Search

OBJECTIVE Basal insulin Fc (BIF) (insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed the safety and efficacy of BIF versus degludec in insulin-naive patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS During this randomized, parallel, open-label study, 278 insulin-naive patients with T2D were randomly assigned (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80–100 mg/dL (4.4 to RESULTS After 26 weeks of treatment, BIF demonstrated a noninferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% CI −0.11, 0.24; P = 0.56). Both BIF and degludec treatment led to significant reductions in FBG from baseline. At week 26, the between-treatment difference for BIF versus degludec was 4.7 mg/dL (90% CI 0.1, 9.3; P = 0.09). The rate of level 2 hypoglycemia was low and not significantly different between treatment groups (BIF 0.22 events/patient/year, degludec 0.15 events/patient/year; P = 0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. CONCLUSIONS Once-weekly BIF achieved excellent glycemic control similar to degludec, with no concerning hypoglycemia or other safety findings.

OBJECTIVE Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once-weekly basal insulin administration. This phase 2 study assessed safety and efficacy of BIF versus degludec in 265 patients with type 1 diabetes (T1D) using multiple daily injections. RESEARCH DESIGN AND METHODS During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to a fasting glucose level of 80–100 mg/dL. The primary end point was HbA1c change from baseline to week 26 (noninferiority margin, 0.4%). Secondary end points included percent time in range (TIR) (70–180 mg/dL), continuous glucose monitoring (CGM) fasting glucose (FG) level, and rate of hypoglycemia. RESULTS After 26 weeks, patients receiving BIF had noninferior HbA1c change from baseline versus those receiving degludec, with a statistically significant treatment difference of 0.17% (90% CI 0.01, 0.32; P = 0.07) favoring the comparator. Percent TIR was similar for patients in the BIF (56.1%) and degludec (58.9%; P = 0.112) groups at week 26. FG values were significantly higher for patients receiving BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; P = 0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 h for level 1 (P = 0.960) or level 2 (P = 0.517) hypoglycemia during the treatment period. Occurrence of serious adverse events was similar between the BIF and degludec groups. CONCLUSIONS Once-weekly BIF demonstrated noninferior glycemic control to once-daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

Objective Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once weekly basal insulin administration. This Phase 2 study assessed safety and efficacy of BIF versus degludec in insulin-naïve patients with type 2 diabetes (T2D) previously treated with oral antihyperglycemic medications. Research Design and Methods During this randomized, parallel, open-label study, 278 insulin-naïve patients with T2D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose of 80-100 mg/dL (4.4 to Results After 26 weeks of treatment, BIF demonstrated non-inferior HbA1c change from baseline versus degludec with a treatment difference of 0.06% (90% CI= -0.11, 0.24; p=0.56).. Both BIF and degludec treatment led to significant reductions in FBG from baseline; at Week 26 the between treatment difference for BIF versus degludec was 4.7 mg/dL [90% CI=0.1, 9.3]; p=0.09). The rate of Level 2 hypoglycemia was low and not significantly different between treatment groups (BIF=0.22; degludec=0.15 events/pt/yr; p=0.64); there was no severe hypoglycemia. The occurrence of treatment-emergent adverse events was also similar between BIF and degludec. Conclusions Once weekly BIF achieved excellent glycemic control similar to degludec with no concerning hypoglycemia or other safety findings.

