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Human foot traffic in urban environments provides essential information for city planners to manage the urban resources and urban residents to plan their activities. Compared to camera or mobile-based solutions, seismic sensors detect human footstep signals with fewer privacy concerns. However, seismic sensors often record signals generated from multiple sources, particularly in an urban outdoor environment. In this article, we monitor people’s running activities during COVID-19 pandemic with a seismic sensor in a park in Singapore. We compare the spectra of natural and urban events in the recorded seismic data. For each 3 s seismic data, we define hierarchical screening criteria to identify footsteps based on the spectrum of the signal and its envelope. We derive the cadence of each runner by detecting the primary frequency of the footstep signals. The resulting algorithm achieves higher accuracy and higher temporal resolution for weak and overlapping signals compared to existing methods. Runner statistics based on four-month long seismic data show that urban running activities have clear daily and weekly cycles. Lockdown measures to mitigate COVID-19 pandemic promoted running activities, particularly over the weekends. Cadence statistics show that morning runners have higher cadence on average.

Three new flavonoids, 4'-O-β-D-glucopyranosyl-2S,3R-3,7-dihydroxy-3'-methoxyflavan (1), (3R)-7,4'-dihydroxy-5,3'-methoxychalcone (2), (3S)-7,2',3'-trihydroxy-6,4'-dimethoxylisoflavan (3), and one new natural occurring product, (3S)-6,2',3'-trihydroxy-7,4'-dimethoxylisoflavan (4), together with eleven known ones (5-15), were isolated from the roots of Indigofera stachyodes. The structures of these compounds were confirmed by UV, IR, MS, and NMR spectroscopic analysis. The absolute configurations of new compounds were elucidated by ECD spectra and chemical method. All the isolated flavonoids were screened for their antioxidant abilities to scavenge DPPH and ABTS

In this study, we investigate the patterns exhibited by integrated neutron-proton interactions (denoted as ) that exhibit systematic differences among particle-particle, hole-hole, hole-particle, and particle-hole cases. A simple formula of is proposed to be in approximate linearity with . This formula yields regular patterns of that are highly consistent with those previously extracted according to binding energies. The observed ordering of , i.e., of the particle-particle case is the largest, of the hole-hole case is in-between, and of the particle-hole and hole-particle cases is the smallest, is explained in terms of the dominant part of originating from symmetry energy and refinement involving the shell correction in the mass formulas.

Megacities are facing internal and external constraints and challenges with the accelerated urbanization. Urbanization can provide convenient and various infrastructures for people, but on the other hand, natural resource and environmental condition will be destroyed due to plenty of land resources used for city development. Nowadays, it is important to keep the balance between urban construction and resource and environment, In order to measure the relationship and how these two factors impact each other, this study took the largest megacity of central China–Wuhan as an example to explore the status of urbanization through a comprehensive analysis framework, and quantify the coupling mechanism and spatial autocorrelation on street level. Through the indicator system, bivariate autocorrelation model, coupling coordination model and spatial lag model (SLM), the main conclusions are listed in the following part. With the increasing distance to the city center, the secondary indicators showed a significant increase in natural resources. Relationship between social economy and regional construction had an obvious overall positive correlation with high aggregation and strong spatial heterogeneity. Streets with lag effects on urban development ability were obviously larger than streets with lag effects on resource and environment level, which means most streets still have potential in terms of resource and environmental supply when compared with the level of urbanization. The results from SLM confirmed that the effects of spatial aggregation can improve both urban development ability and resource and environment level. This study can provide detailed geographical information for policymakers in the development of megacities and surrounding areas based on their urbanization status.

Cryogenic milling was demonstrated as a new and facile method to fabricate nanostructured battery electrode materials. SnSb anode material with 1.2 wt % graphite was selected as a model system to d...

Objective Puerarin has the potential of regulating the differentiation of preadipocytes, but its mechanism of action has not yet been elucidated. Adipocytes found in adipose tissue, the main endocrine organ, are the main sites of lipid deposition, and are widely used as a cell model in the study of in vitro fat deposition. This study aimed to investigate the effects of puerarin on adipogenesis in vitro. Methods Puerarin was added to the culture medium during the process of adipogenesis. The proliferation and differentiation of bovine preadipocytes was measured through cell viability and staining with Oil Red O. The content of triacylglycerol (TG) was measured using a triglyceride assay kit. The mRNA and protein expression levels of adipogenic genes, peroxisome proliferator-activated receptor-γ (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results The addition of puerarin significantly increased adipogenesis of bovine preadipocytes and enhanced the mRNA and protein level expression of PPARγ (p

