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Abstract Background Given the critical importance of medication adherence in HIV/AIDS treatment, this study aims to compare medication adherence measured by self-report (SR) and indirect measurement among antiretroviral therapy (ART) patients, exploring the differences of adherence results measured by different tools. Methods We systematically searched PubMed, Embase, and the Cochrane Library to identify all relevant literature published up to November 22, 2023, without language restrictions, reporting adherence to ART measured by both SR and indirect measurement methods, while also analyzing individual and group adherence separately. Discrepancies between SR and indirect measurement results were assessed using the Mann–Whitney U test or Wilcoxon signed-rank test, with correlations evaluated using the Pearson correlation coefficient. Following one-to-one comparisons, meta-epidemiological one-step analysis was conducted, and network meta-analysis techniques were applied to compare results obtained through specific adherence assessment tools reported in the identified articles. Results The analysis encompassed 65 original studies involving 13,667 HIV/AIDS patients, leading to 112 one-to-one comparisons between SR and indirect measurement tools. Statistically significant differences were observed between SR and indirect measurement tools regarding both individual and group adherence (P

Background/purpose: The number of middle-aged and elderly orthodontic patients is increasing due to changes in age composition. It is important to investigate the detailed mechanisms of bone remodeling in orthodontic tooth movement (OTM) in the elderly. However, there are few reports on the mechanism of tooth movement in the elderly. The purpose of the present study was to analyze OTM and osteoclastogenesis in aged mice and to elucidate the mechanism. Materials and methods: It has been reported that tumor necrosis factor (TNF)-α plays an important role in osteoclast formation and OTM. First, 8-week-old and 78-week-old male C57BL/6J mice were subcutaneously injected with TNF-α into the calvaiae, and micro-CT, tartrate-resistant acid phosphatase (TRAP) staining, and real-time PCR were performed to evaluate osteoclast formation and bone resorption. Furthermore, osteoclastogenesis by TNF-α and receptor activator of nuclear factor-kappa B ligand (RANKL) using bone marrow cells was evaluated in vitro. Finally, a nickel-titanium closed-coil spring was attached, mesial movement of the maxillary left first molar was performed, and tooth movement distance and osteoclast formation were evaluated. Results: Compared to 8-week-old mice, 78-week-old mice had decreased TNF-α-induced bone resorption, osteoclastogenesis, and TRAP and cathepsin K expression in the calvariae. In vitro osteoclast formation also decreased in 78-week-old mice. Furthermore, tooth movement distance and osteoclastogenesis were reduced. Conclusion: OTM decreased in aged mice, which was shown to be caused by a decrease in osteoclastogenesis. Therefore, it was suggested that it is necessary to keep in mind that tooth movement may be suppressed when treating elderly patients.

The ubiquity of refractory organic matter in aquatic environments necessitates innovative removal strategies. Sulfate radical-based advanced oxidation has emerged as an attractive solution, offering high selectivity, enduring efficacy, and anti-interference ability. Among many technologies, sulfite activation, leveraging its cost-effectiveness and lower toxicity compared to conventional persulfates, stands out. Yet, the activation process often relies on transition metals, suffering from low atom utilization. Here we introduce a series of single-atom catalysts (SACs) employing transition metals on g-C3N4 substrates, effectively activating sulfite for acetaminophen degradation. We highlight the superior performance of Fe/CN, which demonstrates a degradation rate constant significantly surpassing those of Ni/CN and Cu/CN. Our investigation into the electronic and spin polarization characteristics of these catalysts reveals their critical role in catalytic efficiency, with oxysulfur radical-mediated reactions predominating. Notably, under visible light, the catalytic activity is enhanced, attributed to an increased generation of oxysulfur radicals and a strengthened electron donation-back donation dynamic. The proximity of Fe/CN's d-band center to the Fermi level, alongside its high spin polarization, is shown to improve sulfite adsorption and reduce the HOMO-LUMO gap, thereby accelerating photo-assisted sulfite activation. This work advances the understanding of SACs in environmental applications and lays the groundwork for future water treatment technologies.