Objective Basal Insulin Fc (BIF; insulin efsitora alfa; LY3209590), a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for once weekly basal insulin administration. This Phase 2 study assessed safety and efficacy of BIF versus degludec in N=265 patients with type 1 diabetes (T1D) using multiple daily injections. Research Design and Methods During this randomized, parallel, open-label study, patients with T1D were randomized (1:1) to receive BIF once weekly or degludec once daily over the 26-week treatment period. Both groups were titrated to fasting glucose 80-100 mg/dL. Primary endpoint was HbA1c change from baseline to Week 26 (non-inferiority margin=0.4%). Secondary endpoints included percent time in range (TIR, 70-180 mg/dL), CGM fasting glucose (FG), and rate of hypoglycemia. Results After 26 weeks, BIF demonstrated non-inferior HbA1c change from baseline versus degludec with a statistically significant treatment difference of 0.17% (90% CI=0.01, 0.32; p=0.07) favoring the comparator. Percent TIR was similar for BIF (56.1%) and degludec (58.9%; p=0.112) at Week 26. FG values were significantly higher for BIF (158.8 mg/dL) versus degludec (143.2 mg/dL; p=0.003). Rates of CGM-derived hypoglycemia were not statistically significantly different for BIF and degludec over 24 hours for Level 1 (p=0.960) or Level 2 (p=0.517) during the treatment period. Occurrence of serious adverse events was similar between BIF and degludec. Conclusions Once weekly BIF demonstrated non-inferior glycemic control to once daily degludec (treatment difference: 0.17% favoring degludec) and no difference in hypoglycemia or other safety findings in patients with T1D.

China, the largest country in Asia, has a land area of approximately 9.6 million square kilometres. There are 1481 bird species (following the taxonomy of IOC World Bird List version 12.1) recorded in two zoogeographical realms, seven regions and 19 subregions in the country. From 1955 to 2017, six authoritative monographs were published, which recorded the distribution area for all bird species in China and were widely quoted by research papers and field guides. This massive amount of data could be used to address many hot topics in ornithology, biogeography and ecology. However, rapid changes in the taxonomic status and different schemes of zoogeographical regionalisation in these six monographs provided limits to the utilisation of these valuable data. By integrating the data from the six monographs, we presented an open-access dataset on the occurrences and residence types of all Chinese bird species in zoogeographical regions over the past 60 years. The taxonomic statuses for these species were determined following the IOC World Bird List version 12.1 and the zoogeographical regions were based on the updated scheme. These data provide valuable information for the research in bird ecology and conservation biology.

Satellite-retrieved and model-based reanalysis precipitation products with high resolution have received increasing attention in recent decades. Their hydrological performance has been widely evaluated. However, whether they can be applied in characterizing the novel category of extreme events, such as compound moist heat-flood (CMHF) events, has not been fully investigated to date. The CMHF refers to the rapid transition from moist heat stress to devastating floods and has occurred increasingly frequently under the current warming climate. This study focuses on the applicability of the Integrated Multi-satellite Retrievals for Global Precipitation Measurement (IMERG) and the fifth generation of European Reanalysis (ERA5-Land) in simulating CMHF events over 120 catchments in China. Firstly, the precipitation accuracy of IMERG and ERA5-Land products is appraised for each catchment, using the gridded in situ meteorological dataset (CN05.1) as a baseline. Then, the ability of IMERG and ERA5-Land datasets in simulating the fraction, magnitude, and decade change of floods and CMHFs is comprehensively evaluated by forcing the XAJ and GR4J hydrological models. The results show that: (a) the IMERG and ERA5-Land perform similarly in terms of precipitation occurrences and intensity; (b) the IMERG yields discernably better performance than the ERA5-Land in streamflow simulation, with 71.7% and 50.8% of catchments showing the Kling–Gupta efficiency (KGE) higher than 0.5, respectively; (c) both datasets can roughly capture the frequency, magnitude, and their changes of floods and CMHFs in recent decades, with the IMERG exhibiting more satisfactory accuracy. Our results indicate that satellite remote sensing and atmospheric reanalysis precipitation can not only simulate individual hydrological extremes in most regions, but monitor compound events such as CMHF episodes, and especially, the IMERG satellite can yield better performance than the ERA5-Land reanalysis.

Bovine parainfluenza virus 3 (BPIV3) is one of several viruses that contribute to bovine respiratory disease complex (BRDC). During this study, isolation of BPIV3 was attempted from 20 PCR-positive swabs by Madin-Darby Bovine Kidney (MDBK) cells. Nine samples showed obvious cytopathic lesions identified as BPIV3 by reverse-transcription polymerase chain reaction amplification and sequencing. The genomes of isolates XJ21032-1 and XJ20055-3 were sequenced using Illumina sequencing technology and determined to have lengths of 15,512 bp and 15,479 bp, respectively. Phylogenetic analysis revealed that isolate XJ21032-1 was genotype B, and isolate XJ20055-3 was genotype C. In addition, the two isolates had multiple amino acid changes in nucleocapsid protein, fusion protein, and hemagglutinin/neuraminidase, major antigenic proteins. This allows the further recognition of the presence of BPIV3 type B in Chinese cattle herds. We hope this will help trace the origin of BPIV3, improve the understanding of differences between genotypes, and provide data support for vaccine development.

