases of type 3 + anteverted pelvis (type 3-AP). The L4/5 disc herniation group had significantly more types 2 and 3 than the other groups, and the L5/S1 disc herniation group had significantly more types 1 and 2 than the other groups. There were no significant differences in the Pfirrmann grade of intervertebral disc degeneration; epiphyseal separation; the height of anterior, middle, and posterior margins of the herniated disc; the difference between left and right facet angle and bilateral facet angle; and the thoracic kyphosis (TK) value among any of the groups (P>0.05). There were significant differences in PI, PT, SS, lumbar lordosis (LL), and height of the anterior and posterior margins of the intervertebral space among all groups (P<0.05). PI values were grouped at 50°; PT, SS, and LL were significantly different (P<0.05), whereas TK values were not significantly different between the 2 groups (P>0.05). SS values were grouped at 35°, and there were significant differences in PI, TK, and LL between the 2 groups (P<0.05). According to the disc herniation segment, the patients were divided into L4/5 and L5/S1 groups. There were significant differences in PI, PT, anterior edge height, anterior to posterior edge height, left facet angle, right facet angle, and bilateral facet angle (P<0.05)., Conclusions: LDH is common in L4/5 and L5/S1 segments. The incidence of Roussouly type 1 and 2 LDH is significantly higher than other types, and type 4 is the lowest. Small PI and small SS are more obvious in the L5/S1 segment. L5/S1 disc herniation is more common in patients with Roussouly type 1 and 2 classifications, whereas L4/5 disc herniation is more frequent in patients with Roussouly type 2 and 3 classifications., Competing Interests: Conflicts of Interest: All authors completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-22-503/coif). The authors have no conflicts of interest to declare., (2023 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion., Objective: This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded '2C3L' for the ablation of PeAF., Study Design: The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded '2C3L' arm or PVI arm in a 1:1 fashion. The upgraded '2C3L' technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months)., Conclusions: The PROMPT-AF study will evaluate the efficacy of the fixed '2C3L' approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation., Competing Interests: Conflict of interest None reported., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Porcine reproductive and respiratory syndrome (PRRS) is an endemic disease in the Republic of Korea. Surveillance of PRRS virus (PRRSV) types is critical to tailor control measures. This study collected 5062 serum and tissue samples between 2018 and 2022. Open reading frame 5 (ORF5) sequences suggest that subgroup A (42%) was predominant, followed by lineage 1 (21%), lineage 5 (14%), lineage Korea C (LKC) (9%), lineage Korea B (LKB) (6%), and subtype 1C (5%). Highly virulent lineages 1 (NADC30/34/MN184) and 8 were also detected. These viruses typically mutate or recombine with other viruses. ORF5 and non-structural protein 2 (NSP2) deletion patterns were less variable in the PRRSV-1. Several strains belonging to PRRSV-2 showed differences in NSP2 deletion and ORF5 sequences. Similar vaccine-like isolates to the PRRSV-1 subtype 1C and PRRSV-2 lineage 5 were also found. The virus is evolving independently in the field and has eluded vaccine protection. The current vaccine that is used in Korea offers only modest or limited heterologous protection. Ongoing surveillance to identify the current virus strain in circulation is necessary to design a vaccine. A systemic immunization program with region-specific vaccinations and stringent biosecurity measures is required to reduce PRRSV infections in the Republic of Korea.

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo , we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrP C , which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration. SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrP C ), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrP C -mediated neurotoxic signaling., (Copyright © 2023 the authors.)

