Fragment-based drug discovery supports drugging 'undruggable' protein-protein interactions.

Protein-protein interactions (PPIs) have important roles in various cellular processes, but are commonly described as 'undruggable' therapeutic targets due to their large, flat, featureless interfaces. Fragment-based drug discovery (FBDD) has achieved great success in modulating PPIs, with more than ten compounds in clinical trials. Here, we highlight the progress of FBDD in modulating PPIs for therapeutic development. Targeting hot spots that have essential roles in both fragment binding and PPIs provides a shortcut for the development of PPI modulators via FBDD. We highlight successful cases of cracking the 'undruggable' problems of PPIs using fragment-based approaches. We also introduce new technologies and future trends. Thus, we hope that this review will provide useful guidance for drug discovery targeting PPIs.

PTMdyna: exploring the influence of post-translation modifications on protein conformational dynamics.

Protein post-translational modifications (PTM) play vital roles in cellular regulation, modulating functions by driving changes in protein structure and dynamics. Exploring comprehensively the influence of PTM on conformational dynamics can facilitate the understanding of the related biological function and molecular mechanism. Currently, a series of excellent computation tools have been designed to analyze the time-dependent structural properties of proteins. However, the protocol aimed to explore conformational dynamics of post-translational modified protein is still a blank. To fill this gap, we present PTMdyna to visually predict the conformational dynamics differences between unmodified and modified proteins, thus indicating the influence of specific PTM. PTMdyna exhibits an AUC of 0.884 tested on 220 protein-protein complex structures. The case of heterochromatin protein 1α complexed with lysine 9-methylated histone H3, which is critical for genomic stability and cell differentiation, was used to demonstrate its applicability. PTMdyna provides a reliable platform to predict the influence of PTM on protein dynamics, making it easier to interpret PTM functionality at the structure level. The web server is freely available at http://ccbportal.com/PTMdyna.

Autophagy Is Essential for Neural Stem Cell Proliferation Promoted by Hypoxia.

Hypoxia as a microenvironment or niche stimulates proliferation of neural stem cells (NSCs). However, the underlying mechanisms remain elusive. Autophagy is a protective mechanism by which recycled cellular components and energy are rapidly supplied to the cell under stress. Whether autophagy mediates the proliferation of NSCs under hypoxia and how hypoxia induces autophagy remain unclear. Here, we report that hypoxia facilitates embryonic NSC proliferation through HIF-1/mTORC1 signaling pathway-mediated autophagy. Initially, we found that hypoxia greatly induced autophagy in NSCs, while inhibition of autophagy severely impeded the proliferation of NSCs in hypoxia conditions. Next, we demonstrated that the hypoxia core regulator HIF-1 was necessary and sufficient for autophagy induction in NSCs. Considering that mTORC1 is a key switch that suppresses autophagy, we subsequently analyzed the effect of HIF-1 on mTORC1 activity. Our results showed that the mTORC1 activity was negatively regulated by HIF-1. Finally, we provided evidence that HIF-1 regulated mTORC1 activity via its downstream target gene BNIP3. The increased expression of BNIP3 under hypoxia enhanced autophagy activity and proliferation of NSCs, which was mediated by repressing the activity of mTORC1. We further illustrated that BNIP3 can interact with Rheb, a canonical activator of mTORC1. Thus, we suppose that the interaction of BNIP3 with Rheb reduces the regulation of Rheb toward mTORC1 activity, which relieves the suppression of mTORC1 on autophagy, thereby promoting the rapid proliferation of NSCs. Altogether, this study identified a new HIF-1/BNIP3-Rheb/mTORC1 signaling axis, which regulates the NSC proliferation under hypoxia through induction of autophagy.

Nontargeted Analysis of Coumarins in Source Water and Their Formation of Chlorinated Coumarins as DBPs in Drinking Water.