Background The COVID-19 Delta variant has presented an unprecedented challenge to countries in Southeast Asia (SEA). Its transmission has shown spatial heterogeneity in SEA after countries have adopted different public health interventions during the process. Hence, it is crucial for public health authorities to discover potential linkages between epidemic progression and corresponding interventions such that collective and coordinated control measurements can be designed to increase their effectiveness at reducing transmission in SEA. Objective The purpose of this study is to explore potential linkages between the spatiotemporal progression of the COVID-19 Delta variant and nonpharmaceutical intervention (NPI) measures in SEA. We detected the space-time clusters of outbreaks of COVID-19 and analyzed how the NPI measures relate to the propagation of COVID-19. Methods We collected district-level daily new cases of COVID-19 from June 1 to October 31, 2021, and district-level population data in SEA. We adopted prospective space-time scan statistics to identify the space-time clusters. Using cumulative prospective space-time scan statistics, we further identified variations of relative risk (RR) across each district at a half-month interval and their potential public health intervention linkages. Results We found 7 high-risk clusters (clusters 1-7) of COVID-19 transmission in Malaysia, the Philippines, Thailand, Vietnam, and Indonesia between June and August, 2021, with an RR of 5.45 (P Conclusions The analyses of space-time clusters and RRs of districts benefit public health authorities with continuous surveillance of COVID-19 dynamics using real-time data. International coordination with more synchronized interventions amidst all SEA countries may play a key role in mitigating the progression of COVID-19.

BACKGROUND The Delta variant of COVID-19 has presented an unprecedented challenge to Southeast Asia (SEA) countries. Its transmission had shown spatial heterogeneity in SEA after countries adopted different public health interventions during the process. Hence, it is crucial for the public health authority to discover the potential linkages between epidemic progression and corresponding interventions, such that collective and coordinated control measurements can be designed to increase their effectiveness at reducing transmission in SEA. OBJECTIVE The purpose of this study was to explore potential linkages between spatiotemporal progression of the Delta variant of COVID-19 and non-pharmaceutical intervention (NPI) measures in Southeast Asia. We detected the space-time clusters of outbreaks of COVID-19 and analyzed how the NPI measures relate to the propagation of COVID-19. METHODS We collected district-level daily new cases of COVID-19 from June 1, 2021 to October 31, 2021, and district-level population data in Southeast Asia. We adopted prospective space-time scan statistics to identify the space-time clusters. Using cumulative prospective space-time scan statistics, we further identified variations of relative risk across each district at a half-month interval and their potential public health intervention linkages. RESULTS Most districts in Malaysia and Philippines, as well as the capital and surrounding areas in Thailand, Vietnam, and Indonesia exhibited high risk of COVID-19 transmission between June and August. Indonesia successfully mitigated the risk of COVID-19 with the assistance of continuous restrictions, while a number of regions in Malaysia, Singapore, Thailand, and Philippines saw an increase of infection risk which is aligned with their loosened restrictions. Continuous strict interventions were effective to mitigate COVID-19, while relaxing restrictions may exacerbate the propagation risk of this epidemic. CONCLUSIONS The analyses of space-time clusters and relative risks of districts benefit public health authorities with continuous surveillance of the COVID-19 dynamics using real-time data. International coordination with more synchronized interventions amidst all SEA countries may play a key role in mitigating the progression of COVID-19.

Simple Summary MicroRNAs are small molecules that can regulate the relative abundance of their target genes by binding to the 3′ untranslated region of the target genes at the post-transcriptional level to affect various biological processes, such as biosynthesis, fat metabolism and proliferation, apoptosis, and cell differentiation. Fertility is one of the most important economic traits in livestock production. Bulls require the continuous production of high-quality spermatozoa in abundance. The quality of semen is an exceptionally important factor affecting the fertilization rate of the dairy cow and is also associated with the increasing conception rate in the process of artificial insemination. Therefore, accurately predicting fertility potential for a semen sample from donor bull for artificial insemination is crucial for consistently high reproductive efficiency. The present study performed a genome-wide sequencing analysis of microRNAs and mRNAs between immature and mature testes of Chinese Red Steppes. These results provide novel candidate microRNAs and functional genes related to bull reproduction traits and the networks between microRNAs and target genes, which will provide a useful genetic mechanism and epigenetic information for marker-assisted selection of bulls with excellent sperm quality in the future. Abstract This study aims to screen potential regulators and regulate fecundity networks between microRNAs (miRNAs) and target genes. The bovine testes of immature and mature Chinese Red Steppes were performed by genome-wide analysis of mRNAs and miRNAs. Compared with testicular tissues of newborns, 6051 upregulated genes and 7104 downregulated genes in adult cattle were identified as differentially expressed genes (DEGs). The DEGs were significantly enriched in 808 GO terms (p < 0.05) including male gonad development, male genitalia development, spermatogenesis, and sperm motility. Moreover, DEGs were also significantly enriched in 105 KEGG pathways (p < 0.05), including cGMP-PKG signaling pathway and calcium signaling pathway. To explore the expression of miRNA-regulated gene expression, 896 differentially expressed target genes negatively regulated with the expression levels of 31 differentially expressed miRNAs (DERs) were predicted and analyzed, and a network-integrated analysis was constructed. Furthermore, real-time PCR was performed to verify the expression levels of DEGs and DERs. Our results identified novel candidate DEGs and DERs correlated with male reproduction and intricate regulating networks between miRNAs and genes, which will be valuable for future genetic and epigenetic studies of sperm development and maturity, as well as providing valuable insights into the molecular mechanisms of male fertility and spermatogenesis in cattle.