Biogas (methane) as a source of renewable energy, was produced in the anaerobic co-digestion of blackwater (BW, municipal toilet wastewater) and organic kitchen waste (KW). The impact on methane production of various BW to KW mixing ratios, with and without the addition of granular activated carbon (GAC), were studied under thermophilic (55 °C) temperatures. GAC is reported to enhance methane production in such digestions through direct interspecies electron transfer. The results showed that the co-digestion of BW and KW under the 1:2 VS ratio significantly improved the biomethane potential (BMP). In the absence of GAC, an optimal BW:KW ratio was found to be 1:2, achieving a BMP of 0.76 g CH4-COD/g feed-COD. With GAC addition, the BMP increased to 0.81 g CH4-COD/g feed-COD, the lag phase in the digestion was significantly reduced, and the methane production rate increased. Microbial communities in the BW-KW anaerobic digestion were analyzed with and without the addition of GAC. Methanothermobacter and Methanosarcina were predominant archaea in BW-KW digests, with and without GAC amendment, while a third methanogen, Methanomassiliicoccus, was enriched with the addition of GAC to the digest. Further, through SEM image, the enrichment of pili-like stucture was observed in GAC surface.

Objective We expanded the previous assessment of a mortality variable suited for real‐world evidence‐focused oncology research. Data source We used a nationwide electronic health record (EHR)‐derived de‐identified database. Data collection We included patients with at least 1 of 18 cancer types between January 1, 2011 and December 31, 2017. Patient‐level structured data (EHRs, obituaries, and Social Security Death Index) and unstructured EHR data (abstracted) were linked to generate a composite mortality variable. Study design We benchmarked sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and ±15‐day agreement against the National Death Index (NDI). Real‐world overall survival (rwOS) was estimated using the Kaplan‐Meier method. We performed sensitivity analyses using a smaller patient cohort that underwent next‐generation sequencing testing. Principal findings Compared with the NDI across 18 cancer types (overall N = 160 436): sensitivity, 83.9%‐91.5% (17/18 cancer types had sensitivity ≥85.0%); specificity, 93.5%‐99.7%; PPV, 96.3%‐98.3%; NPV, 75.0%‐98.7%; ±15‐day agreement, 95.6%‐97.6%; and median rwOS estimates ranging from 2.8% to 12.7% greater. Sensitivity analysis results (n = 17 540) were consistent with the main analysis. Conclusions Across all cancer types analyzed, this composite mortality variable showed high sensitivity, specificity, PPV, NPV, and ±15‐day agreement, and yielded median rwOS values modestly overestimated when compared to NDI‐based results.

Circular RNAs (circRNAs) are emerging as novel regulators in the biological development of various diseases, but their expression profiles, functions and mechanisms in silicosis and pulmonary fibrosis remain largely unexplored. In this study, we constructed a mouse model of pulmonary fibrosis by intratracheal injection of silica particles and then performed transcriptome RNA sequencing of lung tissues. The results showed that 78 circRNAs, 39 miRNAs and 262 mRNAs were differentially expressed. Among them, five circRNAs, three miRNAs and four mRNAs were further selected, and their abnormal expression was verified in mouse fibrotic lung tissues by RT-qPCR assay. The circRNA-associated ceRNA network including 206 ceRNA triplets was constructed based on abnormally expressed circRNAs, miRNAs and mRNAs, and miR-199b-5p, miR-296-5p and miR-708-5p were identified as hub miRNAs connected to circRNAs and mRNAs. Subsequently, GO and KEGG pathway enrichment analyses were performed to detect the potential roles of differentially expressed mRNAs in pulmonary fibrosis, which were mainly involved in immune response, Th17 cell differentiation, NF-κB signaling pathway and PI3K-Akt signaling pathway. Furthermore, we identified that hsa_circ_0006916 was up-regulated in pulmonary fibrosis. To characterize the potential role of hsa_circ_0006916, we transfected siRNA targeting hsa_circ_0006916 into alveolar macrophages and found that knockdown of hsa_circ_0006916 significantly increased the expression levels of M1 molecules IL-1β and TNF-α and reduced the expression level of M2 molecule TGF-β1, indicating that hsa_circ_0006916 may play an important role in the activation of M1-M2 polarization effect in macrophages. Our results provided important evidence on the possible contribution of these abnormal circRNAs to the development of silicosis and pulmonary fibrosis.