Coumarin was detected as one of the most abundant compounds by nontargeted analysis of natural product components in actual water samples prior to disinfection. More importantly, prechlorination of humic acid generated 3-hydroxycoumarin and monohydroxy-monomethyl-substituted coumarin with a total yield of ≤10.1%, which suggested the humic substance in raw water is an important source of coumarins. 7-Hydroxycoumarin, 6-hydroxy-4-methylcoumarin, 6,7-dihydroxycoumarin, and 7-methoxy-4-methylcoumarin were identified in raw water by high-performance liquid chromatography-tandem high-resolution mass spectrometry because only some coumarin standards were commercially available. Their chlorination generated monochlorinated and polychlorinated coumarins, and their structures were confirmed by the synthesized standards. These products could form at various dosages of chlorine and pH levels, and some with a concentration of 600 ng/L can be stable in tap water for days. 3,6,8-Trichloro-7-hydroxycoumarin, 3-chloro-7-methoxy-4-methylcoumarin, and 3,6-dichloro-7-methoxy-4-methylcoumarin were first identified in finished water with concentrations of 0.0670, 78.1, and 14.7 ng/L, respectively, but not in source water, suggesting that they are new DBPs formed during disinfection. The cytotoxicity of 3-chloro-7-methoxy-4-methylcoumarin in CHO-K1 cells was comparable to those of 2,6-dibromo-1,4-benzoquinone and 2,6-dichloro-1,4-benzoquinone in TIC-Tox analyses, suggesting that further investigation of their occurrence and control in drinking water systems is warranted.

WeChat usage and preservation of cognitive functions in middle-aged and older Chinese adults: indications from a nationally representative survey, 2018-2020.

PURPOSE: To investigate the associations between the most popular social media platform WeChat usage and cognitive performance among the middle-aged and older Chinese population using data from a nationally representative survey. METHODS: In total, 17,472 participants (≥ 45 years old) from the China Health and Retirement Longitudinal Study (CHARLS, Wave 4, 2018) were analyzed. Cognitive performance including episodic memory and executive function was assessed using Mini-Mental Status Examination (MMSE). Other confounding variables included socio-economic characteristics, medical status, and lifestyle-related information. Multiple linear regression models were used to test the association between cognitive performance and WeChat usage by introducing covariates hierarchically. Subgroup analyses of age and gender were conducted to estimate the robustness of the primary findings. RESULTS: After adjusting for multiple confounders across all linear models, WeChat usage is significantly associated with executive function, episodic memory, and global cognitive performance (all p values<0.05). Such results remained robust in subgroup analyses, stratified by age and gender, and also verified according to longitudinal analyses. Compared to 'Chat-only' users who only used WeChat for online interpersonal communication, further usage of WeChat functions such as using 'Moments' appeared to be significantly associated with better cognitive performance, especially for episodic memory. CONCLUSION: Social media usage is significantly and positively associated with better cognitive performance among the middle-aged and older Chinese population. Along with point-to-point messaging, using 'Moments' and extended social media platform functions may correlate to better cognitive performance.

Internal iliac artery ligation as a damage control method in hemodynamically unstable pelvic fractures: A systematic review of the literature.

PURPOSE: Internal iliac artery ligation (IIAL) has been used as a damage control procedure to treat hemodynamically unstable pelvic fracture for many years. However, there is ongoing debate regarding the effectiveness and safety of this hemostatic method. Therefore, we performed a systematic literature review to assess the efficacy and safety of IIAL for pelvic fracture hemostasis. METHODS: Three major databases, PubMed, Embase, and Google Scholar, were searched to screen eligible original studies published in English journals. Two reviewers independently read the titles, abstracts, and full texts of all literature. Articles were included if they reported the use and effects of IIAL. RESULTS: A total of 171 articles were initially identified, with 22 fully meeting the inclusion criteria. Among the analyzed cases, up to 66.7% of patients had associated abdominal and pelvic organ injuries, with the urethra being the most frequently injured organ, followed by the bowel. The outcomes of IIAL for achieving hemostasis in pelvic fractures were found to be satisfactory, with an effective rate of 80%. Hemorrhagic shock was the leading cause of death, followed by craniocerebral injury. Notably, no reports of ischemic complications involving the pelvic organs due to IIAL were found. CONCLUSION: IIAL has a good effect in treating hemodynamically unstable pelvic fracture without the risk of pelvic organ ischemia. This procedure should be considered a priority for hemodynamically unstable pelvic fracture patients with abdominal organ injuries.

