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Selective laser melting (SLM) is an additive manufacturing technology to directly form complex metal parts. It has been demonstrated in aerospace and other fields. In the SLM single-pass formation process, the SLM layer distribution was modeled here via the discrete element method model (particle contact force model and particle motion equation). A dynamic behavior model of molten pool based on the particle scale was also established. The governing equations considered the influence of thermodynamic factors such as Marangoni effect, gasification recoil, and gasification heat dissipation. The laser energy model used a Gaussian heat source based on interface tracking. To study the influence of laying powder on SLM single-pass formation, the corresponding simulations were performed from three aspects: particle size distribution, powder bed tightness, and lamination thickness. To obtain a good formation zone in the actual SLM process, metal powder with a smaller average particle size should be used on the basis of saving money, and the proportion of large-sized particles in the powder should be minimized. A higher powder bed tightness is needed on the basis of ensuring a good connection with the substrate or the previous printed layer. Finally, a larger lamination thickness should be used on the basis of ensuring that the powder bed is sufficiently melted in the formation zone. This paper is expected to provide some guidance for the actual SLM laying powder process.

Background. Premenstrual syndrome (PMS) is one of the most common gynecological conditions with no standard modern therapeutic schedule. Some studies have reported the effects of acupuncture in treating PMS, but the intervention time varies. This review evaluated the efficacy of acupuncture for patients with PMS and the appropriate time to initiate acupuncture therapy. The review has been registered on the “PROSPERO” website; the registration number is CRD42018109724. Methods. A comprehensive literature search was performed on 9 electronic databases from the time of inception to September 2018. RCTs studies on acupuncture for PMS compared with medication, sham acupuncture, or no treatment were included. Statistical analysis and investigation of heterogeneity source were carried out using RevMan5. 3. Results. A total of 15 studies, comprising of 1103 cases, were included. Overall, acupuncture significantly increased the effective rate of PMS compared with medicine and sham acupuncture. Subgroup analyses showed no significant difference among different intervention time to start acupuncture treatment. Among the acupoints involved in the treatment of PMS, SP6, LR3, and RN4 were the most commonly used. Conclusions. The current meta-analysis reveals that acupuncture leads to better effective rate, but the intervention time has no significant effect on the efficacy of acupuncture treatment for PMS. SP6, LR3, and RN4 are the most commonly used acupoints in treating PMS. However, large-scale, case-control studies with rigorous designs are required to provide more accurate evidence.

Both the stress-response protein, SIRT1, and the cell cycle checkpoint kinase, CHK2, play critical roles in aging and cancer via the modulation of cellular homeostasis and the maintenance of genomic integrity. However, the underlying mechanism linking the two pathways remains elusive. Here, we show that SIRT1 functions as a modifier of CHK2 in cell cycle control. Specifically, SIRT1 interacts with CHK2 and deacetylates it at lysine 520 residue, which suppresses CHK2 phosphorylation, dimerization, and thus activation. SIRT1 depletion induces CHK2 hyperactivation-mediated cell cycle arrest and subsequent cell death. In vivo, genetic deletion of Chk2 rescues the neonatal lethality of Sirt1−/− mice, consistent with the role of SIRT1 in preventing CHK2 hyperactivation. Together, these results suggest that CHK2 mediates the function of SIRT1 in cell cycle progression, and may provide new insights into modulating cellular homeostasis and maintaining genomic integrity in the prevention of aging and cancer.

Gelled fuel has gained extensive attention because of combination of the main advantages of liquid fuel (throttle ability) and solid fuel (easy handling, etc.). For investigating the combustion characteristics of gelled fuel formed by inorganic gellant, several kinds of kerosene gels were prepared by adding fumed silica as gellant. Suspended single droplet combustion experiment was carried out under normal gravity conditions at room temperature. Experimental observations were compared with pure liquid fuel and organic-gellant-based gel fuel. Under ambient pressure condition, special combustion phenomena occur during the combustion process of an inorganic gelled kerosene droplet, such as the formation, shrinkage and exfoliation of a rigid shell surrounding the droplet. The combustion stability is inferior to pure liquid fuel but superior to organic gels. The pattern of droplet diameter variation basically obeys the d2-law in the early period; the combustion rate of inorganic gel fuel decreases with the increasing of gellant content according to the law. In the late period diameter change deviates from the law because of the incombustible residual gellant. We believe that the combustion rate becomes higher in the later period because the higher thermal conductivity of fumed silica than kerosene vapor enhances the intensity of reverse heat transfer. Unlike organic gels, the ignition delay time and total survival time of inorganic kerosene gels are shorter than that of kerosene, which facilitates the rapid response and shortening the residence time of the fuel in the combustion chamber.