Basal Insulin Fc (BIF; LY3209590) , a fusion protein combining a novel single-chain insulin variant with a human IgG Fc domain, is designed for QW administration. This randomized, parallel, open-label Ph2 study assessed safety and efficacy of BIF vs. DEG in insulin-naïve patients with T2D previously treated with oral antihyperglycemic medication. BIF was injected QW, and DEG was injected QD. Both groups were titrated to fasting blood glucose (FBG) ≤100 mg/dL. The primary endpoint was HbA1c change from baseline (CFBL) to Wk 26 (non-inferiority margin=0.4%) . Patients randomized to BIF (N=129) and DEG (N=135) had a mean age of 58.4 yrs and baseline HbA1c of 8.0%. After 26 wks, BIF showed non-inferiority vs. DEG for HbA1c CFBL with a treatment difference of 0.06% (90% CI = -0.11, 0.24; p = .56) , and both groups had >75% time in range (70-180 mg/dL) on average at Wk 26 (Figure) . BIF and DEG significantly reduced FBG from baseline (treatment difference BIF vs. DEG = 4.7 mg/dL [90% CI = 0.1, 9.3]; p = .09) . Rate of Level 2 hypoglycemia was low and not significantly different (BIF = 0.22; DEG = 0.15 events/pt/yr; p = 0.64) . Occurrence of treatment-emergent adverse events was similar between BIF and DEG. QW BIF achieved excellent glycemic control similar to DEG with no concerning hypoglycemia or other safety findings, supporting continued development of BIF in Ph3. Disclosure J.M. Bue-Valleskey: None. C.M. Kazda: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Ma: None. J. Chien: Employee; Eli Lilly and Company. Q. Zhang: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. E. Chigutsa: Employee; Eli Lilly and Company. W. Landschulz: Employee; Eli Lilly and Company. J. Swan: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. J. Frias: Advisory Panel; Altimmune, Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi. Consultant; 89bio, Inc., Akero Therapeutics, Inc., Altimmune, Becton, Dickinson and Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk, Pfizer Inc., Sanofi. Research Support; Afimmune Limited, Akero Therapeutics, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Carmot Therapeutics, Inc., Eli Lilly and Company, Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Janssen Pharmaceuticals, Inc., Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi. Speaker's Bureau; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. Funding Funded by Eli Lilly and Company.

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

A graph-based particle filter bathymetric simultaneous localization and mapping (BSLAM) method is proposed to solve the oscillation problem of the trajectories estimated by particles when using a low precise vehicle motion model and obtain accurate navigation results for autonomous underwater vehicles (AUVs). A graph-based trajectory update method is proposed to update the trajectories stored in particles before particle weighting to weaken the influence of the low precise odometer model on the particle trajectories. A particle weighting method based on submap matching is proposed to improve the robustness of the particle filter. Besides, a graph-based map generation method is proposed to solve the map selection problem of the particle filtering theory. The performance of the proposed method is demonstrated using a simulated dataset and a field dataset collected from a sea trial. The results show that the proposed method is more accurate and effective compared with a state-of-art particle filter BSLAM method.