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma.

OBJECTIVE: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

Single cell landscape of parietal epithelial cells in healthy and diseased states.

The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis.

Knockdown of miR-150-5p reduces hypoxia-induced autophagy and epithelial-mesenchymal transition of endometriotic cells via regulating the PDCD4/NF-κB signaling pathway.

BACKGROUND: Hypoxia is an important microenvironmental factor that induces Endometriosis (EMs), but its mechanism remains unclear. Our study aims to investigate the mechanisms of miR-150-5p on hypoxia-induced EMs. METHODS: Ovarian endometriosis cyst wall stromal cell lines CRL-7566 cells were treated with hypoxia. Cell migration ability was measured by Transwell assay. qRT-PCR was performed to detect miR-150-5p and PDCD4 expression. The autophagy-related proteins (LC3-I, LC3-II, Beclin-1, and p62), epithelial-mesenchymal transition (EMT) related proteins (E-cadherin, N-cadherin, and Vimentin) and NF-κB signaling pathway related proteins p65 expression were measured by western blot. Dual-luciferase reporter gene assay verified the binding relationship between miR-150-5p and PDCD4. RESULTS: After hypoxia treatment, the miR-150-5p expression was up-regulated in CRL-7566 cells, while the expression of PDCD4 was down-regulated. In CRL-7566 cells, autophagy, migration and EMT were increased after hypoxia treatment. The autophagy inhibitor 3-MA inhibited hypoxia-induced the autophagy, migration and EMT of CRL-7566 cells. Hypoxia-induced autophagy and EMT of CRL-7566 cells were inhibited after knocking down miR-150-5p. Then miR-150-5p negatively regulated PDCD4 expression. PDCD4 knockdown reversed the inhibitory effect of miR-150-5p silencing on hypoxia-induced autophagy and EMT of CRL-7566 cells. Inhibiting the NF-κB signaling pathway weakened the effect of PDCD4 knockdown on hypoxia-induced autophagy and EMT of CRL-7566 cells. CONCLUSION: MiR-150-5p silencing inhibited hypoxia-induced autophagy and EMT of endometriotic cells by regulating the PDCD4/NF-κB signaling pathway.

lncRNA EGFR-AS1 facilitates leiomyosarcoma progression and immune escape via the EGFR-MYC-PD-L1 axis.

AIM: this study aimed to investigate the role of long non-coding RNA (lncRNA) epidermal growth factor receptor antisense RNA 1 (EGFR-AS1), an antisense transcript of EGFR, in leiomyosarcoma (LMS) and the underlying mechanisms. METHODS: levels of EGFR-AS1 and programmed death ligand 1 (PD-L1) were measured in LMS tissues and cell lines using quantitative real-time PCR (qRT-PCR), as well as western blotting and/or immunohistochemical staining; flow cytometry was employed to validate the role of EGFR-AS1 in altering the activity of CD8+ T cells; interaction of EGFR-AS1 and EGFR was determined by fluorescent in situ hybridization (FISH) and RNA pull-down; regulation of MYC on the PD-L1 promoter was assessed by chromatin immunoprecipitation (ChIP); a xenograft in vivo tumor growth assay was applied to verify the EGFR-AS1/EGFR/MYC/PD-L1 axis in vivo. RESULTS: up-regulation of EGFR-AS1 and PD-L1 in LMS tissues was negatively correlated with CD8+ T-cell infiltration; EGFR-AS1 positively regulated PD-L1, thereby strengthening interaction of LMS cells and CD8+ T cells and triggering CD8+ T cell apoptosis via the PD-1/PD-L1 checkpoint; EGFR-AS1 co-localized and interacted with EGFR to promote MYC activity; MYC was identified as a transcriptional activator of PD-L1. CONCLUSION: lncRNA EGFR-AS1 was demonstrated to increase PD-L1 expression through the EGFR/MYC pathway in LMS cells, thereby repressing T-cell infiltration and contributing to immune escape.