BackgroundNormalising tumour vessels had become a significant research focus in tumour treatment research in recent years. Curcumae rhizoma (CR) is an essential plant in traditional Chinese medicine as it promotes blood circulation and removes blood stasis. Similarly, CR improves local blood circulation.PurposeWe explored the anti-colon cancer effects of essential oil from CR (OCR) by investigating its role in normalising tumour vessels. We also provided a basis for research and development into new anti-cancer drugs.MethodsWe used colon cancer as a research focus to investigate OCR. We established an in vitro co-culture model of colon cancer cells and human umbilical vein endothelial cells (HUVEC). We also established an in vivo subcutaneous implant colon cancer model in nude mice. These studies allowed us to evaluate the comprehensive effects of OCR in in vivo and in vitro colon cancer and its role in normalising tumour blood vessels.ResultsIn vitro, we found that OCR inhibited Human colon cancer cells (HCT116) and HUVEC cell proliferation and inhibited vascular endothelial growth factor-a (VEGFa) mRNA and protein expression in HUVECs in a co-culture system. Our in vivo studies showed that OCR inhibited colon cancer tumour growth, reduced angiogenesis in tumours and increased vascular endothelial (VE)-cadherin and pericyte coverage in tumour vessels.ConclusionsOCR inhibited colon cancer growth both in in vivo and in vitro models, reduced angiogenesis in tumours, improved tumour vessel structures and normalised tumour vessels.

Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cytosolic enzyme that mainly catalyzes the oxidation of acetaldehyde into acetic acid and participates in the regulation of differentiation and gene expression in fat cell growth and development. However, the physiological role of ALDH1A1 in the formation of fat cell precursors in the Yan Yellow Cattle is still not clear. Herein, we investigated the specific regulation of the gene encoding for ALDH1A1 during the differentiation process of the adipocyte cells of the Yan Yellow Cattle by interfering or overexpressing the ALDH1A1 gene. As a result, we found that the mRNA expression levels of ALDH1A1 were significantly increased during the formation of progenitor cells. In addition, the expression levels of the Lipoprotein lipase (LPL) and transcription factors (PPARγ, C/EBPα) were also significantly increased. ALDH1A1 gene overexpression and RNA interfering promoted and inhibited respectively the lipid accumulation and triglyceride production in mature adipocytes, and the expression of the LPL and transcription factors (PPARγ, C/EBPα). The changes in the protein expression levels of ALDH1A1 and adipogenic factors were in accord with the changes observed in the mRNA levels. In conclusion, our results indicate that ALDH1A1 plays an important regulatory role in the differentiation of preadipocyte cells.

The insulin-like growth factor binding-protein 7 (IGFBP7) has binding affinities to IGFs and is able to either positively or negatively regulate the IGFs signaling pathway. It also plays a crucial role in cell growth, differentiation and development in an IGF-independent manner. Herein, we investigated the specific regulation of the gene encoding for IGFBP7during the differentiation process of the adipocyte cells of the Yan Yellow Cattle by interfering with or by overexpressing the IGFBP7 gene. As a result, we found that the mRNA expression levels of IGFBP7 were significantly increased during the formation of progenitor cells. In addition, the expression levels of the lipoprotein lipase (LPL) and transcription factors (PPARγ, C/EBPα) were also significantly increased. IGFBP7 gene overexpression and RNA interfering promoted and inhibited respectively the lipid accumulation and triglyceride production in mature adipocytes, and the expression of the LPL and transcription factors (PPARγ, C/EBPα). The changes in the protein expression levels of IGFBP7 and adipogenic factors were in accord with the changes observed in the mRNA levels. In conclusion, our results indicate that IGFBP7 plays an important regulatory role in the differentiation of preadipocyte cells.