Achieving the sustainable development goals puts new demands on land use/land cover (LULC) forecasting and thermal environment improvement. Local climate zone (LCZ) characterization reduces LULC uncertainty in climate research. This study designed a future multiscenario LCZ thermal environment assessment framework that integrates remote sensing images, a patch-level land use simulation model, and a contribution algorithm. An urban heat island (UHI) classification was used to represent the degree of heat hazard. We sought to quantitatively evaluate the spatiotemporal distribution of LCZ and its heat hazard and explore the coordination mode of LULC patterns and the thermal environment. We considered four future scenarios: a natural development scenario (NDS), urban development scenario (UDS), food security scenario, and ecological protection scenario. The results show that the Shenyang metropolitan area has experienced large-scale land urbanization, forming the main UHI areas with Shenyang–Fushun, Liaoyang–Anshan, and Fuxin as the core. This is expected to become the first area for heat hazard management in the future. The areas that produce heat hazards are mainly distributed as LCZ D and building-LCZs. By 2060, the average heat hazard in the UDS is expected to increase by 1.035 °C and that in the NDS by 0.286 °C compared to that in 2020. From the perspective of the “historical future,” the study results provide a theoretical reference for the continuous improvement of environmental quality in the new era, promoting the coordinated development of metropolitan areas and actively responding to climate change.

The escalation of greenhouse gas emissions has led to a continuous rise in land surface temperature (LST). Studies have highlighted the substantial influence of urban morphology on LST; however, the impact of different dimensional indicators and their gradient effects remain unexplored. Selecting the urban area of Shenyang as a case, we chose various indicators representing different dimensions. By employing XGBoost for regression analysis, we aimed to explore the effects of urban 2-D and 3-D morphology on seasonal LST and its gradient effect. The following results were obtained: 1) the spatial pattern of LST in spring and winter in Shenyang was higher in the suburbs than in the center; 2) the correlation patterns of the indicators in spring and winter were similar, except for the proportion of woodland and grass, digital elevation model, and sky view factor, which exhibited opposing trends in summer and autumn; 3) vegetation and construction had the highest influence on LST in the 2-D index, followed by building forms and natural landscapes in the 3-D urban morphology; and 4) the influence of each indicator varied significantly across different gradients. Among all the indicators, the landscape index, social development, building forms, and skyscape had the highest impacts on urban areas. Vegetation and built-up areas had a greater influence on suburban areas. The findings of this study can assist in adjusting urban morphology and provide valuable recommendations for targeted improvements in thermal environments, thereby contributing to urban sustainable development.

Summary: Global warming has led to a surge in heat health risks (HHRs), the impacts of which are particularly pronounced in metropolitan areas of developing countries. In the current study, six metropolitan areas - Beijing, China; Cairo, Egypt; Jakarta, Indonesia; Mumbai, India; Rio de Janeiro, Brazil; and Tehran, Iran - were selected as the study area to further differentiate the built-up landscapes by utilizing the concept of local climate zones. Moreover, we assessed the similarities and differences in HHR associated with the landscape. Results revealed a 30.67% higher HHR in compact built-up landscapes than in the open built-up type. Urban green spaces played an effective but differentiated role in mitigating HHR. That is, low vegetation in urbanized areas and trees in suburban areas significantly mitigated HHR. Collectively, our findings emphasize the role of effective planning and management in addressing HHR and provide empirical support for implementing HHR mitigation and adaptation strategies.

IntroductionHypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo.MethodsIn vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted.ResultsAzilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group.ConclusionThese findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo.

Global climate change is causing various negative impacts on urban ecosystems and energy systems. To effectively mitigate and adapt to these changes, it is important to understand the contributions of background climate and local effects to urban thermal environment variation. This study utilized the empirical orthogonal function (EOF) approach to deconstruct long-term MODIS land surface temperature (LST) datasets to obtain the main features of change in daytime and nighttime thermal environments. Local bivariate spatial autocorrelation analysis was used to explore the underlying causes of these changes. The main EOF modes explained 73.14% and 81.33% of daytime and nighttime thermal environment variation, respectively. The correlation coefficient between the time coefficient of the main modes and the average LST was > 0.99, reflecting the role of global effect caused by background climate change. The secondary EOF modes explained 12.51% and 4.12% of daytime and nighttime thermal environment variation, respectively, and were spatially correlated with changes in landscape thermal intensity, reflecting local effect caused by landscape change and anthropogenic heat emissions. In expansion and renewal areas, industrial zones and compact high-rise buildings had the most obvious warming effect on the daytime thermal environment, while mid-to-high-rise buildings had the most obvious warming effect on the nighttime thermal environment. The results of this study provide valuable insights into the mechanisms of background climate and local effects on the urban thermal environment, and provide a reference for formulating effective strategies for mitigating and adapting to change in urban areas, and for promoting sustainable development.