As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2 -/- mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2 -/- mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2 -/- mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2 -/- AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2 -/- mice abolished while transfer of TLR2 -/- resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Porcine reproductive and respiratory syndrome virus (PRRSV) is major economic problem given its effects on swine health and productivity. Therefore, we evaluated the genetic stability of a codon pair de-optimized (CPD) PRRSV, E38-ORF7 CPD, as well as the master seed passage threshold that elicited an effective immune response in pigs against heterologous virus challenge. The genetic stability and immune response of every 10th passage (out of 40) of E38-ORF7 CPD was analyzed through whole genome sequencing and inoculation in 3-week-old pigs. E38-ORF7 CPD passages were limited to 20 based on the full-length mutation analysis and animal test results. After 20 passages, the virus could not induce antibodies to provide effective immunity and mutations accumulated in the gene, which differed from the CPD gene, presenting a reason for low infectivity. Conclusively, the optimal passage number of E38-ORF7 CPD is 20. As a vaccine, this may help overcome the highly diverse PRRSV infection with substantially enhanced genetic stability.

Commercially used porcine respiratory and reproductive syndrome (PRRS) modified live virus (MLV) vaccines provide limited protection with heterologous viruses, can revert back to a virulent form and they tend to recombine with circulating wild-type strains. Codon pair deoptimization (CPD) is an advanced method to attenuate a virus that overcomes the disadvantages of MLV vaccines and is effective in various virus vaccine models. The CPD vaccine against PRRSV-2 was successfully tested in our previous study. The co-existence of PRRSV-1 and -2 in the same herd demands protective immunity against both viruses. In this study, live attenuated PRRSV-1 was constructed by recoding 22 base pairs in the ORF7 gene of the E38 strain. The efficacy and safety of the CPD live attenuated vaccine E38-ORF7 CPD to protect against virulent PRRSV-1 were evaluated. Viral load, and respiratory and lung lesion scores were significantly reduced in animals vaccinated with E38-ORF7 CPD. Vaccinated animals were seropositive by 14 days post-vaccination with an increased level of interferon-γ secreting cells. In conclusion, the codon-pair-deoptimized vaccine was easily attenuated and displayed protective immunity against virulent heterologous PRRSV-1.

Itaconate has emerged as a novel anti-inflammatory and antioxidative endogenous metabolite, yet its role in allergic airway inflammation (AAI) and the underlying mechanism remains elusive. Here, the itaconate level in the lung was assessed by High Performance Liquid Chromatography (HPLC), and the effects of the Irg1/itaconate pathway on AAI and alveolar macrophage (AM) immune responses were evaluated using an ovalbumin (OVA)-induced AAI model established by wild type (WT) and Irg1 -/- mice, while the mechanism of this process was investigated by metabolomics analysis, mitochondrial/cytosolic protein fractionation and transmission electron microscopy in the lung tissues. The results demonstrated that the Irg1 mRNA/protein expression and itaconate production in the lung were significantly induced by OVA. Itaconate ameliorated while Irg1 deficiency augmented AAI, and this may be attributed to the fact that itaconate suppressed mitochondrial events such as NLRP3 inflammasome activation, oxidative stress and metabolic dysfunction. Furthermore, we identified that the Irg1/itaconate pathway impacted the NLRP3 inflammasome activation and oxidative stress in AMs. Collectively, our findings provide evidence for the first time, supporting the conclusion that in the allergic lung, the itaconate level is markedly increased, which directly regulates AMs' immune responses. We therefore propose that the Irg1/itaconate pathway in AMs is a potential anti-inflammatory and anti-oxidative therapeutic target for AAI.

The process of handling and bonding copper (Cu) and graphene inevitably creates defects. To use graphene/Cu composites as electronic devices with new physical properties, it is essential to evaluate the effect of such defects. Since graphene is an ultrathin anisotropic material having a hexagonal structure, an evaluation of graphene/Cu composites containing defects was conducted taking into account the inherent structural characteristics. The purpose of this study is to evaluate defects that may occur in the manufacturing process and to present a usable basic method for the stable design research and development of copper/graphene composites essential for commercialization of copper/graphene composites. In the future, when performing analytical calculations on various copper/graphene composites and defect shapes in addition to the defect conditions presented in this paper, it is considered that it can be used as a useful method considering defects that occur during application to products of desired thickness and size. Herein, density functional theory was used to evaluate the behavior of graphene/Cu composites containing defects. The density of states (DOS) values were also calculated. The analysis was implemented using three kinds of models comprising defect-free graphene and two- and four-layered graphene/Cu composites containing defects. DOS and Fermi energy levels were used to gage the effect of defects on electrical properties.