To improve the utilization efficiency of steel slag in cement industry, cement clinkers are prepared by simulated multi-phased clinker sintering technology with crushed steel slag (without grinding). The results show that after high temperature treatment, the inert components and tough phases of steel slag such as iron phase, calcium ferrite phase and RO phase (CaO FeO MnO MgO solid solution) are reduced; the soundness, grindability and hydration activity of steel slag can be certainly improved; hydration activity of the multi-phased cement at early age is a little lower than that of grade 42.5 ordinary Portland cement, while develops faster than later. The multi-phased cement clinker prepared at 1400 °C with the raw material contains 16.86% steel slag has comparable grindability and soundness to the normal Portland cement clinker. Compared to traditionally using steel slag as a cement raw meal, the multi-phased clinker sintering technology has much greater technical and economic advantage. It is a promising approach to the extensive utilization of steel slag in cement industry.

Proliferative vitreoretinopathy (PVR) is the most serious fibrous complication that causes vision loss after intraocular surgery, and there is currently no effective treatment in clinical. Autophagy is an important cell biological mechanism in maintaining the homeostasis of tissues and cells, resisting the process of EMT. However, it is still unclear whether autophagy could resist intraocular fibrosis and prevent PVR progression. In this study, we investigated the expression of mesenchymal biomarkers in autophagy deficiency cells and found these proteins were increased. The mesenchymal protein transcription factor Twist can bind to autophagy related protein p62 and promote the degradation of Twist, which reduced the expression of mesenchymal markers. By constructing an EMT model of retinal pigment epithelial (RPE) cells in vitro, we found that autophagy was activated in the EMT process of RPE cells. Moreover, in autophagy deficient RPE cell line via knockdown autophagy related protein 7 (Atg7), the expression of epithelial marker claudin-1 was suppressed and the mesenchymal markers were increased, accompanied by an increase in cell migration and contractility. Importantly, RPE epithelial properties can be maintained by promoting autophagy and effectively reversing TFG-β2-induced RPE fibrosis. These observations reveal that autophagy may be an effective way to treat PVR.

The expression and activity of CCAAT/enhancer-binding protein α (C/EBPα) are involved in sumoylation modification, which is critical to divert normal cells from differentiation to proliferation. However, the role and underlying mechanism of C/EBPα in cancer is poorly understood. Human MORC2 (microrchidia family CW-type zinc-finger 2), is a member of the MORC proteins family containing a CW-type zinc-finger domain. Here, we found that MORC2 interacted with TE-III domain of C/EBPα, and the overexpression of MORC2 promoted wild-type C/EBPα sumoylation and its subsequent degradation, which didn’t significantly observe in mutant C/EBPα-K161R. Furthermore, the overexpression of MORC2 inhibited C/EBPα-mediated C2C12 cell differentiation to maintain cell cycle progression. Moreover, the striking correlation between the decreased C/EBPα expression and the increased MORC2 expression was also observed in the poor differentiation status of gastric cancer tissues. Most notably, the high expression of MORC2 is correlated with an aggressive phenotype of clinical gastric cancer and shorter overall survival of patients. Taken together, our findings demonstrated that MORC2 expression regulated C/EBPα-mediated the axis of differentiation/proliferation via sumoylation modification, and affected its protein stability, causing cell proliferation and tumorigenesis.

Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). SIRT2, an NAD

High-throughput metabolomics using liquid chromatography and mass spectrometry (LC/MS) provides a useful method to identify biomarkers of disease and explore biological systems. However, the majority of metabolic features detected from untargeted metabolomics experiments have unknown ion signatures, making it critical that data should be thoroughly quality controlled to avoid analyzing false signals. Here, we present a postalignment method relying on intermittent pooled study samples to separate genuine metabolic features from potential measurement artifacts. We apply the method to lipid metabolite data from the PREDIMED (PREvención con DIeta MEDi-terránea) study to demonstrate clear removal of measurement artifacts. The method is publicly available as the R package MetProc, available on CRAN under the GPL-v2 license., This work was supported by NIH research Grant HL118264. The PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140 to R.E.; RTIC RD 06/0045 to M.A.M.-G.; and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición [CIBEROBN]), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, and PI13/01090), Ministerio de Ciencia e Innovación (AGL-2009-13906-C02 and AGL2010-22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA-COMP2010-181, GVACOMP2011-151, CS2010-AP-111, and CS2011-AP-042), and Regional Government of Navarra (P27/2011).