Glucose-insulinotropic polypeptide (GIP) is an incretin hormone that induces insulin secretion and decreases blood glucose levels. In addition, it has been reported to suppress osteoclast formation. Native GIP is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). (D-Ala2)GIP is a newly developed GIP analog that demonstrates enhanced resistance to DPP-4. This study aimed to evaluate the influence of (D-Ala2)GIP on osteoclast formation and bone resorption during lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro. In vivo, mice received supracalvarial injections of LPS with or without (D-Ala2)GIP for 5 days. Osteoclast formation and bone resorption were evaluated, and TNF-α and RANKL expression were measured. In vitro, the influence of (D-Ala2)GIP on RANKL- and TNF-α-induced osteoclastogenesis, LPS-triggered TNF-α expression in macrophages, and RANKL expression in osteoblasts were examined. Compared to the LPS-only group, calvariae co-administered LPS and (D-Ala2)GIP led to less osteoclast formation, lower bone resorption, and decreased TNF-α and RANKL expression. (D-Ala2)GIP inhibited osteoclastogenesis induced by RANKL and TNF-α and downregulated TNF-α expression in macrophages and RANKL expression in osteoblasts in vitro. Furthermore, (D-Ala2)GIP suppressed the MAPK signaling pathway. The results suggest that (D-Ala2)GIP dampened LPS-triggered osteoclast formation and bone resorption in vivo by reducing TNF-α and RANKL expression and directly inhibiting osteoclastogenesis.

Open chromatin regions are the genomic regions associated with basic cellular physiological activities, while chromatin accessibility is reported to affect gene expressions and functions. A basic computational problem is to efficiently estimate open chromatin regions, which could facilitate both genomic and epigenetic studies. Currently, ATAC-seq and cfDNA-seq (plasma cell-free DNA sequencing) are two popular strategies to detect OCRs. As cfDNA-seq can obtain more biomarkers in one round of sequencing, it is considered more effective and convenient. However, in processing cfDNA-seq data, due to the dynamically variable chromatin accessibility, it is quite difficult to obtain the training data with pure OCRs or non-OCRs, and leads to a noise problem for either feature-based approaches or learning-based approaches. In this paper, we propose a learning-based OCR estimation approach with a noise-tolerance design. The proposed approach, named OCRFinder, incorporates the ideas of ensemble learning framework and semi-supervised strategy to avoid potential overfitting of noisy labels, which are the false positives on OCRs and non-OCRs. Compared to different noise control strategies and state-of-the-art approaches, OCRFinder achieved higher accuracies and sensitivities in the experiments. In addition, OCRFinder also has an excellent performance in ATAC-seq or DNase-seq comparison experiments.

# Background A large number of patient reported outcome measures (PROMs) have been developed for specific lower extremity orthopaedic pathologies. However, a consensus as to which PROMs are recommended for use in evaluating treatment outcomes for patients with hip, knee, ankle and/or foot pathology based on the strength of their psychometric properties is lacking. # Objective To identify PROMs that are recommended in systematic reviews (SRs) for those with orthopaedic hip, knee, foot, and ankle pathologies or surgeries and identify if these PROMs are used in the literature. # Study design Umbrella Review # Methods PubMed, Embase, Medline, Cochrane, CINAHL, SPORTDisucs and Scopus were searched for SRs through May 2022. A second search was done to count the use of PROMs in seven representative journals from January 2011 through May 2022. SRs that recommended the use of PROMs based on their psychometric properties were included in the first search. SRs or PROMs not available in the English were excluded. The second search included clinical research articles that utilized a PROM. Case reports, reviews, and basic science articles were excluded. # Results Nineteen SRs recommended 20 PROMs for 15 lower extremity orthopaedic pathologies or surgeries. These results identified consistency between recommended PROMs and utilization in clinical research for only two of the 15 lower extremity pathologies or surgeries. This included the use of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Copenhagen Hip and Groin Outcome Score to assess outcomes (HAGOS) for those with knee osteoarthritis and groin pain, respectively. # Conclusion A discrepancy was found between the PROMs that were recommended by SRs and those used to assess clinical outcomes in published research. The results of this study will help to produce more uniformity with the use of PROMs that have the most appropriate psychometric properties when the reporting treatment outcomes for those with extremity pathologies. # Level of evidence 3a