Recently, we introduced an epoxy group to mebendazole by a reaction with epichlorohydrin and obtained two isoforms, mebendazole C1 (M-C1) and mebendazole C2 (M-C2). The in vitro effects of mebendazole derivatives at different concentrations on Echinococcus multilocularis protoscoleces and metacestodes as well as cytotoxicity in rat hepatoma (RH) cells were examined. The results demonstrated that the solubility of the two derivatives was greatly improved compared to mebendazole. The mortality of protoscoleces in vitro reached to 70–80% after 7 days of exposure to mebendazole or M-C2, and M-C2 showed higher parasiticidal effects than mebendazole (P > 0.05). The parasiticidal effect of M-C1 was low, even at a concentration of 30 µm. The percentage of damaged metacestodes that were treated with mebendazole and M-C2 in vitro at different concentrations were similar, and M-C1 exhibited insignificant effects on metacestodes. Significant morphological changes on protoscoleces and metacestodes were observed after treatment with mebendazole and M-C2. In addition, the introduction of an epoxy group to mebendazole also reduced its cytotoxicity in RH cells. Our results demonstrate that the introduction of an epoxy group not only improved the solubility of mebendazole, but also increased its parasiticidal effects on E. multilocularis and reduced its cytotoxicity in RH cells.

According to conservative estimates, >230 million people are infected with schistosomiasis,which becomes one of the most common parasitic diseases. This study focuses on investigating in vivo and in vitro effects of mmu-miR-92a-2-5p in Schistosoma japonicum-induced liver fibrosis by targeting TLR2. Through bioinformatic analysis, the overexpression of TLR2 and the down-regulation of mmu-miR-92a-2-5p were revealed in the progression of S. japonicum-induced liver fibrosis. BALB/C mice were taken advantage to construct normal control and schistosomiasis liver fibrosis (SLF) model. The mice in model groups were transfected recombinant lentivirus (Lenti-mmu-miR-92a-2-5p or Lenti-NC) to alter the expression of mmu-miR-92a-2-5p in vivo. HE and Masson staining were employed to observe the pathological changes and collagenous fibrosis. QRT-PCR showed that mmu-miR-92a-2-5p was decreased while TLR2 was elevated in the infected groups. However, lenti-mmu-miR-92a-2-5p group could inhibit liver fibrosis. Then the effect of mmu-miR-92a-2-5p on S. japonicum-induced liver fibrosis including cell apoptosis rates, proliferation and proteins related to liver fibrosis was examined in NIH-3T3 mouse embryonic fibroblasts. Moreover, the association between mmu-miR-92a-2-5p and TLR2 was detected by dual-luciferase reporter gene assay and the expression of cytokines IL-4, IFN-γ and TNF-α in SLF model was detected by ELISA. Further, the knockout of TLR2 in C57BL/6J mice was used to confirm the association between mmu-miR-92a-2-5p and TLR2. Thus, these findings demonstrated that mmu-miR-92a-2-5p inhibited S. japonicum-induced liver fibrosis by targeting TLR2 in vitro and in vivo.

BackgroundSevere deep neck space infection is rare and critical.The objective is to deepen the understanding of severe deep neck space infection and improve the level of clinical diagnosis and treatment. Case presentationA retrospective analysis of the diagnosis and treatment of 5 cases of serious deep neck infections admitted to our department. The 5 patients were all diagnosed by cervical CT and surgical exploration. 3 patients with diabetes, 2 patients with diabetic ketoacidosis, 3 patients with mediastinal infection; 3 patients underwent tracheotomy and 2 patients with tracheal intubation; All patients were treated by neck incision, drainage, dressing change and targeted antibiotics. Conclusions Severe deep neck infections are prone to occur in patients with diabetes and other systemic basic diseases. Early diagnosis, timely neck incision exploration, drainage to maintain airway patency and targeted antibiotic treatment are the keys to diagnosis and treatment.

Background Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)‐β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF‐targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC). Methods This is a multicenter, open‐label, phase 1b study of galunisertib, an inhibitor of TGF‐β receptor 1, and ramucirumab, an anti‐VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha‐fetoprotein and TGF‐β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1–14 of a 28‐day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks. Results Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose‐limiting toxicities were observed. Treatment‐related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment‐related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose‐proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively. Conclusion Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF‐targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab., The combination of galunisertib (up to 150 mg twice as day) and ramucirumab 8 mg/kg intravenously every 2 weeks (standard dose) was safe and tolerable and displayed favorable pharmacokinetics in patients with advanced hepatocellular carcinoma. The results do not support the preclinical hypothesis that blocking transforming growth factor‐beta signaling enhances efficacy of VEGF‐targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.