Methanogenesis is central to anaerobic digestion processes. The conversion of propionate as a key intermediate for methanogenesis requires syntrophic interactions between bacterial and archaeal partners. In this study, a series of methanogenic enrichments with propionate as the sole substrate were developed to identify microbial populations specifically involved in syntrophic propionate conversion. These rigorously controlled propionate enrichments exhibited functional stability with consistent propionate conversion and methane production; yet, the methanogenic microbial communities experienced substantial temporal dynamics, which has important implications on the understanding of mechanisms involved in microbial community assembly in anaerobic digestion. Syntrophobacter was identified as the most abundant and consistent bacterial partner in syntrophic propionate conversion regardless of the origin of the source culture, the concentration of propionate, or the temporal dynamics of the culture. In contrast, the methanogen partners involved in syntrophic propionate conversion lacked consistency, as the dominant methanogens varied as a function of process condition and temporal dynamics. Methanoculleus populations were specifically enriched as the syntrophic partner at inhibitory levels of propionate, likely due to the ability to function under unfavorable environmental conditions. Syntrophic propionate conversion was carried out exclusively via transformation of propionate into acetate and hydrogen in enrichments established in this study. Microbial populations highly tolerant of elevated propionate, represented by Syntrophobacter and Methanoculleus, are of great significance in understanding methanogenic activities during process perturbations when propionate accumulation is frequently encountered. Key points • Syntrophobacter was the most consistent bacterial partner in propionate metabolism. • Diverse hydrogenotrophic methanogen populations could serve as syntrophic partners. • Methanoculleus emerged as a methanogen partner tolerant of elevated propionate.

Cadmium (Cd) and other heavy metals usually coexist in soils. Effects of coexisting heavy metals on the accumulation and transfer of Cd in field soils by wheat remain poorly understood. Here we revealed changeable effects of coexisting Pb, Zn and Cu on the Cd transfer from soils to wheat grains. Soil burdens of Cd were found to exhibit positive correlations (r = 0.459–0.946) with those of coexisting Pb, Zn and Cu (particularly Pb). Effects of three coexisting metals on to the uptake of Cd by wheat varied in the directions and/or extents with types of metals and transfer processes of Cd. Coexisting Zn inhibited the uptake of Cd by wheat grains to higher extent than Pb and Cu. Soil Zn, along with soil Cd, soil pH and soil Ca, was used to construct the predictive model of grain Cd (R2 = 0.868). External verifications of the model on 572 datasets of large representation performed well. The predictive accuracy was about 54%, 73% and 89% for a factor of 1, 2 and 5 above and below the ideal fit, respectively. This finding has practical interest in risk assessments and remediation measures of Cd-contaminated soil sites in regional scales.

International audience; Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.

The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript’s publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.

Dysregulation of the cell cycle and the resulting aberrant cellular proliferation has been highlighted as a hallmark of cancer. Certain traditional Chinese medicines can inhibit cancer growth by inducing cell cycle arrest. In this study we explore the effect of Hedyotis diffusae Herba-Andrographis Herba on the cell cycle of nasopharyngeal carcinoma (NPC). Hedyotis diffusae Herba-Andrographis Herba-containing serum was prepared and then added to the cell culture medium. BrdU, comet, and FUCCI assays, western blot analysis and flow cytometry analysis revealed that Hedyotis diffusae Herba-Andrographis Herba treatment significantly alters cell proliferation, DNA damage, and cell cycle distribution. Xenograft mouse model experiments were performed, confirming these in vitro findings in vivo. Treatment with Hedyotis diffusae Herba-Andrographis Herba inhibited cell proliferation, promoted DNA damage, and arrested NPC cells progression from G1 to S phase. Further examination of the underlying molecular mechanisms revealed that treatment with Hedyotis diffusae Herba-Andrographis Herba increased the expression of p53 and p21, while reducing that of CCND1, Phospho-Rb, E2F1, γH2AX, and Ki-67 both in vivo and in vitro. Conversely, the inhibition of p53 and p21 could abolish the promoting effect of Hedyotis diffusae Herba-Andrographis Herba on the NPC cell cycle arrest at the G1 phase, contributing to the proliferation of NPC cells. Hedyotis diffusae Herba-Andrographis Herba suppressed the tumor growth in vivo. Overall, these findings suggest that Hedyotis Diffusae Herba-Andrographis prevent the progression of NPC by inducing NPC cell cycle arrest at the G1 phase through a p53/p21-dependent mechanism, providing a novel potential therapeutic treatment against NPC.