# Background A large number of patient reported outcome measures (PROMs) have been developed in the English language for various lower extremity orthopaedic pathologies. Twenty different PROMs were recommended for 15 specific musculoskeletal lower extremity pathologies or surgeries. However, the availability of cross-culturally adapted versions of these recommended PROMs is unknown. # Purpose The purpose of this study was to identify the cross-culturally adapted versions of recommended PROMs for individuals experiencing orthopedic lower extremity pathologies or undergoing surgeries, and to identify the psychometric evidence that supports their utilization. # Study design Literature Review # Methods PubMed, Embase, Medline, Cochrane, CINAHL, SPORTDisucs and Scopus were searched for cross-culturally adapted translated studies through May 2022. The search strategy included the names of the 20 recommended PROMs from previous umbrella review along with the following terms: reliability, validity, responsiveness, psychometric properties and cross-cultural adaptation. Studies that presented a non-English language version of the PROM with evidence in at least one psychometric property to support its use were included. Two authors independently evaluated the studies for inclusion and independently extracted data. # Results Nineteen PROMS had cross-culturally adapted and translated language versions. The KOOS, WOMAC, ACL-RSL, FAAM, ATRS, HOOS, OHS, MOXFQ and OKS were available in over 10 different language versions. Turkish, Dutch, German, Chinese and French were the most common languages, with each language having more than 10 PROMs with psychometric properties supporting their use. The WOMAC and KOOS were both available in 10 languages and had all three psychometric properties of reliability, validity, and responsiveness supporting their use. # Conclusion Nineteen of the 20 recommended instruments were available in multiple languages. The PROM most frequently cross-culturally adapted and translated were the KOOS and WOMAC. PROMs were most frequently cross-culturally adapted and translated into Turkish. International researchers and clinicians may use this information to more consistently implement PROMs with the most appropriate psychometric evidence available to support their use. # Level of evidence 3a

ABSTRACTObjective To explore the manifestations of bacteriophages in different oral disease ecologies, including periodontal diseases, dental caries, endodontic infections, and oral cancer, as well as to propel phage therapy for safer and more effective clinical application in the field of dentistry.Methods In this literature review, we outlined interactions between bacteriophages, bacteria and even oral cells in the oral ecosystem, especially in disease states. We also analyzed the current status and future prospects of phage therapy in the perspective of different oral diseases.Results Various oral bacteriophages targeting at periodontal pathogens as Porphyromonas gingivalis, Fusobacterium nucleatum, Treponema denticola and Aggregatibacter actinomycetemcomitans, cariogenic pathogen Streptococcus mutans, endodontic pathogen Enterococcus faecalis were predicted or isolated, providing promising options for phage therapy. In the realm of oral cancer, aside from displaying tumor antigens or participating in tumor-targeted therapies, phage-like particle vaccines demonstrated the potential to prevent oral infections caused by human papillomaviruses (HPVs) associated with head-and-neck cancers.Conclusion Due to their intricate interactions with bacteria and oral cells, bacteriophages are closely linked to the progression and regression of diverse oral diseases. And there is an urgent need for research to explore additional possibilities of bacteriophages in the management of oral diseases.

Abstract Long non-coding RNAs (lncRNAs) is known to play vital roles in modulating tumorigenesis. We previously reported that LCAT1, a novel lncRNA, promotes the growth and metastasis of lung cancer cells both in vitro and in vivo. However, the underlying mechanism(s) of LCAT1 as an oncogenic regulator remains elusive. Here, we showed that LCAT1 physically interacts with and stabilizes IGF2BP2, an m6A reader protein, by preventing its degradation via autolysosomes. IGF2BP2 is overexpressed in lung cancer tissues, which is associated with poor survival of non-small cell lung cancer patients, suggesting its oncogenic role. Biologically, IGF2BP2 depletion inhibits growth and survival as well as the migration of lung cancer cells. Mechanistically, the LCAT1/IGF2BP2 complex increased the levels of CDC6, a key cell cycle regulator, by stabilizing its mRNA in an m6A-dependent manner. Like IGF2BP2, CDC6 is also overexpressed in lung cancer tissues with poor patient survival, and CDC6 knockdown has oncogenic inhibitory activity. Taken together, the LCAT1-IGF2BP2-CDC6 axis appears to play a vital role in promoting the growth and migration of lung cancer cells, and is a potential therapeutic target for lung cancer. Importantly, our finding also highlights a previously unknown critical role of LCAT1 in m6A-dependent gene regulation by preventing autolytic degradation of IGF2BP2.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that exerts physiological effects via G protein-coupled receptor 120 (GPR120). In our previous studies, we figured out the inhibitory effects of DHA on TNF-α (Tumor necrosis factor-α)-induced osteoclastogenesis via GPR120 in vivo. Moreover, DHA directly suppressed RANKL expression in osteoblasts via GPR120 in vitro. In this study, we generated bone marrow chimeric mice using GPR120 deficient mice (GPR120-KO) to study the inhibitory effects of DHA on bone resorption and osteoclast formation. Bone marrow cells of wild-type (WT) or GPR120-KO mice were transplanted into irradiated recipient mice, which were WT or GPR120 deficient mice. The resulting chimeric mice contained stromal cells from the recipient and bone marrow cells, including osteoclast precursors, from the donor. These chimeric mice were used to perform a series of histological and microfocus computed tomography (micro-CT) analyses after TNF-α injection for induction of osteoclast formation with or without DHA. Osteoclast number and bone resorption were found to be significantly increased in chimeric mice, which did not express GPR120 in stromal cells, compared to chimeric mice, which expressed GPR120 in stromal cells. DHA was also found to suppress specific signaling pathways. We summarized that DHA suppressed TNF-α-induced stromal-dependent osteoclast formation and bone resorption via GPR120.