H9N2 avian influenza viruses are widely prevalent in birds and pose an increasing threat to humans because of their enhanced virulence and transmissibility in mammals. Active surveillance on the prevalence and evolution of H9N2 viruses in different avian hosts will help develop eradication measures. We isolated 16 H9N2 viruses from chickens, green peafowls, and wild birds in eastern China from 2017 to 2019 and characterized their comparative genetic evolution, receptor-binding specificity, antigenic diversity, replication, and transmission in chickens and mice. The phylogenetic analysis indicated that the green peafowl viruses and swan reassortant shared the same ancestor with the poultry H9N2 viruses prevalent in eastern China, while the seven wild bird viruses belonged to wild bird lineage. The chicken, peafowl, and swan H9N2 viruses that belonged to the poultry lineage preferentially recognized α-2, 6-linked sialic acids (human-like receptor), but the wild bird lineage viruses can bind both α-2, 3 (avian-like receptor) and human-like receptor similarly. Interestingly, the H9N2 viruses of poultry lineage replicated well and transmitted efficiently, but the viruses of wild bird lineage replicated and transmitted with low efficiency. Importantly, the H9N2 viruses of poultry lineage replicated in higher titer in mammal cells and mice than the viruses of wild birds lineage. Altogether, our study indicates that co-circulation of the H9N2 viruses in poultry, wild birds, and ornamental birds increased their cross-transmission risk in different birds because of their widespread dissemination.

An electroplex, the counterpart of an exciplex, mainly occurs in an electric field and has been attracting the attention of researchers to explore and study its properties and applications in electroluminescent devices. In this work, we designed an efficient way to control the electroplex emission using dendritic molecular engineering. Increasing the peripheral alkyl-chain carbazole groups can not only inhibit the formation of electromers effectively but can also regulate the distance between the donor and acceptor molecules. Thus, it provides an effective strategy to study the formation mechanism of exciplexes and electroplexes via dendritic molecular engineering. Remarkably, TCTA-O-CZ and TCTA-O-2CZ demonstrate different photophysical and electroluminescent properties when blended with PhPO. The TCTA-O-CZ:PhPO mixture exhibits a new photoluminescence (PL) emission peak at 450 nm and an electroluminescence (EL) emission peak at 480 nm, which correspond to the exciplex and electroplex emissions, respectively. However, TCTA-O-2CZ shows only the electroplex emission at 480 nm under electrical excitation, which indicates that the electroplex features a long-range charge-transfer process. In addition, the electromer emission peaks at long wavelengths are also suppressed to a large extent. Thus, the spatial regulation between the donor and acceptor molecules seriously influences the formation of the exciplex, electromer and electroplex. Finally, solution-processed blue phosphorescence OLEDs (PHOLEDs) were fabricated using TCTA-O-CZ:PhPO and TCTA-O-2CZ:PhPO as the host and FIrpic as the guest. These devices, based on the TCTA-O-CZ:PhPO host (Device D) and TCTA-O-2CZ:PhPO host (Device E), show good performances with turn-on voltages of 4.2 V and 5.1 V, and current efficiencies of 17.1 cd A−1 and 9.6 cd A−1, respectively. The lower efficiency roll-off of Device E based on the TCTA-O-2CZ:PhPO host indicates that efficient encapsulation via dendritic molecular engineering can suppress the electromer emission and energy leakage.

To obtain independent navigation results for autonomous underwater vehicles (AUVs) and construct high-resolution consistent seabed maps, a particle filter-based bathymetric simultaneous localization and mapping (BSLAM) method with the mean trajectory map representation is proposed. To reduce the computational consumption, particles only keep the current estimated position of the vehicle, while all historical states of the vehicle are stored in the mean trajectory map. Using this set-up, only the weights of the particles which closed to the mean trajectory map are calculated with newly collected bathymetric data. A hierarchical clustering procedure is also discussed to identify invalid loop closures. The performance of the proposed method is validated using both the simulated data and the field data collected from sea trails. The results demonstrate that the proposed method is 50% more accurate and 50% faster than a state-of-the-art particle filter-based BSLAM method, and it has similar accuracy but 30% faster compared with a graph-based BSLAM method.