Alternative splicing is a ubiquitous regulatory mechanism in gene expression that allows a single gene generating multiple messenger RNAs (mRNAs). Significant differences in fat deposition ability and meat quality traits have been reported between Japanese black cattle (Wagyu) and Chinese Red Steppes, which presented a unique model for analyzing the effects of transcriptional level on marbling fat in livestock. In previous studies, the differentially expressed genes (DGEs) in longissimus dorsi muscle (LDM) samples between Wagyu and other breeds of beef cattle have been reported. In this study, we further investigated the differences in alternative splicing in LDM between Wagyu and Chinese Red Steppes cattle. We identified several alternative splicing types including cassette exon, mutually exclusive exons, alternative 5′ splice site, alternative 3′ splice site, alternative start exon, and intron retention. In total, 115 differentially expressed alternatively spliced genes were obtained, of which 17 genes were enriched in the metabolic pathway. Among the 17 genes, 5 genes, including MCAT, CPT1B, HADHB, SIRT2, and DGAT1, appeared to be the novel spliced candidates that affect the lipid metabolism in cattle. Additionally, another 17 genes were enriched in the Gene Ontology (GO) terms related to muscle development, such as NR4A1, UQCC2, YBX3/CSDA, ITGA7, etc. Overall, altered splicing and expression levels of these novel candidates between Japanese black cattle and Chinese Red Steppes revealed by RNA-seq suggest their potential involvement in the muscle development and fat deposition of beef cattle.

BackgroundWe assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.MethodsThis was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1–14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase.ResultsThe galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes.ConclusionGalunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.Trial registration numberClinicalTrials.gov identifier: NCT02734160.

Ambient noise generated by the anthropological activities in the urban environments may contain both Rayleigh and Love waves. Due to the differences in the physics of Rayleigh and Love waves, a pre-knowledge of the wave modes in the cross-correlogram is essential for an accurate inversion of the subsurface velocity model. Several studies (Martin and Biondi, 2017; Martin et al., 2017; Luo et al., 2020) demonstrated that only Rayleigh waves can be extracted by cross-correlation if the virtual source is colinear with the DAS array based on the assumption that the ambient noise sources are random and uniformly distributed. However, in realistic cases, ambient noise sources may come from a certain direction (e.g., Dou et al., 2017; Zhang et al., 2019). Moreover, the source propagation direction should be resolved and used to correct the apparent dispersion curves. Zhao et al. (2020) and van den Ende et al. (2020) proposed that beamforming results are not always reliable due to the measurements of DAS.Based on the synthetic DAS ambient noise data recorded by a near “L” shape array (Source-West corner of the Stanford DAS-1 array), we prove that beamforming can resolve the source direction when the ambient sources are mainly coming from one direction. Two important processing procedures are that: check the polarity in the data and apply polarity flip on one part of the data; apply amplitude normalization on the data if strong amplitude difference exits in the data. Based on the source direction, the coordinate of the DAS array, and amplitude ratio of the data recorded by the two segments of the DAS array, we propose an inversion method to calculate the amplitude ratio of the Rayleigh and Love waves generated by the ambient sources.We apply the method to two 100-second DAS ambient noise data recorded by the Stanford DAS-1 array. We first resolve the source propagation direction from the two data. The results indicate that the ambient noise in the data were mainly generated by the motor vehicles running on the Campus Drive in the northwest of the array. Then we invert for the Rayleigh and Love waves amplitude ratio using the proposed method. The ratios for the two data are 0.2 and 0.13, respectively. The results suggest that the ambient noise generated by motor vehicles running on the northwest corner of the Campus Drive mainly contain Love waves.

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. Patients and Methods: Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. Results: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. Conclusions: LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.

e21157 Background: In ORIENT-11, first-line (1L) SPP improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) compared with placebo plus pemetrexed-platinum (PPP) in pts with AMnsqNSCLC. We report outcomes from ORIENT-11 (NCT03607539) for pts treated with SPP with stage III (b & c) compared with stage IV disease. Methods: Pts with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR/ALK alterations were randomly assigned to SPP (n = 266) or PPP (n = 131), stratified by PD-L1 expression, platinum-chemotherapy and sex. Primary endpoint was PFS (RECIST v1.1). Secondary endpoints included OS, ORR, DoR and safety. Kaplan-Meier method was used to analyze median PFS, OS and DoR. Stratified Cox model was used to analyze the hazard ratio (HR) of SPP vs. PPP. Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of ORR for each group. Miettinen-Nurminen method was used to analyze 95% CI of ORR difference between SPP and PPP. Data cutoff for OS data was September 15, 2021, providing a median follow-up of 30.8 months. Cutoff for other data was November 15, 2019, providing a median follow-up of 8.9 months. Results: 21 pts (7.9%) receiving SPP had stage III disease and 245 pts (92.1%) had stage IV disease. Baseline sex, age and PD-L1 expression ≥1% were similar between subgroups (Table). There were differences between subgroups in number of pts receiving carboplatin and ECOG performance status at baseline. PFS, OS, ORR and DoR outcomes were comparable between pts with stage III and stage IV disease based on the ad-hoc analyses. Any-grade adverse events (AEs) (100.0% vs. 99.6%) and AEs of Grade ≥3 (57.1% vs. 62.0%) were similar in pts with stage III and stage IV disease. Conclusions: In ORIENT-11, outcomes for pts receiving SPP as 1L therapy in AMnsqNSCLC with stage III and stage IV disease were comparable. Clinical trial information: NCT03607539. [Table: see text]