Aspartame-Sweetened Tap Water: Transformation Products and 2,6-Dichloro-1,4-Benzoquinone Formation.

Aspartame (APM), a dipeptide of aspartic acid (ASP) and phenylalanine (PHE), is a widely used artificial sweetener in beverages. It is unclear whether residual chlorine in tap water can react with APM to form disinfection byproducts (DBPs). Therefore, we investigated the formation of DBPs from the reaction of APM with residual chlorine in authentic tap water. APM and a commercial sweetener (CS) packet containing APM were studied under authentic and simulated tap water conditions. Eight chlorinated products of APM were detected using solid-phase extraction (SPE) and high performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS). These new chloro-products were tentatively identified based on accurate masses, isotopic patterns of 35,37Cl, and MS/MS spectra. Furthermore, we identified APM as a precursor to 2,6-dichloro-1,4-benzoquinone (DCBQ). DCBQ significantly increased to 2.3-12 ng/L with the addition of APM or CS in tap waters collected from different locations compared to 1.4-1.8 ng/L in the same tap water samples without sweetener. DCBQ and two of the chlorinated transformation products were identified in cold prepared tea containing APM. DCBQ formation was eliminated when the residual chlorine in tap water was reduced by ascorbic acid or boiling prior to the addition of APM or CS. This study found that eight new DBPs and DCBQ were produced by the reactions of residual chlorine with APM and CS. These findings show an unintended exposure source of emerging DBPs via APM sweetened beverages.

2-Aminobenzothiazoles in anticancer drug design and discovery.

Cancer is one of the major causes of mortality and morbidity worldwide. Substantial research efforts have been made to develop new chemical entities with improved anticancer efficacy. 2-Aminobenzothiazole is an important class of heterocycles containing one sulfur and two nitrogen atoms, which is associated with a broad spectrum of medical and pharmacological activities, including antitumor, antibacterial, antimalarial, anti-inflammatory, and antiviral activities. In recent years, an extraordinary collection of potent and low-toxicity 2-aminobenzothiazole compounds have been discovered as new anticancer agents. Herein, we provide a comprehensive review of this class of compounds based on their activities against tumor-related proteins, including tyrosine kinases (CSF1R, EGFR, VEGFR-2, FAK, and MET), serine/threonine kinases (Aurora, CDK, CK, RAF, and DYRK2), PI3K kinase, BCL-XL, HSP90, mutant p53 protein, DNA topoisomerase, HDAC, NSD1, LSD1, FTO, mPGES-1, SCD, hCA IX/XII, and CXCR. In addition, the anticancer potentials of 2-aminobenzothiazole-derived chelators and metal complexes are also described here. Moreover, the design strategies, mechanism of actions, structure-activity relationships (SAR) and more advanced stages of pre-clinical development of 2-aminobenzothiazoles as new anticancer agents are extensively reviewed in this article. Finally, the examples that 2-aminobenzothiazoles showcase an advantage over other heterocyclic systems are also highlighted.

Scoparone suppresses mitophagy-mediated NLRP3 inflammasome activation in inflammatory diseases.