Micro- and nanoscale photonic structures and devices play important roles in the development of advanced biophotonic systems, in particular, implantable light sources for optogenetic stimulations. In this paper, we numerically investigate silicon (Si) photonics based microprobes that can achieve multi-site, multi-spectral optical excitation in the deep animal brain. On Si substrates, silicon nitride (Si3N4) based planar waveguides can deliver visible light in the deep tissue with low losses, and couple to grating emitters diffracting light in targeted brain regions. In our model, we combine near-field wave optic and far-field ray tracing simulations, showing that the designed photonic structures spectrally split blue, green and red photons into different locations in the tissue. Furthermore, by introducing dual grating components, photons at different wavelengths can be spatially separated at different depths. Therefore, these photonic probes can be used to selectively activate or inhibit specific neurons and nuclei, when expressing various corresponding light sensitive opsins. We anticipate that such device strategies can find wide applications in the design of advanced implantable photonic systems for neuroscience and neuroengineering.

Objective: We developed an implantable wireless blue micro light-emitting diode (micro-LED) device and evaluated the utility of continuous antimicrobial blue light (aBL) irradiation emitted from th...

Ultra-rapid lispro (URLi) is a new prandial insulin lispro formulation. In the PRONTO-T2D study, URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior to lispro (HumalogPRONTO-T2D was a phase 3, 26-week, double-blind, treat-to-target study in people with type 2 diabetes. In this sub-group analysis, we compared URLi to lispro on the change from baseline in HbA1c and rate of level 2 hypoglycemia ( 54 mg/dl) in patients aged 65 (N = 406) and ≥ 65 years (N = 267).At baseline, patients 65 versus ≥ 65 years had mean age of 54.9 versus 69.2 years and duration of diabetes 14.6 versus 19.4 years. Mean HbA1c at screening and randomization was 8.35 and 7.34%, respectively, in patients 65 years, and 8.21 and 7.23%, respectively, in patients ≥ 65 years. At endpoint, mean HbA1c with URLi versus lispro was 6.92 versus 6.90%, respectively, in patients 65 years and 6.89 versus 6.79%, respectively, in patients ≥ 65 years. URLi significantly reduced 1- and 2-h PPG excursions with a standardized meal test in both age groups: between-treatment differences at 1-h postmeal for younger and older patients was - 9.8 and - 15.1 mg/dl, respectively; and at 2-h postmeal, - 18.7 and - 15.1 mg/dl, respectively, all p 0.05. Severe and nocturnal hypoglycemia were similar between groups. The relative rate (URLi/Humalog) of level 2 hypoglycemia was lower in older versus younger patients, with a significant treatment-by-age interaction observed. No differential treatment effects were noted for insulin dose, weight, and fasting and maximum glucose after the meal test.URLi, in a basal-bolus regimen, resulted in endpoint HbA1c 7% and significantly lower PPG excursions compared to lispro in both age groups, with reduced level 2 hypoglycemia in older versus younger patients.ClinicalTrials.gov, NCT03214380.

TRPV4 (transient receptor potential vanilloid 4), a calcium permeable TRP ion channel, is known to play a key role in endocytosis. However, whether it contributes to exocytosis remains unclear. Here, we report that activation of TRPV4 induced massive exocytosis in both melanoma A375 cell and heterologous expression systems. We show here that, upon application of TRPV4-specific agonists, prominent vesicle priming from endoplasmic reticulum (ER) was observed, followed by morphological changes of mitochondrial crista may lead to cell ferroptosis. We further identified interactions between TRPV4 and folding/vesicle trafficking proteins, which were triggered by calcium entry through activated TRPV4. This interplay, in turn, enhanced TRPV4-mediated activation of folding and vesicle trafficking proteins to promote exocytosis. Our study revealed a signaling mechanism underlying stimulus-triggered exocytosis in melanoma and highlighted the role of cellular sensor TRPV4 ion channel in mediating ferroptosis.

Aims To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D). Materials and Methods This was a randomized, double‐blind, four‐period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. Results URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half‐maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P

Background Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). Methods This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18–45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Results Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39–41% lower, and exposure duration was reduced by 72–74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11–12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44–54% lower, and duration of action was reduced by 34–44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. Conclusion In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124. Electronic supplementary material The online version of this article (10.1007/s40262-020-00903-0) contains supplementary material, which is available to authorized users.