Educational facilities serve as community hubs and consequently hotspots for exposure to pathogenic microorganisms. Therefore, it is of critical importance to understand processes shaping the indoor microbiomes in educational facilities to protect public health by reducing potential exposure risks of students and the broader community. In this study, the indoor surface bacterial microbiomes were characterized in two multifunctional university buildings with contrasting levels of human occupancy, of which one was recently constructed with minimal human occupancy while the other had been in full operation for six years. Higher levels of human occupancy in the older building were shown to result in greater microbial abundance in the indoor environment and greater proportion of the indoor surface bacterial microbiomes contributed from human-associated microbiota, particularly the skin microbiota. It was further revealed that human-associated microbiota had greater influence on the indoor surface bacterial microbiomes in areas of high occupancy than areas of low occupancy. Consistent with minimal impact from human occupancy in a new construction, the indoor microbiomes in the new building exhibited significantly lower influence from human-associated microbiota than in the older building, with microbial taxa originating from soil and plants representing the dominant constituents of the indoor surface bacterial microbiomes. In contrast, microbial taxa in the older building with extensive human occupancy were represented by constituents of the human microbiota, likely from occupants. These findings provide insights into processes shaping the indoor microbiomes which will aid the development of effective strategies to control microbial exposure risks of occupants in educational facilities.

MicroRNAs (miRNAs) play important roles in regulated gene expression and miRNA biogenesis is also subject to regulation, together constituting critical regulatory circuitries in numerous physiological and pathological processes. As a dsRNA binding protein, interleukin enhancer binding factor 3 (ILF3) has been implicated as a negative regulator in miRNA biogenesis, but the mechanism and specificity have remained undefined. Here, combining small-RNA-seq and CLIP-seq, we showed that ILF3 directly represses many miRNAs or perhaps other types of small RNAs annotated in both miRBase and MirGeneDB. We demonstrated that ILF3 preferentially binds to A/U-enriched motifs, which tend to lengthen and/or stabilize the stem-loop in pri-miRNAs, thereby effectively competing with the Microprocessor to block miRNA biogenesis. Focusing on the biological function of ILF3-suppressed miR-582-3p, we discovered that this LINE-derived miRNA targets a critical interferon-inducible gene RIG-I for repression, thus establishing a novel ILF3/miR-582/RIG-I axis in the antiviral response.

Escherichia albertii is an emerging foodborne enteropathogen with increasing outbreaks worldwide, particularly in Japan recently. However, major features of this zoonotic pathogen, such as prevalence, virulence, and antibiotic resistance (AR), still remain under characterized. In a recent pilot study, we reported isolation of E. albertii from a chicken farm in Tennessee, suggesting chicken is an important reservoir for E. albertii. In this large-scale study, we examined prevalence of E. albertii in 9 farms in Mississippi and Alabama. Of a total of 270 cloacal swabs (30 per farm), 43 were PCR positive and 12 E. albertii strains were isolated with different isolation rates in individual farms ranging from 0 to 23.3 %. Both PFGE and whole genome analysis showed the E. albertii from different farms were phylogenetically distant, but those from the same farm displayed clonal relationships. Consistently, the antibiogram, AR gene profiles, and plasmid replicon types were similar across the strains in the same farm. Notably, 9 of the 12 E. albertii strains displayed multidrug resistance; one strain was even resistant to imipenem, a clinically important carbapenem antibiotic. In addition, comparative genomics analysis showed that two chicken E. albertii clusters displayed very close evolutionary relationships and similar virulence gene profiles to human E. albertii strains. In vitro growth assay demonstrated that the anti-enterobactin antibodies could dramatically inhibit the growth of two representative chicken E. albertii, supporting the feasibility of the novel enterobactin-based immune intervention for controlling this emerging pathogen. Taken together, the findings from this study further indicated chickens as an important reservoir for E. albertii in the U.S., highlighting the need to prevent and control E. albertii in poultry production.

Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. This is a challenging task as currently it is not clear how small molecules are fragmented in mass spectrometry. The existing approaches use the domain knowledge from chemistry to predict fragmentation of molecules. However, these rule-based methods fail to explain many of the peaks in mass spectra of small molecules. Recently, spectral libraries with tens of thousands of labelled mass spectra of small molecules have emerged, paving the path for learning more accurate fragmentation models for mass spectral database search. We present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by (i) utilizing an efficient algorithm to generate mass spectrometry fragmentations, and (ii) learning a probabilistic model to match small molecules with their mass spectra. We show our database search is an order of magnitude more efficient than the state-of-the-art methods, which enables searching against databases with millions of molecules. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that our probabilistic model can correctly identify nearly six times more unique small molecules than previous methods. Moreover, by applying molDiscovery on microbial datasets with both mass spectral and genomics data we successfully discovered the novel biosynthetic gene clusters of three families of small molecules.AvailabilityThe command-line version of molDiscovery and its online web service through the GNPS infrastructure are available at https://github.com/mohimanilab/molDiscovery.

