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Objective. To study the risk factors for granulocytopenia caused by antithyroid drugs. Methods. Patients who were diagnosed with Graves’ hyperthyroidism and regularly treated with antithyroid drugs (ATDs) from January 2010 to July 2022 at Nanjing Drum Tower Hospital, aged >18 years, were selected for general information and laboratory tests and divided into two groups according to the occurrence of granulocytopenia. Independent risk factors for the development of granulocytopenia in patients treated with ATDs were analyzed using one-way and multiway logistic regression analyses, and the predictive value of each index was evaluated using the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Results. A total of 818 patients were enrolled, of which 95 developed granulocytopenia. Univariate analysis revealed that sex, white blood cell (WBC) counts, neutrophil-to-lymphocyte ratio (NLR), glutamic-pyruvic transaminase (ALT), aspartate transaminase (AST), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) before medication were risk factors for ATD-induced granulocytopenia ( P < 0.05 ). The abovementioned indicators were taken as independent variables, and multivariate logistic regression analysis showed that female sex, higher ALT levels before medication, and lower NLR and WBC levels were independent risk factors for granulocytopenia using ATDs ( P < 0.05 ). ROC curve analysis showed that sex, NLR, ALT, and WBC count had significant predictive values ( P < 0.05 ), and NLR and WBC count had higher predictive values (AUC = 0.916 and 0.700, respectively). Conclusion. Sex, NLR, ALT, and WBC were the main risk factors for granulocytopenia in patients with ATD.

None-Line-of-Sight (NLOS) signals denote Global Navigation Satellite System (GNSS) signals received indirectly from satellites and could result in unacceptable positioning errors. To meet the high mission-critical transportation and logistics demand, NLOS signals received in the built environment should be detected, corrected, and excluded. This paper proposes a cost-effective NLOS impact mitigation approach using only GNSS receivers. By exploiting more signal Quality Indicators (QIs), such as the standard deviation of pseudorange, Carrier-to-Noise Ratio (C/N0), elevation and azimuth angle, this paper compares machine-learning-based classification algorithms to detect and exclude NLOS signals in the pre-processing step. The probability of the presence of NLOS is predicted using regression algorithms. With a pre-defined threshold, the signals can be classified as Line-of-Sight (LOS) or NLOS. The probability of the occurrence of NLOS is also used for signal subset selection and specification of a novel weighting scheme. The novel weighting scheme consists of both C/N0 and elevation angle and NLOS probability. Experimental results show that the best LOS/NLOS classification algorithm is the random forest. The best QI set for NLOS classification is the first three QIs mentioned above and the difference of azimuth angle. The classification accuracy obtained from this proposed algorithm can reach 93.430%, with 2.810% false positives. The proposed signal classifier and weighting scheme improved the positioning accuracy by 69.000% and 40.700% in the horizontal direction, 79.361% and 75.322% in the vertical direction, and 75.963% and 67.824% in the 3D direction.

[Image: see text] The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.

Prostaglandin E2 (PGE2) generated by the cyclooxygenase (COX) pathways regulates both inflammation and tumor microenvironment (TME). Among the four E-type prostanoid receptors EP1-4, it has been demonstrated that PGE2 exhibits its immune suppression and tumorigenic function through engagement with EP2 and EP4. Mechanistically, tumor-derived PGE2 acts on EP2 and EP4 in immune cells (e.g., NK cells and dendritic cells) and elicits immunosuppression in TME1,2. Importantly, the deletion of both EP2 and EP4, but not deletion of either receptor, is required to reverse PGE2-mediated immune evasion. Furthermore, high levels of PGE2-EP2/EP4 associated inflammatory signature have been shown in multiple human cancer types to correlate with poor prognosis and worse response to immune checkpoint blockade in the clinic1. Therefore, PGE2-EP2/EP4 signaling likely acts as a key regulatory node linking inflammation and immunosuppression in TME, and its inhibition may lead to a less immunosuppressive TME and enhance the response to immune checkpoint inhibitors. COX inhibitors have been used to block PGE2 synthesis but cause cardiovascular and gastrointestinal risks due to the inhibition of all prostanoids synthesis3. Thus, therapeutically targeting both EP2 and EP4 is an effective and more selective approach to limit the immunosuppressive functions of PGE2 while avoiding potential side effects associated with COX inhibition. Here we describe the discovery of a potent and selective EP2/EP4 dual antagonist DX-002. At 10 nM concentration, it displayed >90% inhibition of PGE2 binding to EP2 or EP4, whereas no significant inhibition was seen towards PGE2 binding to EP1 or EP3. In human NK cells DX-002 reversed PGE2-mediated inhibition of IFN-γ production more potently than selective EP2 or EP4 antagonist. DX-002 has excellent pharmacokinetics profiles across all animal species. In the mouse tumor model, treatment of DX-002 produced superior tumor regression as a monotherapy over selective EP2 or EP4 antagonists. In addition, DX-002 also provided significant synergistical effect for tumor regression in combination with anti-PD1 in both immune checkpoint inhibitor insensitive and sensitive models, in association with increased tumor infiltration of CD8+ T cells. Based on its in vitro and in vivo profiles along with other properties, DX-002 is being profiled as a development candidate as a potential cancer immunotherapeutic agent. Citation Format: Lintong Li, Guorui Yao, Wei Zheng, Yongshuai Chai, Zhongying Huang, Guojian Ma, Linlin Nie, Dengfeng Xu, Jiuquan Yang, Nanxin Li. DX-002, a dual EP2 and EP4 antagonist, alters the tumor microenvironment to enhance tumor immunogenicity and responses to immune checkpoint inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5175.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.