Recent evidence shows that targeting NLRP3 inflammasome activation is an important means to treat inflammasome-driven diseases. Scoparone, a natural compound isolated from the Chinese herb Artemisia capillaris Thunb, has anti-inflammatory activity. In this study we investigated the effect of scoparone on NLRP3 inflammasome activation in inflammatory diseases. In LPS-primed, ATP or nigericin-stimulated mouse macrophage J774A.1 cells and bone marrow-derived macrophages (BMDMs), pretreatment with scoparone (50 µM) markedly restrained canonical and noncanonical NLRP3 inflammasome activation, evidenced by suppressed caspase-1 cleavage, GSDMD-mediated pyroptosis, mature IL-1ß secretion and the formation of ASC specks. We then conducted a transcriptome analysis in scoparone-pretreated BMDMs, and found that the differentially expressed genes were significantly enriched in mitochondrial reactive oxygen species (ROS) metabolic process, mitochondrial translation and assembly process, as well as in inflammatory response. We demonstrated in J774A.1 cells and BMDMs that scoparone promoted mitophagy, a well-characterized mechanism to control mitochondrial quality and reduce ROS production and subsequent NLRP3 inflammasome activation. Mitophagy blockade by 3-methyladenine (3-MA, 5 mM) reversed the protective effects of scoparone on mitochondrial damage and inflammation in the murine macrophages. Moreover, administration of scoparone (50 mg/kg) exerted significant preventive effects via inhibition of NLRP3 activation in mouse models of bacterial enteritis and septic shock. Collectively, scoparone displays potent anti-inflammatory effects via blocking NLRP3 inflammasome activation through enhancing mitophagy, highlighting a potential action mechanism in treating inflammasome-related diseases for further clinical investigation.

Exploring the expression of SNHG1 and its effect on the PI3K-AKT axis in nasopharyngeal cancer.

Radiotherapy and chemotherapy have improved the 5-year survival rate of nasopharyngeal carcinoma (NPC) patients, but the side effects generally lead to unsatisfactory clinical efficacy. It's imperative to explore the pathogenesis of NPC to find better diagnostic and therapeutic methods. Small nucleolar RNA host genes (SNHGs) are special lncRNAs, which can be further spliced to produce small nucleolar RNAs (snoRNAs). SNHG1 has been found to be associated with various cancers. However, only a few studies reported the relationship between SNHG1 and NPC. This study first analyzed the diagnostic performance and related signaling pathways of SNHG1 in NPC through bioinformatics. The expression of SNHG1 was verified by RT-qPCR, and the expression of the signaling pathway was detected using immunohistochemistry. Bioinformatics analysis results showed that SNHG1 was significantly overexpressed in head and neck squamous cell carcinoma (HNSC) and NPC tissues. RT-qPCR detection confirmed the significant overexpression of SNHG1 in NPC tissues. Enrichment analysis showed that SNHG1 may act on NPC through the PI3K-AKT signaling pathway. Immunohistochemistry experiment revealed PI3K-AKT signaling pathway proteins (PI3K AKT and EGFR) positively expressed and CASP3 weakly positively expressed in NPC tissues. Therefore, we concluded that SNHG1 is a prospective biomarker and may act on NPC through the PI3K-AKT signaling pathway.

Is CO2 laser microsurgery better than radiotherapy in early glottic cancer: a meta-analysis.