Mengzhu Lv,1,* Simeng Zhang,2,* Yuqing Dong,1 Liu Cao,3 Shu Guo1 1Department of Plastic Surgery, China Medical University the First Hospital, Shenyang, 110001, Liaoning Province, People’s Republic of China; 2Department of Medical Oncology, China Medical University the First Hospital, Shenyang, 110001, Liaoning Province, People’s Republic of China; 3Key Laboratory of Medical Cell Biology, Ministry of Education, Institute of Translational Medicine, China Medical University, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, 110001, Liaoning Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shu GuoDepartment of Plastic Surgery, China Medical University the First Hospital, No. 155, Nan Jing Street, Heping District, Shenyang, 110001, Liaoning Province, People’s Republic of ChinaTel/Fax +86-24-83282779Email sguo@cmu.edu.cnLiu CaoInstitute of Translational Medicine, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, Liaoning Province, People’s Republic of ChinaTel +86 24 31939630Fax +86 024 31939630Email 1021815514@qq.comPurpose: Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death. There is a critical need for the development of novel therapies in GC. DNA polymerase gamma (PolG) has been implicated in mitochondrial homeostasis and affects the development of numerous types of cancer, however, its effects on GC and molecular mechanisms remain to be fully determined. The aim of the present research was to clarify the effects of PolG on GC and its possible molecular mechanism of action.Methods: The GSE62254 dataset was used to predict the effect of PolG on prognostic value in GC patients. Lentivirus-mediated transduction was used to silence PolG expression. Western blot analysis evinced the silencing effect. Co-immunoprecipitation (Co-IP) analysis was performed to explore the potential molecular mechanism of action. Analysis of the glycolysis process in GC cells was also undertaken. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Cell migration was detected using the Transwell device. Animal experiments were used to measure in vivo xenograft tumor growth.Results: GC patients with low PolG expression have worse overall survival (OS) and progression-free survival (PFS). PolG binds to PKM2 and affects the activation of Tyr105-site phosphorylation, thus interfering with the glycolysis of GC cells. In vitro tumor formation experiments in mice also confirmed that PolG silencing of GC has a stronger proliferation ability. PolG can suppress GC cell growth both in vivo and in vitro.Conclusion: Our study reveals a potential molecular mechanism between PolG and the energy metabolic process of GC tumor cells for the first time, suggesting PolG as an independent novel potential therapeutic target for tumor therapy, and providing new ideas for clinical GC treatment.Keywords: DNA polymerase gamma, energy metabolism, tumor suppressor, PKM protein, stomach neoplasms

In this paper, we focus on the performance of vehicle-to-vehicle (V2V) communication adopting the Dedicated Short Range Communication (DSRC) application in periodic broadcast mode. An analytical model is studied and a fixed point method is used to analyze the packet delivery ratio (PDR) and mean delay based on the IEEE 802.11p standard in a fully connected network under the assumption of perfect PHY performance. With the characteristics of V2V communication, we develop the Semi-persistent Contention Density Control (SpCDC) scheme to improve the DSRC performance. We use Monte Carlo simulation to verify the results obtained by the analytical model. The simulation results show that the packet delivery ratio in SpCDC scheme increases more than 10% compared with IEEE 802.11p in heavy vehicle load scenarios. Meanwhile, the mean reception delay decreases more than 50%, which provides more reliable road safety.

The outbreak of coronavirus disease 2019 (COVID-19) rapidly spreads across worldwide and becomes a global pandemic. Remdesivir is the only COVID-19 treatment approved by U.S. Food and Drug Administration (FDA); however, its effectiveness is still under questioning as raised by the results of a large WHO Solidarity Trial. Herein, we report that the parent nucleotide of remdesivir, GS-441524, potently inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Vero E6 and other cells. It exhibits good plasma distribution and longer half-life (t1/2=4.8h) in rat PK study. GS-441524 is highly efficacious against SARS-CoV-2 in AAV-hACE2 transduced mice and murine hepatitis virus (MHV) in mice, reducing the viral titers in CoV-attacked organs, without noticeable toxicity. Given that GS-441524 was the predominant metabolite of remdesivir in the plasma, the anti-COVID-19 effect of remdesivir may partly come from the effect of GS-441524. Our results also supported that GS-441524 as a promising and inexpensive drug candidate in the treatment of COVID-19 and future emerging CoVs diseases.