Background Asthma, a common respiratory disease, is harmful biological effect to our health. As a traditional Chinese medicine for asthma, Majie cataplasm could alleviate the symptoms of asthma and its compositions have immunomodulatory effects. Previous experiments showed that Majie cataplasm was an effective approach to mitigate asthma airway remodeling and had the potential to regulate Th2 cytokines of IL-5 and IL-13. Therefore, our further research focuses on the explanation about the regulatory effect of Majie cataplasm on reshaping Th1/Th2 through their related transcription factors. Methods In this experiment, the launch of asthma model was made by inducing with Ovalbumin (OVA) in C57 mice (n = 40), including 4 groups: the untreated control group (n = 10), the asthma model group (n = 10), the dexamethasone group (n = 10) and the Majie cataplasm group (n = 10). After the intervention, all groups of animals got detected for serum IgE levels, and HE staining of lung tissues was to observe and examine pathological changes. Meanwhile, we analyzed the secretion of IL-4+ T cells and IFN-γ+ T cells in spleen by flow cytometry. The expressions of transcription factor STAT6 mRNA, GATA-3 mRNA and T-bet mRNA in lung tissues was tested by PCR, and western blot had been used to detect levels of JAK2 and STAT3. Results We found that Majie cataplasm eased the content of serum IgE and lung inflammation. It could lower the increased number of IL-4+ T cells and IFN-γ+ T cells (P P P , P P P P Conclusion These data suggest that Majie cataplasm exert an anti-inflammatory effect of Th2 by rebalancing Th1/Th2 through corresponding transcription factor STAT6, GATA-3, STAT3, and T-bet, which providing a strong cornerstone for asthma control.

Operational factors and microbial interactions affect the ecology in anaerobic digestion systems. From 12 lab-scale reactors operated under distinct engineering conditions, bacterial communities were found driven by temperature, while archaeal communities by both temperature and substrate properties. Combining the bacterial and archaeal community clustering patterns led to five sample groups (ambient, mesophilic low-solid-substrate, mesophilic, mesophilic co-digestion and thermophilic) for co-occurrence network analysis. Network topological properties were associated with substrate characteristics and hydrolysis-methanogenesis balance. The hydrolysis efficiency correlated (p Defficiency) correlated negatively with the average path length (p

Activating macrophage NLRP3 inflammasome can promote excessive inflammation, leading to severe cell and tissue damage and organ dysfunction. Here, we showed that pharmacological or genetic inhibition of pyruvate dehydrogenase kinase (PDHK) significantly attenuated macrophage NLRP3 inflammasome activation. Broad rewiring of intracellular metabolism and enhanced autophagic flux occurred in inflammasome-activated macrophages, but neither was necessary for the PDHK-regulated reduction of NLRP3 inflammasome activity. PDHK inhibition protected against inflammation-induced mitochondrial fragmentation and cristae remodeling and improved mitochondrial function by repurposing mitochondria from ROS production to ATP generation. Inhibition of PDHK increased the expression of the mitochondrial fusion protein optic atrophy-1 (OPA1). Suppression of OPA1 partially reversed the effect of PDHK inhibition on NLRP3 inflammasome activation. In conclusion, our study suggests that inhibition of PDHK dampens macrophage NLRP3 inflammasome activation during acute inflammation by ameliorating mitochondrial damage in a mechanism separate from its canonical role as a metabolic regulator.

Off-target toxicity remains a major limitation of current cancer therapy, necessitating an alternative precision approach to treat cancers. Herein, a tumor microenvironment (TME)-triggered anticancer strategy was developed by constructing an anti-alcoholism drug disulfiram (DSF)-loaded, Cu-doped zeolite imidazolate frameworks-8 (DSF-Cu/ZIF-8) nanoparticle followed by PEGylation (PEG-DSF-Cu/ZIF-8) to realize in situ generation of cytotoxic compounds specifically in TME. The PEG-DSF-Cu/ZIF-8 demonstrated excellent hydrolytic stability in normal physiological conditions, guaranteeing the minimized off-target release of disulfiram and Cu ions. Under the TME condition, the PEG-DSF-Cu/ZIF-8 exhibited acidity-triggered biodegradation and the associated payload release, through which low-toxic compounds (disulfiram and Cu