The choice between radiotherapy (RT) and CO2 laser surgery (CO2-LS) for early glottic cancer remains controversial. We systematically examined electronic databases in order to identify prospective trials comparing patients who had undergone CO2-LS or RT to treat early glottic cancer. Eleven studies involving 1053 patients were included. In the selected literature, the parameter setting of CO2 laser equipment can be summarized as wavelength 10.6 µm, superpulsed mode, continuous setting, power tailored on target structures (1-3 W for subtle resections and 4-15 W for cutting a larger tumor), and approximately 2080-3900 W/cm2 of laser energy. Using RevMan 5.3, we estimated pooled odds ratios (ORs) for dichotomous variables and pooled mean differences (MDs) for continuous variables, along with associated 95% confidence intervals (CIs). The heterogeneity in the treatment variables was measured using Higgins' inconsistency test and expressed as I2 values. The continuous variables were then depicted as histograms developed using PlotDigitizer 2.6.8. Compared to patients treated with CO2-LS, those treated with RT had better jitter (MD 1.27%, 95% CI 1.21 ~ 1.32, P < 0.001), and high scores on the "Grade (MD 6.54, 95% CI 5.31 ~ 7.76, P < 0.001), Breathiness (MD 9.08, 95% CI 4.02 ~ 14.13, P < 0.001), Asthenia (MD 2.13, 95% CI 0.29 ~ 3.98, P = 0.02), and Strain (MD 3.32, 95% CI 0.57 ~ 6.07, P = 0.02)" scale. Patients treated with CO2-LS had worse local control rates (OR 3.14, 95% CI 1.52 ~ 6.48, P = 0.002) while lower incidence of second primary tumor (OR 0.30, 95% CI 0.15 ~ 0.61, P < 0.001). It is hoped that retrospective analysis can provide suggestions for early glottis patients to choose personalized treatment.

A Modified Suture Technique to Improve Scar Appearance in Wounds Under High Tension.

ABSTRACT: The purpose of this study was to introduce a modified suture technique and to compare its effects on skin scar formation with 2 traditional suture methods: simple interrupted suture (SIS) and vertical mattress suture (VMS). Three groups of healthy adult female Sprague-Dawley rats were selected (6 replicates in each group), and the full-thickness skin of 5 cm × 0.2 cm was cut off on the back of the rats after anesthesia. The wounds were then sutured using 1 of the 3 methods for each group: SIS, VMS, and a newly introduced modified vertical mattress suture (M-VMS) technique with the needle reinsertion at the exit point. A traction device was installed on the back of the rats to achieve high tension wounds. The tensile distance was increased by 1 mm every day for 20 days. After 20 days of healing, the hematoxylin-eosin staining method was used for observation of scar morphology. The collagen production rate was measured by Masson staining, and the type I collagen and type III collagen were detected by the immunofluorescence method. Immunohistochemical staining was used to detect the expression of myofibroblast marker α-smooth muscle actin, and real-time quantitative polymerase chain reaction and Western blot techniques were used to detect the expressions of transforming growth factors TGFß1, TGFß2, and TGFß3 to understand the mechanisms of scar formation. Results showed that the quantity and density of collagen fibers were both lower in the M-VMS group than in the other 2 groups. Immunofluorescence results showed that type I collagen was significantly lower, whereas type III collagen was significantly higher in the M-VMS group than in the other 2 groups. The expressions of α-smooth muscle actin and TGFß1 both were lower in the M-VMS group than in the other 2 groups. The expression of TGFß2 and TGFß3 had no obvious difference among the 3 groups. For wounds under high tension, compared with SIS and VMS methods, the M-VMS technique we proposed can reduce scar formation due to the reduction of collagen formation, myofibroblast expression, and TGFß1 expression.

Refresh Rate-Based Caching and Prefetching Strategies for Internet of Things Middleware.

One of the research directions in Internet of Things (IoT) is the field of Context Management Platforms (CMPs) which is a specific type of IoT middleware. CMPs provide horizontal connectivity between vertically oriented IoT silos resulting in a noticeable difference in how IoT data streams are processed. As these context data exchanges can be monetised, there is a need to model and predict the context metrics and operational costs of this exchange to provide relevant and timely context in a large-scale IoT ecosystem. In this paper, we argue that caching all transient context information to satisfy this necessity requires large amounts of computational and network resources, resulting in tremendous operational costs. Using Service Level Agreements (SLAs) between the context providers, CMP, and context consumers, where the level of service imperfection is quantified and linked to the associated costs, we show that it is possible to find efficient caching and prefetching strategies to minimize the context management cost. So, this paper proposes a novel method to find the optimal rate of IoT data prefetching and caching. We show the main context caching strategies and the proposed mathematical models, then discuss how a correctly chosen proactive caching strategy and configurations can help to maximise the profit of CMP operation when multiple SLAs are defined. Our model is accurate up to 0.0016 in Root Mean Square Percentage Error against our simulation results when estimating the profits to the system. We also show our model is valid using the t-test value tending to 0 for all the experimental scenarios.