Background: Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. There is a critical need for the development of novel therapies in GC. DNA polymerase gamma (PolG) has been implicated in mitochondrial homeostasis and affects the development of a numerous of cancer types. However, its effects in GC and molecular mechanisms remain to be fully determined. Methods: GSE62254 dataset was used to predict the impact of PolG on prognostic valule in GC patients. Lentivirus-mediated transduction was used to silence PolG expression. Western blot analysis the knockdown effect. Co-immunoprecipitation analysis was performed to explore the potential molecular mechanism. Analysis of the glycolysis process in GC cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Cell migration was detected using transwell method. Animal experiment was used to measure the In vivo xenograft tumor growth.Results: GC patients with low PolG expression have worse OS and pFS . PolG binds to PKM2 and affects the activation of the Tyr105 site phosphorylation, then interfering with the glycolysis of Gastric cancer cells. In vitro tumor formation experiments in mice also confirmed that PolG knockdown GC has stronger proliferation ability. PolG can suppress GC cells growth in both vivo and vitro.Conclusion: Our study reveals a potential molecular mechanism between PolG and the energy metabolic process of GC tumor cells, suggesting PolG as an independent novel potential therapeutic target for tumor therapy.

Built environments, occupants, and microbiomes constitute a system of ecosystems with extensive interactions that impact one another. Understanding the interactions between these systems is essential to develop strategies for effective management of the built environment and its inhabitants to enhance public health and well-being. Numerous studies have been conducted to characterize the microbiomes of the built environment. This review summarizes current progress in understanding the interactions between attributes of built environments and occupant behaviors that shape the structure and dynamics of indoor microbial communities. In addition, this review also discusses the challenges and future research needs in the field of microbiomes of the built environment that necessitate research beyond the basic characterization of microbiomes in order to gain an understanding of the causal mechanisms between the built environment, occupants, and microbiomes, which will provide a knowledge base for the development of transformative intervention strategies toward healthy built environments. The pressing need to control the transmission of SARS-CoV-2 in indoor environments highlights the urgency and significance of understanding the complex interactions between the built environment, occupants, and microbiomes, which is the focus of this review.

Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. This is a challenging task as currently it is not clear how small molecules are fragmented in mass spectrometry. The existing approaches use the domain knowledge from chemistry to predict fragmentation of molecules. However, these rule-based methods fail to explain many of the peaks in mass spectra of small molecules. Recently, spectral libraries with tens of thousands of labelled mass spectra of small molecules have emerged, paving the path for learning more accurate fragmentation models for mass spectral database search. We present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by (i) utilizing an efficient algorithm to generate mass spectrometry fragmentations, and (ii) learning a probabilistic model to match small molecules with their mass spectra. We show our database search is an order of magnitude more efficient than the state-of-the-art methods, which enables searching against databases with millions of molecules. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that our probabilistic model can correctly identify nearly six times more unique small molecules than previous methods. Moreover, by applying molDiscovery on microbial datasets with both mass spectral and genomics data we successfully discovered the novel biosynthetic gene clusters of three families of small molecules. Availability: The command-line version of molDiscovery and its online web service through the GNPS infrastructure are available at https://github.com/mohimanilab/molDiscovery.

Identification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. The existing approaches are based on chemistry domain knowledge, and they fail to explain many of the peaks in mass spectra of small molecules. Here, we present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by learning a probabilistic model to match small molecules with their mass spectra. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that molDiscovery correctly identify six times more unique small molecules than previous methods., A large number of mass spectra from different samples have been collected, and to identify small molecules from these spectra, database searches are needed, which is challenging. Here, the authors report molDiscovery, a mass spectral database search method that uses an algorithm to generate mass spectrometry fragmentations and learns a probabilistic model to match small molecules with their mass spectra.

SIRT2-mediated deacetylation of SMC1A promotes its phosphorylation and overcomes the oncogenic stress for tumor cell survival., Improper distribution of chromosomes during mitosis can contribute to malignant transformation. Higher eukaryotes have evolved a mitotic catastrophe mechanism for eliminating mitosis-incompetent cells; however, the signaling cascade and its epigenetic regulation are poorly understood. Our analyses of human cancerous tissue revealed that the NAD-dependent deacetylase SIRT2 is up-regulated in early-stage carcinomas of various organs. Mass spectrometry analysis revealed that SIRT2 interacts with and deacetylates the structural maintenance of chromosomes protein 1 (SMC1A), which then promotes SMC1A phosphorylation to properly drive mitosis. We have further demonstrated that inhibition of SIRT2 activity or continuously increasing SMC1A-K579 acetylation causes abnormal chromosome segregation, which, in turn, induces mitotic catastrophe in cancer cells and enhances their vulnerability to chemotherapeutic agents. These findings suggest that regulation of the SIRT2-SMC1A axis through deacetylation-phosphorylation permits escape from mitotic catastrophe, thus allowing early precursor lesions to overcome oncogenic stress.