In this study, two nonsingular three-dimensional (3D) guidance strategies to intercept a stationary target with desired impact angles, subject to nonlinear coupled dynamics, field-of-view (FOV) limit and lateral acceleration bounds, are investigated. As a stepping stone, two novel sliding mode surfaces are designed, the convergence and boundedness of the two sliding mode surfaces can guarantee the impact-angle-constrained interception while maintaining the seeker's lock-on condition during the guidance. A novel auxiliary system is also presented to compensate for the effects caused by input saturation. In addition, the analytical achievable impact angles set is presented in terms of the initial engagement condition. Numerical simulations with various constraints, a realistic missile model and comparison study have been considered to show the feasibility and effectiveness of the proposed 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 ISA. Published by Elsevier Ltd. All rights reserved.)

In this study, the homojunction thin-film transistors (TFTs) with amorphous indium gallium zinc oxide (a-IGZO) as active channel layers and source/drain electrodes were fabricated by RF magnetron sputtering. The effect of oxygen partial pressure on the phase, microstructure, optical and electrical properties of IGZO thin films was investigated. The results showed that amorphous IGZO thin films always exhibit a high transmittance above 90% and wide band gaps of around 3.9 eV. The resistivity increases as the IGZO thin films are deposited at a higher oxygen partial pressure due to the depletion of oxygen vacancies. In addition, the electrical behaviors in homojunction IGZO TFTs were analyzed. When the active channel layers were deposited with an oxygen partial pressure of 1.96%, the homojunction IGZO TFTs exhibited optimal transfer and output characteristics with a field-effect mobility of 13.68 cm 2 V -1 s -1 . Its sub-threshold swing, threshold voltage and on/off ratio are 0.6 V/decade, 0.61 V and 10 7 , respectively., (© 2022 IOP Publishing Ltd.)

Organochalcogen heterocycles are ubiquitously present and widely utilized in various fields. Among them, oxirane has been extensively studied, and all of the stereoisomeric forms are readily available. In contrast, synthetic studies on thiirane were rarely reported, and thus the useful sulfur-congener of oxirane has been difficult to access in a stereodefined form. In this research, a general stereoselective synthesis of cis-thiiranes is accomplished by taking advantage of stereospecific electrocyclization of trans-thiocarbonyl ylides, which are generated in situ from readily available E,E-aldazine N-oxides upon treatment with Lawesson's reagent. This newly developed practical method provides a variety of cis-1,2-diarylthiiranes as essentially single diastereomers in high yields under mild reaction conditions. The intermediacy of trans-thiocarbonyl yilde is confirmed by mechanistic experiments, and the excellent stereocontrol is rationalized by DFT calculation., (© 2022. The Author(s).)

In this study, a porous titanium zirconium (TiZr)-based bulk metallic foam was successfully fabricated using the Cu spacer by employing the hot press method. TiZr-based bulk metallic foams with porosities ranging from 0% to 50% were fabricated and analyzed. The results indicate that thermal conductivity increased with the addition of Cu spacer; the increased thermal conductivity reduced the holding time in the hot press method. Moreover, the compressive strength decreased from 1261 to 76 MPa when the porosity of the TiZr-based bulk metallic foam increased to 50%, and the compressive strength was predictable. In addition, the foam demonstrated favorable biocompatibility in cell viability, cell migration capacity, and calcium deposition tests. Moreover, the pore size of the porous TiZr-based bulk metallic foam was around 120 µm. In conclusion, TiZr-based bulk metallic foam has favorable biocompatibility, mechanical property controllability, and porous structure for bone ingrowth and subsequent enhanced osteointegration. This porous TiZr-based bulk metallic foam has great potential as an orthopedic implant to enhance bone healing and decrease healing time.

Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (μ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBL Oprm1 neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBL Oprm1 activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBL Oprm1 neurons constitute two distinct subpopulations in a "core-shell" configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)