Abstract The large leakage current of the roof arrester caused by the high‐frequency resonant overvoltage on the high‐speed train occurs intermittently, which will cause the arrester to overheat locally. In this work, the overheating issue of the arrester under Ultra Harmonics Overvoltage is studied. Then, the relationship between the active power and the voltage (including amplitude and frequency) of the arrester is investigated, and the impact mechanism of the harmonic voltage on the overheating fault of the arrester is analysed based on experiments in this work. It is found that the total leakage current of the arrester is proportional to the amplitude and frequency of the applied voltage. The internal resistance of the arrester is independent of the amplitude of the voltage, but it will decrease with the increase of the frequency. The main reason that leads to thermal breakdown of the arrester valve under high‐frequency harmonic voltage is the heating power elevation of the arrester valve. The research study can provide theoretical basis and data support for the design, type selection and monitoring of the high‐speed train roof arrester.

Summary: Land surface temperature (LST) is subject to location and environmental influences, which makes quantification difficult in terms of timeliness. Based on 10-d geostationary satellite LST TCI products, we quantitatively evaluated the thermal environment differentiation of various ground objects in North, South, and Northwest China from 2017 to 2021. We found that the thermal condition index (TCI) in Northwest China decreased, whereas it increased in North and South China. In contrast, Moran’s I index increased in Northwest and South China, with strong spatial agglomeration. The TCI for artificial surfaces decreased from North (0.633) to Northwest (0.554) and South China (0.384). The bare land TCI was always the lowest among the land use/land cover (LULC) types in each region. Our results reflect the LULC thermal environment of China against the background of new urbanization and provide theoretical support for scientific planning to improve the ecological environment.

The association between a high-fat diet (HFD) consumption and emotional/cognitive disorders is widely documented. One distinctive feature of the prefrontal cortex (PFC), a kernel emotion- and cognition-related brain region, is its protracted adolescent maturation, which makes it highly vulnerable to the detrimental effects of environmental factors during adolescence. Disruption of the PFC structure and function is linked to emotional/cognitive disorders, especially those that emerge in late adolescence. A HFD consumption is common among adolescents, yet its potential effects on PFC-related neurobehavior in late adolescence and any related underlying mechanisms are yet to be established. In the present study, adolescent (postnatal days 28–56) male C57BL/6J mice were fed a control diet (CD) or a HFD and underwent behavioral tests in addition to Golgi staining and immunofluorescence targeting of the medial PFC (mPFC). The HFD-fed adolescent mice exhibited anxiety- and depression-like behavior and abnormal mPFC pyramidal neuronal morphology accompanied by alterations in microglial morphology indicative of a heightened state of activation and increased microglial PSD95+ inclusions signifying excessive phagocytosis of the synaptic material in the mPFC. These findings offer novel insights into the neurobehavioral effects due to adolescent HFD consumption and suggest a contributing role in microglial dysfunction and prefrontal neuroplasticity deficits for HFD-associated mood disorders in adolescents.