Background Peritoneal metastasis (PM) is an important pathological process in the progression of gastric cancer (GC). The metastatic potential of tumor and stromal cells is governed by hypoxia, which is a key molecular feature of the tumor microenvironment. Mesothelial cells also participate in this complex and dynamic process. However, the molecular mechanisms underlying the hypoxia-driven mesothelial-tumor interactions that promote peritoneal metastasis of GC remain unclear. Methods We determined the hypoxic microenvironment in PM of nude mice by immunohistochemical analysis and screened VEGFA by human growth factor array kit. The crosstalk mediated by VEGFA between peritoneal mesothelial cells (PMCs) and GC cells was determined in GC cells incubated with conditioned medium prepared from hypoxia-treated PMCs. The association between VEGFR1 and integrin α5 and fibronectin in GC cells was enriched using Gene Set Enrichment Analysis and KEGG pathway enrichment analysis. In vitro and xenograft mouse models were used to evaluate the impact of VEGFA/VEGFR1 on gastric cancer peritoneal metastasis. Confocal microscopy and immunoprecipitation were performed to determine the effect of hypoxia-induced autophagy. Results Here we report that in the PMCs of the hypoxic microenvironment, SIRT1 is degraded via the autophagic lysosomal pathway, leading to increased acetylation of HIF-1α and secretion of VEGFA. Under hypoxic conditions, VEGFA derived from PMCs acts on VEGFR1 of GC cells, resulting in p-ERK/p-JNK pathway activation, increased integrin α5 and fibronectin expression, and promotion of PM. Conclusions Our findings have elucidated the mechanisms by which PMCs promote PM in GC in hypoxic environments. This study also provides a theoretical basis for considering autophagic pathways or VEGFA as potential therapeutic targets to treat PM in GC.

There exists an intricate collaboration between autophagy and other types of PCD. These processes can be activated in parallel or sequentially, and have either common or opposite objectives. Determining which interactions between them are important in the regulation of cell death. A comprehensive and in-depth study of the crosstalk between autophagy and apoptosis, necroptosis, or pyroptosis will bring breakthroughs in the treatment of many diseases, including cancer, cardiovascular disease, and neurodegenerative disorders.

A hydroponic experiment was conducted to explore the differences in growth status and Cd accumulation characteristics of two

Recently, Artificial Intelligence (AI) has achieved its momentum in various areas such as image processing and natural language processing thanks to the advances in processing speed, data acquisition and storage. Many research efforts have been exerted to apply AI to computer networking. Performance evaluation of network systems using AI techniques can be conducted using ns-3, and such studies can be facilitated if ns-3 is able to interact with the existing open-source AI frameworks. In the past year, an ns-3 extension module called ns3-gym connecting ns-3 with the OpenAI Gym toolkit has been developed, which utilizes Zero MQ sockets as an interprocess communications (IPC) mechanism. In this paper, we propose a newly designed module between ns-3 and multiple Python-based AI frameworks, namely ns3-ai, to provide efficient and high-speed data exchange between the AI engines and ns-3. This module is built based on a shared memory implementation for IPC, which can achieve an IPC transfer speed up to 100 times faster than that of ns3-gym on a benchmark example. We also present our high-level interface design to improve the abstraction between ns-3 and different AI frameworks, and provide an example use case based on a 5G NR scenario. Our evaluation results show that this ns3-ai framework offers performance advantages over ns3-gym, especially for the use cases where large amounts of data must be transferred between ns-3 and the AI framework. This ns-3 extension module may foster the performance evaluation of AI algorithms in computer networking research with much reduced development workload.

Background The clinical impact of sarcopenia on the immune checkpoint inhibitor’s (ICI) efficacy and immune-related adverse events in non-small cell lung cancer (NSCLC) patients is unclear. Therefore, the purpose of this study is to evaluate the association between sarcopenia and clinical outcomes of ICI immunotherapy. Methods A systematic literature search of PubMed, Embase, Cochrane CENTRAL, and conference databases was conducted for the relevant studies. The primary outcomes were progression-free survival (PFS) and overall survival (OS) measured by hazard ratio (HR) with 95% confidence interval (CI), and the secondary outcomes were disease control rate, overall response rate, and immune-related adverse events measured by relative risk (RR) with 95% CI. Subgroup and sensitivity analysis were performed. Results Pre-immunotherapy sarcopenia was significantly associated with worse OS (HR = 1.61, 95% CI = 1.24–2.10) and PFS (HR = 1.98, 95% CI = 1.32–2.97). Development or worsening of sarcopenia during immunotherapy also predicted worse OS and PFS. Both pre-immunotherapy sarcopenia (RR = 0.70, 95% CI = 0.56–0.86) and development or worsening of sarcopenia (RR = 0.62, 95% CI = 0.40–0.96) resulted in a lower disease control rate. Sarcopenia tended toward a lower overall response rate, although there was no significant difference (RR = 0.54, 95% CI = 0.19–1.53). Moreover, sarcopenia did not increase immune-related adverse events (RR = 0.99, 95% CI = 0.21–4.67). Conclusion Sarcopenia was associated with worse treatment response and shorter long-term efficacy in NSCLC patients treated with ICI immunotherapy. Moreover, sarcopenia does not increase the rate of immune-related adverse events.