Cryogenic milling was demonstrated as a new and facile method to fabricate nanostructured battery electrode materials. SnSb anode material with 1.2 wt% graphite was selected as a model system to demonstrate the feasibility and benefits of this method. Ball milling at a cryogenic temperature can suppress cold welding, exfoliate bulk graphite powder into nanoplatelets, and evenly disperse them between the grains. Aberration-corrected scanning transmission electron microscopy and post-cycling scanning electron microscopy showed refined grain sizes and well-dispersed carbon nanoplatelets, which can stabilize the nanostructure and alleviate volume expansion and cracking upon cycling. The cryomilled SnSb-C composite anode showed a reversible volumetric capacity of 1842 Ah/L, average coulombic efficiency of 99.6 ± 0.3%, and capacity retention of 90% over 100 cycles. The cryomilled sample showed improved electrochemical performance compared to the conventional ball milled specimen. This new method of cryogenic milling can produce various other high-performance nanostructured electrode materials.

Urban activities cause minute vibrations of the earth surface that can be detected by highly sensitive seismometers. In the island city-state Singapore, human activities have been dramatically changed since April 2020 by government measures to suppress the spread of COVID-19. By analyzing the high- frequency seismic signals, the impact of the pandemic and its corresponding mitigation measures were quantified as traffic flow at the exit of the National University of Singapore (NUS) and at the intersection between Pasir Panjang Port Terminal and West Coast Park, representing activities at nonessential workplaces, essential workplaces, and recreational areas. The anonymity of seismic data enabled an unprecedented spatial and temporal resolution that is pivotal to understand the heterogeneity and evolution of pandemic responses in different sectors of an urban society. The rich information extracted from seismic data provide an opportunity for real time activity monitoring and dynamic policy making in order to ensure a successful pandemic mitigation and a less disturbed urban lifestyle.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). Patients and Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N = 15) or combined with ramucirumab (N = 10), abemaciclib (N = 24), or merestinib (N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.

Background: Traditional Chinese medicine (TCM) often uses Rhizoma Curcumae and Rhizoma Sparganii (RCRS) ，the natural herbs for the treatment of UL. RCRS has been shown to be effective in the treatment of UL in our previous study. This study was to investigate the molecular mechanism by which RCRS inhibits fibroblast activation protein (FAP) activation and prevents uterine leiomyoma in rats. Methods: The SD rat model of uterine leiomyoma was established by estrogen and progesterone load combined with external stimulation. Subsequently, histological analyses, enzyme-Linked immunosorbent assays, western blotting were performed to evaluate the effect of the drug on uterine leiomyoma and its mechanism. Results: Our data showed that treatment of rats with RCRS significantly reduced the expression of FAP, TGF-β (the FAP activating factor), and significantly decreased the phosphorylation of cell proliferation pathway-related signaling factors AKT/MEK/ERK, as well as the expression of the extracellular matrix component collagen. Conclusions: Our results showed that RCRS is very effective in prevention and treatment of uterine leiomyoma in rats, and RCRS may exert its actions by inhibiting the activation of tumor-associated fibroblasts, inhibiting the cell proliferation, and improving tumor extracellular matrix.

Urban subsurface monitoring requires high temporal-spatial resolution, low maintenance cost, and minimal intrusion to nearby life. Distributed acoustic sensing (DAS), in contrast to conventional station-based sensing technology, has the potential to provide a passive seismic solution to urban monitoring requirements. Based on data recorded by the Stanford Fiber Optic Seismic Observatory, we demonstrate that near-surface velocity changes induced by the excavation of a basement construction can be monitored using existing fiber optic infrastructure in a noisy urban environment. To achieve the satisfactory results, careful signal processing comprising of noise removal and source signature normalization are applied to raw DAS recordings. Repeated blast signals from quarry sites provide free, unidirectional, and near-impulsive sources for periodic urban seismic monitoring, which are essential for increasing the temporal resolution of passive seismic methods. Our study suggests that DAS will likely play an important role in urban subsurface monitoring.

