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With the acceleration of urbanization, excessive urbanization and cluster expansion threaten the traditional environment of historical and cultural districts. The preservation of historical and cultural districts has become an important issue for urban development. Through literature review and case analysis, the six success factors are summarized in this article for historical and cultural district preservation: historical and cultural heritage, public participation, government actions, community construction, economic subsidies, and landscape appearance. By using the interpretive structure model to integrate the success factors, it has been concluded that historical and cultural heritage is the most basic factor. The results of this research provide an effective reference to enhance the preservation of historical areas.

Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure-activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic-pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.

Objective: To investigate the musculoskeletal status and psychological status of female recruits during military boot enlistment training. Methods: The musculoskeletal status and psychological status of 110 boot training patients were assessed by scale, the psychological status of the subjects was assessed by Zung Anxiety Self-Rating Scale and Zung Depression Self-Evaluation Scale, the musculoskeletal status was assessed by visual analogue scale, Neck disability index, JOA low back pain evaluation form, Knee injury and Osteoarthritis Outcome Score scale, the medical document data during boot training were collated, and the risk factors affecting physical and mental health were analyzed. Thus, interventions are taken to reduce the injury rate and improve training performance.Results: Logistic regression analysis showed that neck dysfunction was a risk factor for depressive state and lumbar dysfunction; lumbar dysfunction was a risk factor for anxiety state, neck dysfunction and pain symptoms around the knee joint; pain around the knee joint was a risk factor for lumbar dysfunction and a protective factor for neck dysfunction; anxiety state was a risk factor for depressive state; depression state was a risk factor for anxiety state and neck dysfunction; and young age was a protective factor for anxiety state. Conclusion: In 10 weeks of military training, the site with the highest musculoskeletal injury is around the knee joint, followed by the neck and waist. Knee injury and Osteoarthritis Outcome Score scale scores were significantly associated with mental health status, with neck dysfunction increasing the risk of depression and lumbar dysfunction increasing the risk of anxiety in recruits. Prevention and treatment need to pay attention to these parts, gradually improve the balance, flexibility, strength of the body, while paying close attention to the mental health of recruits, so as to reduce the rate of injury. Keywords: recruits; military training; female soldiers; anxiety; depression; musculoskeletal injury.

An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6–difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)–3–phenylpyrrolidin–3–yl)sulfone template, the 2,6–difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRβ. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X–ray co–crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.

We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.

[Image: see text] A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of RORγt inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure–activity relationship studies, a polar set of amides at N1-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXRα, and LXRβ. Further optimization led to the discovery of (1R,4r)-4-((R)-3-((4-fluorophenyl)sulfonyl)-3-(4-(perfluoropropan-2-yl)phenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

Heatwaves are likely to increase over different regions of the world as the climate warms, which poses potential risk to the environment, society, and public health. Concurrent daytime and nighttime heatwaves have a more significant impact on human health than individually occurring heatwaves, especially in regions with high population density. The Huai River Basin (HRB) is taken as a case in this study to explore the characteristics of concurrent daytime and nighttime heatwaves in a high-population-density area, including quantification of the population’s exposure to concurrent heatwaves. Nighttime hot events are found to increase to greater extent than daytime hot events from 1961 to 2017. A single daytime or nighttime hot event can provide 40–60 % capacity for the concurrent daytime and nighttime hot events. The concurrent daytime and nighttime heatwaves show an obvious southeast-northwest gradient with high values in the southeast and low values in the northwest of the HRB. Daytime hot events, nighttime hot events, and concurrent daytime and nighttime heatwave events all show significant upward trends from 1987 to 2017. The population exposed to the heat extremes increased significantly over this period, especially in regards to concurrent daytime and nighttime heatwaves. The population exposure in terms of the quantity, duration, and magnitude of concurrent daytime and nighttime heatwaves increased by around 5-, 9-, and 35-fold from 1984 to 2017. Atmospheric circulation analysis of the 2013 concurrent daytime and nighttime heatwaves in the HRB shows a long-lasting anomalous circulation background (e.g., anomalous high pressure system and low cloud water content) leading to severe concurrent daytime and nighttime heatwaves.

This study provides references for establishment of the evaluation index system of intelligent building information communication system engineering for the living space of the elderly. In this study, first of all, through the collection and collation of the literature, all levels of indexes for the construction of the intelligent building information communication system engineering for the living space of the elderly are evaluated. The results of the expert questionnaires are analyzed by decision making trial and evaluation laboratory (DEMATEL), so that a new evaluation index system is obtained.

A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.

Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.

Novel ((2-substituted-1H-benzo[d]imidazol-1-yl)methyl)benzamides were found to be excellent P1' substituents in conjunction with unique constrained beta-amino hydroxamic acid scaffolds for the discovery of potent selective inhibitors of TNF-alpha Converting Enzyme (TACE). Optimized examples proved potent for TACE, exceptionally selective over a wide panel of MMP and ADAM proteases, potent in the suppression of LPS-induced TNF-alpha in human whole blood and orally bioavailable.

New inhibitors of tumor necrosis factor-α converting enzyme (TACE) were discovered using an N -hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC 50 s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFα production in a human whole blood assay (WBA) with an IC 50 of 0.42 μM.

Discuss the new method of individual internal fixation with steel plate customization.Customize individual internal fixation with steel plate according to 3D reconstruction of CT images and Ugnx. Pro/E machining method.Success in customization about the first individual internal fixation with clavicular hook plate for the treatment of multisegmental fracture of clavicle.The new method of individual internal fixation with steel plate customization according to 3D reconstruction of CT images and Ugnx, Pro/E machining technique is a good news for patients of orthopaedic trauma. We are fully confident of the future development of the method of individual internal fixation with steel plate customization.

Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.

Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.

Using a pyrimidine-2,4,6-trione motif as a zinc-binding group, a series of selective inhibitors of tumor necrosis factor-α converting enzyme (TACE) was discovered. Optimization of initial lead 1 resulted in a potent inhibitor (51), with an IC50 of 2 nM in a porcine TACE assay. To the best of our knowledge, compound 51 and related analogues represent first examples of non-hydroxamate-based inhibitors of TACE with single digit nanomolar potency.

New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with a pyrimidine-2,4,6-trione in place of the commonly used hydroxamic acid. These non-hydroxamate TACE inhibitors were developed by incorporating a 4-(2-methyl-4-quinolinylmethoxy)phenyl group, an optimized TACE selective P1' group. Several leads were identified with IC50 values around 100 nM in a porcine TACE assay and selective over MMP-1, -2, -9, -13, and aggrecanase.

New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.