The discovery and utilization of favorable genes in Oryza longistaminata.

Asian cultivated rice has been domesticated from ancestors of the wild rice species Oryza rufipogon. During this process, important changes have occurred in many agronomic traits, such as plant height, grain shattering, and panicle shape, and the yield has also greatly increased. However, many favored traits (e.g., stress resistance) have been lost. The genome of O. longistaminata is of the same AA type as O. sativa, harboring many genes conferring resistance to biotic and abiotic stresses, and it is considered as a potential gene pool for genetic improvement of O. sativa. In this review, we summarize the basic research on O. longistaminata, including its resistance to biotic and abiotic stresses, its rhizome traits, and other traits that are of potential application value, such as bacterial blight resistance, drought resistance, heat tolerance, self-incompatibility, nitrogen efficiency, and high yield. Furthermore, we present the current applied research progress on perennial rice breeding based on the rhizome trait of O. longistaminata. Lastly, the possibility of de novo domestication of O. longistaminata is discussed. We expect this article to provide information to enhance the basic research of O. longistaminata and accelerate the genetic improvement of cultivated rice.

Unveiling toxicity profile for food risk components: A manually curated toxicological databank of food-relevant chemicals.

Rigorous risk assessment of chemicals in food and feed is essential to address the growing worldwide concerns about food safety. High-quality toxicological data on food-relevant chemicals are fundamental for risk modeling and assessment in the food safety area. The organization and analysis of substantial toxicity information can positively support decision-making by providing insight into toxicity trends. However, it remains challenging to systematically obtain fragmented toxicity data, and related toxicological resources are required to meet the current demands. In this study, we collected 221,439 experimental toxicity records for 5,657 food-relevant chemicals identified from extensive databases and literature, along with their information on chemical identification, physicochemical properties, environmental fates, and biological targets. Based on the aggregated data, a freely available web-based databank, Food-Relevant Available Chemicals Toxicology Databank (FRAC-TD) is presented, which supports multiple browsing ways and search criterions. Applying FRAC-TD for data-driven analysis, we revealed the underlying toxicity profiles of food-relevant chemicals in humans, mammals, and other species in the food chain. Expectantly, FRAC-TD could positively facilitate toxicological studies, toxicity prediction, and risk assessments in the food industry.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.

BACKGROUND: The incidence of osteosarcoma as a secondary neoplasm in glioblastoma patient is extremely rare. The genetic characteristic still remains unclear until now. CASE DESCRIPTION: We reported a 47-year-old female patient with multiple intracranial disseminations and infiltrations (splenium of the corpus callosum and lateral ventricular wall) of a rapid progressive glioblastoma underwent occipital craniotomy and total resection of all the enhancing lesions. Whole-exome sequencing and pathological examination revealed glioblastoma, IDH1 wild type, PTEN deficient, TERT mutated, NF1mutated, MGMT unmethylated. After surgery, the patient received combined therapeutic regimen of TTFields (tumor-treating fields) plus pembrolizumab plus temozolomide and TTFields plus everolimus, which displayed significant clinical benefits. During the combined therapeutic course, an extremely rare secondary malignant neoplasm occurred, femur MR and pathological detection of biopsy tissue demonstrated osteosarcoma. The result of whole-exome sequencing revealed 7 germline mutated genes (EPAS1, SETD2, MSH3, BMPR1A, ERCC4, CDH1, AR). Bioinformatic analysis showed the two germline mutations (MSH3 and ERCC4) induced deficiency in the DNA repair machinery, which resulting in the accumulation of mutations and may generate neoantigens contributing to the development of a secondary osteosarcoma in this case. CONCLUSION: Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.