OBJECTIVES In our research, we aimed to investigate the roles of CC-chemokine receptor 7 (CCR7) and relevant signaling pathways in Leishmania major-infected human dendritic cells (DCs). METHODS Differentially expressed genes (DEGs) in L. major-infected human DCs were selected out and visualized using R program. Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted for investigation of significantly enriched signaling pathways and Gene Ontology enrichment analysis was carried out for the unveiling of enriched Molecular Functions and Biological Processes in L. major-infected human DCs. Besides, Hub gene was screened out using weighted gene coexpression network analysis and Cytoscape. In addition, enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction were used for detection of relative expression of CCR7, interleukin-12 (IL-12), and interferon-γ (IFN-γ) in L. major-infected human DCs and western blot analysis was used for detection of relative expression of CCR7 and other proteins in JAK-STAT signaling pathway in L. major-infected human DCs. RESULTS CCR7 was upregulated and both chemokine and JAK-STAT signaling pathway were activated in L. major-infected human DCs. During the L. major infection, total number of L. major-infected human DCs were increased, as well as the relative expression levels of CCR7, IL-12, and IFN-γ and proteins in the JAK-STAT signaling pathway. Overexpression of CCR7 not only increased expression levels of IL-12 and IFN-γ but also activated the JAK-STAT signaling pathway to affect the leishmaniasis progression. CONCLUSION L. major infection-induced activation of CCR7, as well as JAK2 and STAT1, might well upregulate the expression of BAX yet suppress the expression of both Bcl2 and c-Jun to affect leishmaniasis progression.

Cyclic AMP response element-binding protein 1 (CREB1), a member of the CREB family, is known to be involved in follicular growth, ovulation, and ovarian disease. However, the physiological function of CREB1 in mouse granulosa cells (mGCs) remains lagerly unknown. The aim of this study was to determine the role of CREB1 in mGCs by knocking down CREB1 expression. CREB1 knock-down in mGCs at the mRNA and protein levels, was confirmed by quantitative real-time polymerase chain reaction and western blot. Results of enzyme linked immunosorbent assay revealed that CREB1 knockdown significantly decreased the concentrations of estradiol (E2) and progesterone (P4) in mGCs. Furthermore, the CREB1 knockdown in mGCs promoted cell proliferation and apoptosis, and arrested the cell cycle in S-phase. To elucidate the regulatory mechanism underlying the effects of CREB1 knockdown on steroid synthesis, cell cycle, and apoptosis, we measured the protein expression levels of several related genes in mGCs knocked down CREB1. When CREB1 was knocked down, the expression of Cyp1b1 and Cyp19a1, which encode steroidogenic enzymes, was down-regulated; the expression of the cell cycle factors CyclinA1, CyclinB1, and CyclinD2 were significantly decreased. Among apoptosis-related genes, Bcl-2 was down-regulated, whereas Bax and cleaved Caspase3 were upregulated. Moreover, CREB1 knockdown significantly decreased expression level of Has2, Ptgs2, and Igfbp4, which are essential genes for folliculogenesis in mGCs. Taken together, these findings suggested that CREB1 might be a key regulator of mGCs through regulating steroid synthesis, cell proliferation, cell cycle, apoptosis, and other regulators of folliculogenesis.

Flexible computational domains and their corresponding irregular absorbing boundary conditions (ABCs) have previously been shown to improve the efficiency of finite difference (FD) modelling. However, these proposed ABCs for irregular boundaries are based on irregular grid methods. Although they can improve geometric flexibility of FD modelling, irregular grid methods are still complex to implement due to computationally expensive meshing process. To avoid complex mesh generation, FDs in mesh-free discretisation have been developed for nontrivial geometric settings, where scattered nodes can be placed suitably with respect to irregular boundaries and arbitrarily shaped anomalies without coordinate mapping or mesh-element forming. Radial-basis-function-generated FD (RBF-FD) has been proven successful in modelling seismic wave propagation based on mesh-free discretisation. Using RBF-FD, we develop a hybrid ABC for piecewise smooth curved boundary in 2D acoustic wave modelling based on straightforward expanding strategies for sampled boundary and corner nodes. The whole irregular computational domain is combined by an objective zone and a transition zone separated by piecewise smooth curved boundary. Nodal distribution in the objective zone is adaptive to the model structure through special alignment and varying density of nodes, while the transition zone are designed for solving one way wave equation more easily and accurately in the presence of piecewise smooth curved boundary. Modelling examples for homogenous and heterogeneous models with differently shaped computational domains demonstrate the effectiveness of our proposed method.