This study characterized dynamic behaviors of batch anaerobic digesters treating food waste in terms of methane production, organics destruction and process stability under different organic loads (OLs), substrate to inoculum (S/I) ratios [on volatile solid (VS) basis] and initial pH. The results showed that OL, S/I ratio and initial pH significantly affected batch anaerobic process. Methane yield was proved to be inversely proportional to OL and S/I ratio. Digester with lowest OL (5 g VS/L) obtained greatest methane yield (551.4 mL/g VS), highest organics removal (94.1%) and good stability. Enhancing OL to 10 g VS/L was recommended for satisfactory stability and higher volumetric methane productivity. When OL was designated as 10 g VS/L, digester with low S/I ratio (1/2) achieved satisfactory methane yield (539.3 mL/g VS), high organics removal (92.3%) and stable performance. When OL was relatively high (20 g VS/L), adjusting initial pH to 7.5 contributed to stable performance via enhancing buffering capacity against volatile fatty acids (VFA) disturbance. Strong VFA inhibition occurred under high OL (40 g VS/L) or great S/I ratio (2/1) or acidic initial pH (6.5). In this case, acetate was dominant VFA, followed by butyrate. However, when digester was stable, acetate was main VFA, followed by propionate. This study provided practical guidance on process configurations for batch digesters of food waste needed to achieve satisfactory performance and stability.

The development history of passing neutral section technology was introduced, and the advantages of ground auto-passing neutral section technology were analyzed. By analyzing the working principles and system compositions of the ground auto-passing neutral section system, problems such as no backup system and poor reliability were found. A design scheme of ground auto-passing neutral section logical control system was proposed which based on double 2-vote-2 redundant structure and used microprocessor as the arithmetic unit and depended on the mature technology of the secure computer platform. This article analyzed the hardware components of the system, the working logic in the software design, and system reliability. After field testing, the system has verified the output information, added the backup system, reduced the failure rate of the ground auto-passing neutral section system, enhanced the reliability of the locomotive auto-passing neutral section, improved the locomotive operating efficiency, and achieved the requirements of the design.

The analysis of mammographic images effectively is a burning question recently. So the research of binary classification whether a whole mammographic image has masses or not is proposed in this paper. The two main issues are the class imbalance of INbreast database and the effect of classification. To address these, focal loss, center loss and three kinds of schemes are proposed. Focal loss is put forward to address class imbalance by multiplying a modulating factor. Center loss concerns about enhancement of discriminative power by handling inter-class features, that is similar to the first two schemes. Moreover, the third scheme is used to solve the class imbalance with $L_{1}$ norm. The experimental analyses demonstrate the effectiveness of the combination of diverse loss functions and schemes. The convergence rate increases to varying degrees.

Role of trace elements (TEs) in long-term anaerobic digestion of food waste (FW) under fixed and stepwise increasing loads and under early and medium volatile fatty acid (VFA) inhibition was investigated. Digesters under high load suffered VFA inhibition. Mismatch between scarce TEs in FW and essential TEs for sustainable methanogenesis suppressed Methanosaeta causing blocked aceticlastic methanogenesis and shift to CO2 reduction pathway, as indicated by decreased Methanosaeta from above 70.0% to below 42.0% and enriched hydrogenotrophic methanogens (Methanospirillum, Methanoculleus, Methanobacterium) from below 15.0% to above 53.6%. Dual stresses of VFA inhibition and TEs deficiency resulted in recession of syntrophic Bacteria Syntrophomonadaceae. Conversely, digesters with TEs supplementation maintained high activity of Syntrophomonadaceae and ensured predominant aceticlastic methanogenesis and powerful methanogenic community functions. Early and medium VFA inhibition were reversed by TEs supplementation or coupling with pH adjustment by stimulating VFAs degradation via syntrophic metabolism and unclogging acetate conversion via aceticlastic methanogenesis.