Herpes simplex virus type 1 (HSV-1) is a highly successful pathogen that primarily infects epithelial cells of the orofacial mucosa. After initial lytic replication, HSV-1 enters sensory neurons and undergoes lifelong latency in the trigeminal ganglion (TG). Reactivation from latency occurs throughout the host’s life and is more common in people with a compromised immune system. HSV-1 causes various diseases depending on the site of lytic HSV-1 replication. These include herpes labialis, herpetic stromal keratitis (HSK), meningitis, and herpes simplex encephalitis (HSE). HSK is an immunopathological condition and is usually the consequence of HSV-1 reactivation, anterograde transport to the corneal surface, lytic replication in the epithelial cells, and activation of the host’s innate and adaptive immune responses in the cornea. HSV-1 is recognized by cell surface, endosomal, and cytoplasmic pattern recognition receptors (PRRs) and activates innate immune responses that include interferons (IFNs), chemokine and cytokine production, as well as the recruitment of inflammatory cells to the site of replication. In the cornea, HSV-1 replication promotes type I (IFN-α/β) and type III (IFN-λ) IFN production. This review summarizes our current understanding of HSV-1 recognition by PRRs and innate IFN-mediated antiviral immunity during HSV-1 infection of the cornea. We also discuss the immunopathogenesis of HSK, current HSK therapeutics and challenges, proposed experimental approaches, and benefits of promoting local IFN-λ responses.

It is hard for traditional current protection to solve problems of distribution networks with highly penetrative DGs. The fault information required by the most protection methods cannot be provided by the poor infrastructure of distribution networks. In this paper, a sufficient criterion based on the maximal current differences between adjacent transmission lines is proposed to promote selective configuration of protection scheme. The principle of the criterion and its advantages on current protection application are analyzed. The suppress influence of DG on the current of downstream transmission line current can be processed without high demand for communication in distribution network with DGs. Through the simulation in Matlab/Simulink, the effectiveness of the proposed criterion is validated.

Summary: In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations’ specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors’ functional genomic distribution.

The COVID-19 epidemic is raging around the world. Neutralizing antibodies are powerful tools for the prevention and treatment of SARS-CoV-2 infection. Antibody CR3022, a SARS-CoV neutralizing antibody, was found to cross-react with SARS-CoV-2, but its affinity was lower than that of its binding with SARS-CoV, which greatly limited the further development of CR3022 against SARS-CoV-2. Therefore, it is necessary to improve its affinity to SARS-CoV-2 in vitro. In this study, the structure-based molecular simulations were utilized to virtually mutate the possible key residues in the complementarity-determining regions (CDRs) of the CR3022 antibody. According to the criteria of mutation energy, the mutation sites that have the potential to impact the antibody affinity were then selected. Then optimized CR3022 mutants with the enhanced affinity were further identified and verified by enzyme-linked immunosorbent assay (ELISA), surface plasma resonance (SPR) and autoimmune reactivity experiments. Finally, molecular dynamics (MD) simulation and binding free energy calculation (MM/PBSA) were performed on the wild-type CR3022 and its two double-site mutants to understand in more detail the contribution of these sites to the higher affinity. It was found that the binding affinity of the CR3022 antibody could be significantly enhanced more than ten times after the introduction of the S103F/Y mutation in HCDR–3 and the S33R mutation in LCDR–1. The additional hydrogen-bonding, hydrophobic interactions, as well as salt-bridges formed between the modified double-site mutated antibody and SARS-CoV-2 RBD were identified. The computational and experimental results clearly demonstrated that the affinity of the modified antibody has been greatly enhanced. This study indicates that CR3022 as a neutralizing antibody recognizing the conserved region of RBD against SARS-CoV with cross-reactivity with SARS-CoV-2, a different member in a large family of coronaviruses, could be improved by the computational and experimental approaches which provided insights for developing antibody drugs against SARS-CoV-2.

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM–GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.

Introduction: Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/ Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation in vivo. Methods: In vivo, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-a) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)- positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-kB ligand (RANKL), and TNF-a were also evaluated. In vitro, the effect of azilsartan (0, 0.01, 0.1, 1, and 10 mM) on RANKL and TNF-atriggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-a mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted. Results: Azilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. In vivo, LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-a mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-a-triggered osteoclastogenesis in vitro. Compared to macrophages treated with LPS, TNF-a mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-a injection group and TNF-a with azilsartan injection group. Conclusion: These findings imply that azilsartan prevents LPS-triggered TNF-a production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption in vivo. [ABSTRACT FROM AUTHOR]