Negative damping of prime movers is a major cause of sustained frequency oscillations in power systems. Increasing the damping torque of prime movers by adjusting governor parameters is an effective measure to prevent frequency oscillations. The oscillation frequency is volatile and turbine parameters change under loading conditions. To guarantee robustness and adaptability, the governor parameters should be adjusted to ensure sufficient damping torque over the entire range of oscillation frequency and under different turbine parameters. An optimization model of governor parameters is proposed. A constraint of the model is that the damping torque of the prime mover over the entire oscillation frequency range, and under different turbine parameters, must be greater than the threshold. The composite dynamic performance of primary frequency regulation under different loading conditions is the optimization objective. Test results validate the proposed method. The stability of the frequency oscillation mode under different conditions can be guaranteed.

This study aimed to evaluate the effects of feeding frequency on growth, antioxidant status, immune response and resistance to hypoxia stress challenge on juvenile dolly varden char Salvelinus malma (average weight: 9.40 ± 0.30 g). Fish were randomly assigned to one of six feeding frequencies (1, 2, 3, 4, 5 and 6 times/day) following the same ration size for 8 weeks. Weight gain increased significantly as feeding frequency increased from 1 to 5 times/day, but decreased with further increasing feeding frequency. Feed intake, whole body crude lipid content, serum aspartate transaminase, alanine transaminase and malondialdehyde content increased significantly as feeding frequency increased. Serum total antioxidant capacity increased significantly as feeding frequency increased from 1 to 5 times/day. Hepatosomatic index, serum lysozyme activity and 50% haemolytic complement content of fish fed 1–2 times/day were lower than those of fish fed 3–6 times/day. During the hypoxia challenge, cumulative mortality increased significantly as feeding frequency or hypoxia time increased. This study indicates that lower and higher feeding frequencies had a negative influence on growth of dolly varden char; the optimal feeding frequency to enhance growth and boost immunity of this species at juvenile stage is 4 times/day.

Conventional time-space domain and frequency-space domain prediction filtering methods assume that seismic data consists of two parts, signal and random noise. That is, the so-called additive noise model. However, when estimating random noise, it is assumed that random noise can be predicted from the seismic data by convolving with a prediction error filter. That is, the source-noise model. Model inconsistencies, before and after denoising, compromise the noise attenuation and signal-preservation performances of prediction filtering methods. Therefore, this study presents an inversion-based time-space domain random noise attenuation method to overcome the model inconsistencies. In this method, a prediction error filter (PEF), is first estimated from seismic data; the filter characterizes the predictability of the seismic data and adaptively describes the seismic data’s space structure. After calculating PEF, it can be applied as a regularized constraint in the inversion process for seismic signal from noisy data. Unlike conventional random noise attenuation methods, the proposed method solves a seismic data inversion problem using regularization constraint; this overcomes the model inconsistency of the prediction filtering method. The proposed method was tested on both synthetic and real seismic data, and results from the prediction filtering method and the proposed method are compared. The testing demonstrated that the proposed method suppresses noise effectively and provides better signal-preservation performance.

The study aimed to explore the regulation of heat shock protein 47 (HSP47) on expressions of receptors associated with hepatic stellate cell (HSC) in liver fibrosis mouse models induced bySchistosoma japonicum(S. japonicum). Mouse fibroblasts (NIH/3T3) were transfected with HSP47 shRNA plasmid by lipofectamine transfection, and experimental fibrosis in HSCs was studied inS. japonicummouse models treated with HSP47 shRNAin vivo. HSP47 expression was assessed using Western blot and real-time PCR. Flow cytometry was adopted to determine the expression of cell membrane receptors. HSP47-shRNA could markedly down-regulate the expression of collagen (Col1a1 and Col3a1). The expressions of HSP47, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) significantly increased in the liver tissue of infected mice. However, the expressions of ETAR and HSP47 and ETBR remarkably decreased after the administration of HSP47 shRNAin vitroandin vivo. ETAR and ETBR levels were found to be positively correlated with HSP47 expression. HSP47 might exert influence on liver fibrosis via the regulation of ETAR and ETBR.

Urban subsurface monitoring requires high temporal-spatial resolution, low maintenance cost, and minimal intrusion to nearby life. Distributed acoustic sensing (DAS), in contrast to conventional station-based sensing technology, has the potential to provide a passive seismic solution to urban monitoring requirements. Based on data recorded by the Stanford Fiber Optic Seismic Observatory, we demonstrate that near-surface velocity changes induced by the excavation of a basement construction can be monitored using existing fiber optic infrastructure in a noisy urban environment. To achieve the satisfactory results, careful signal processing comprising of noise removal and source signature normalization are applied to raw DAS recordings. Repeated blast signals from quarry sites provide free, unidirectional, and near-impulsive sources for periodic urban seismic monitoring, which are essential for increasing the temporal resolution of passive seismic methods. Our study suggests that DAS will likely play an important role in urban subsurface monitoring.