This paper uses patent data from the U.S. Patent and Trademark Office to investigate the association between inventor collaboration and joint assignee ownership, both domestic and international, and patent quality as measured by the number of claims and citations associated with a patent. Specifically, we compare the quality implications of research collaboration and joint patent ownership for the quality of U.S. and Chinese patents. Overall, we find that domestic inventor collaboration is associated with higher quality results for U.S. patents than Chinese patents. However, for China, international collaboration is associated with more positive quality outcomes; for U.S. patents, international collaboration implies lower quality than that associated with domestic U.S. collaboration. Part of this disparity is due to substantially different quality outcomes associated with joint U.S.-Chinese patents – quality gains for China and quality reductions for the U.S. We also investigate the quality implications of different organization-centered research, including dyadic and triadic collaborations, for patent quality as well as the quality implications of various assignee-inventor relationships, operating through incentive and scale effects. While most firms, particularly those in the U.S., appear to exploit advantages of fewer owner-assignees coordinating the scale benefits of more inventors, universities and research institutes in China appear to rely less on coordination-scale effects and more on the incentive effects associated with assigning patent ownership to inventors.

The nicotinic acetylcholine receptor is the prototype ligand-gated ion channel. A number of aromatic amino acids have been identified as contributing to the agonist binding site, suggesting that cation–π interactions may be involved in binding the quaternary ammonium group of the agonist, acetylcholine. Here we show a compelling correlation between: ( i ) ab initio quantum mechanical predictions of cation–π binding abilities and ( ii ) EC 50 values for acetylcholine at the receptor for a series of tryptophan derivatives that were incorporated into the receptor by using the in vivo nonsense-suppression method for unnatural amino acid incorporation. Such a correlation is seen at one, and only one, of the aromatic residues—tryptophan-149 of the α subunit. This finding indicates that, on binding, the cationic, quaternary ammonium group of acetylcholine makes van der Waals contact with the indole side chain of α tryptophan-149, providing the most precise structural information to date on this receptor. Consistent with this model, a tethered quaternary ammonium group emanating from position α149 produces a constitutively active receptor.

The integral membrane proteins of neurons and other excitable cells are generally resistant to high-resolution structural tools. In this thesis we present our efforts to probe the structure of the agonist-binding site of the nicotinic acetylcholine receptor (nAChR) using the tethered agonist approach, which combines chemical synthesis, the nonsense suppression methodology for unnatural amino acid incorporation and electrophysiology. In Chapter 2, we present the results of incorporating a series of tethered quaternary ammonium derivatives of tyrosine into the nAChR using the in vivo nonsense suppression methodology for incorporating unnatural amino acids site-specifically. At three sites, a constitutively active receptor results, but the pattern of activation as a function of chain length is different. At position alpha149, there is a clear preference for a three-carbon tether, while at position alpha93 tethers of 2-5 carbons are comparably effective. At position gamma55/delta57, all tethers except the shortest one can activate the receptor. Based on these and other data, a model for the binding site of the receptor can be developed by analogy to the acetylcholine esterase crystal structure. In Chapter 3, we report evidence that the N-terminal extracellular domain of nAChR is closely related to acetylcholine binding protein (AChBP), whose crystal structure was solved in May 2001. Based on the model obtained from docking acetylcholine into the structure of AChBP, we designed and incorporated a new tethered agonist, lysyl-carbamylcholine. Incorporation of this tethered agonist at several positions produced constitutively active receptors, with significant activity seen at alpha192, alpha193, and gamma119/delta121. These results demonstrated that the loop E residue gamma119/delta121 on the complementary subunit is very near the agonist-binding site. We also investigated the role of an intersubunit hydrogen bond, which was seen in the crystal structure of AChBP. Incorporation of tryptophan analogs that abolish the hydrogen bonding abilities slowed the desensitization of the receptor, which implied that this hydrogen bond might play a key role in the allosteric transitions of desensitization. In Chapter 4, we describe our efforts to prepare a short tethered agonist and the results of incorporating it into nAChR at alpha198 by chemical modification of cysteine mutants introduced by nonsense suppression methodology. Methanethiosulphonate ethyltrimethylammonium (MTSET) modification resulted in constitutive activity, which suggested the closeness of alpha198 to the agonist-binding site. In Chapter 5, methods in molecular biology, electrophysiology and molecular docking, and the synthesis of amino acids and dinucleotide dCA-amino acids are summarized.