Oil and gas production applications demand high reliability, which implies low failure probability over the lifetime of the components. The service environments encompass high pressure high temperature (HPHT) conditions inside and seawater with cathodic protection (CP) systems on the outside. New material combinations are being employed, including thermo-mechanically processed low alloy steels and corrosion resistant alloys (CRA). Additively manufactured (AM) alloys are also entering the market, creating further variability and directionality in properties. Material qualification involves two types of accelerated, laboratory tests – standard and fit-for-purpose. However, the acceleration vectors used in these types of tests are usually not clearly identified. Relating the materials qualification tests to service performance requires a systematic approach that considers the uncertainties in the acceleration vectors such as, loading conditions, environmental compositions, operating parameters, and material microstructures. In this paper, we describe the acceleration vectors typically used in qualification tests and a risk framework that may be used to relate the test results to long term service performance. The benefit of a risk informed approach is not only avoidance of unnecessary testing, but also investing the testing resources to attain highest reliability.

Cellular senescence is a potent tumor-suppressive program that prevents neoplastic events. Paradoxically, senescent cells develop an inflammatory secretome, termed the senescence-associated secretory phenotype, which is implicated in age-related pathologies including cancer. Here, we report that senescent cells actively synthesize and release small extracellular vesicles (sEV) with a distinctive size distribution. Mechanistically, SIRT1 loss supported accelerated sEV production despite enhanced proteome-wide ubiquitination, a process correlated with ATP6V1A downregulation and defective lysosomal acidification. Once released, senescent stromal sEVs significantly altered the expression profile of recipient cancer cells and enhanced their aggressiveness, specifically drug resistance mediated by expression of ATP-binding cassette subfamily B member 4 (ABCB4). Targeting SIRT1 with agonist SRT2104 prevented development of cancer resistance by restraining sEV production by senescent stromal cells. In clinical oncology, sEVs in peripheral blood of posttreatment cancer patients were readily detectable by routine biotechniques, presenting an exploitable biomarker to monitor therapeutic efficacy and predict long-term outcome. Together, this study identifies a distinct mechanism supporting pathologic activities of senescent cells and provides a potent avenue to circumvent advanced human malignancies by cotargeting cancer cells and their surrounding microenvironment, which contributes to drug resistance via secretion of sEVs from senescent stromal cells. Significance: Senescent stromal cells produce a large number of sEVs to promote cancer resistance in therapeutic settings, a process driven by SIRT1 decline in stromal cells and ABCB4 augmentation in cancer cells. See related commentary by Wiley, p. 3193

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2(−/−) mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.

In general, rheological properties of gelled fuels change dramatically when temperature changes. In this work, we investigate flow and heat transfer of water-gel in a straight pipe and a tapered injector for non-isothermal conditions, which mimic the situations when gelled fuels are used in propulsion systems. The gel-fluid is modeled as a non-Newtonian fluid, where the viscosity depends on the shear rate and the temperature, a correlation fitted with experimental data is used. For the fully developed flow in a straight pipe with heating, the mean apparent viscosity at the cross section when the temperature is high is only 44% of the case with low temperature, this indicates that it is feasible to control the viscosity of gel fuel by proper thermal design of pipes. For the flow in the typical tapered injector, larger temperature gradients along the radial direction results in a more obvious plug flow, that is, when the fuel is heated the viscosity near the wall is significantly reduced, but the effect is not obvious in the area far away from the wall. Therefore, for the case of the tapered injector, as the temperature of the heating wall increases, the mean apparent viscosity at the outlet decreases first and increases then due to the high viscosity plug formed near the channel center, which encourages further proper design of the injector in future. Furthermore, the layer of low viscosity near the walls plays a role similar to lubrication, thus the supply pressure of the transport system is significantly reduced, the pressure drop for high temperature is only 62% of that of low temperature. It should be noticed that for a propellent system the heating source is almost free, therefore, by introducing a proper thermal design of the transport system, the viscosity of the gelled fuel can be greatly reduced, thus reducing the power input to the supply pressure at a lower cost.