Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Calcineurin suppresses rat H9c2 cardiomyocyteprotective autophagy under chronic intermittent hypoxia by downregulating the AMPK pathway.

Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes. However, whether calcineurin can regulate cardiomyocyte autophagy under conditions of chronic intermittent hypoxia (CIH) remains unclear. Here, we showed that CIH induced calcineurin activity in H9c2 cells, which attenuated adenosine monophosphate-activated protein kinase (AMPK) signaling and inhibited autophagy. In H9c2 cells, autophagy levels, LC3 expression, and AMPK phosphorylation were significantly elevated under conditions of CIH within 3 days. However, after 5 days of CIH, these effects were reversed and calcineurin activity and apoptosis were significantly increased. The calcineurin inhibitor 17-Allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.04,9]octacos-18- ene-2,3,10,16-tetrone (FK506) restored AMPK activation and LC3 expression and attenuated CIH-induced H9c2 cell apoptosis. In contrast, calcineurin overexpression significantly attenuated the increase in LC3 expression and enhanced H9c2 cell apoptosis under conditions of CIH. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9c2 cells expressing a kinase-dead K45R AMPK mutant. Autophagy inhibition abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicate that calcineurin suppresses adaptive autophagy during CIH by downregulating AMPK activation. Our findings reveal the underlying mechanism of calcineurin and autophagy regulation during H9c2 cell survival under conditions of CIH and may provide a new strategy for preventing CIH-induced cardiomyocyte damage.

How do inpatients' costs, length of stay, and quality of care vary across age groups after a new case-based payment reform in China? An interrupted time series analysis.

CONTEXT: A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. OBJECTIVE: This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. METHODS: An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18-64 years) and an older group (≥ 65 years), further stratified into young-old (65-79 years) and oldest-old (≥ 80 years) groups. RESULTS: The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. CONCLUSION: Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.

Structural Modification Endows Small-Molecular SN38 Derivatives with Multifaceted Functions.

As a camptothecin derivative, 7-ethyl-10-hydroxycamptothecin (SN38) combats cancer by inhibiting topoisomerase I. SN38 is one of the most active compounds among camptothecin derivatives. In addition, SN38 is also a theranostic reagent due to its intrinsic fluorescence. However, the poor water solubility, high systemic toxicity and limited action against drug resistance and metastasis of tumor cells of SN38 indicates that there is great space for the structural modification of SN38. From the perspective of chemical modification, this paper summarizes the progress of SN38 in improving solubility, increasing activity, reducing toxicity and possessing multifunction and analyzes the strategies of structure modification to provide a reference for drug development based on SN38.

Pre-deployment risk factors for PTSD in active-duty personnel deployed to Afghanistan: a machine-learning approach for analyzing multivariate predictors.

Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study-the Fort Campbell Cohort study-examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90-180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67-0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78-0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75-0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79-0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Aim: Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST). Materials & methods: MRIs acquired every two cycles were assessed centrally using RECIST 1.1, m-RECIST and TVS and tissue damage score (TDS). Results: Thirty-one evaluable TGCT patients were treated with pexidartinib. From baseline to last visit, 94% of patients (29/31) showed a decrease in tumor size (median change: -60% [RECIST], -66% [m-RECIST], -79% [TVS]). All methods showed 100% disease control rate. For TDS, improvements were seen in bone erosion (32%), bone marrow edema (58%) and knee effusion (46%). Conclusion: TVS and m-RECIST offer potentially superior alternatives to conventional RECIST for monitoring disease progression and treatment response in TGCT. TDS adds important information about joint damage associated with TGCT.

Baoshanmycin and a New Furanone Derivative from a Soil-Derived Actinomycete, Amycolatopsis sp. YNNP 00208.

Actinomycetes have being regarded as a treasure reservoir of various bioactive secondary metabolites and devoted many antibiotics in clinicals. Amycolatopsis sp. YNNP 00208 was isolated from a soil sample collected in Gaoligong Mountain area, Yunnan Province, China. Chemical investigation of its fermentation broth led to a new amide, baoshanmycin (1), and a new furanone derivative, 3-(1,3-dihydroxybutyl)-4-methylfuran-2(H)-one (2), together with eight known compounds, including two amides (3-4), four cyclic dipeptides (5-8), and two deoxyribonucleosides (9-10). Their structures were established on basis of the 1D- and 2D-NMR spectroscopic data, along with the HR-ESI-MS experiments. Baoshanmycin (1) showed moderate antimicrobial activities against Candida albicans, and weak activities against Staphylococcus aureus, multi-drug resistant Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes, fluconazole-resistant Candida albicans. Baoshanmycin (1) presented strong antioxidant activity and moderate anti-acetylcholinesterase activity. The other compound 3-(1,3-dihydroxybutyl)-4-methylfuran-2(H)-one (2) and the known compounds (3-10) showed moderate antioxidant activity.

Koninginin W, a New Polyketide from the Endophytic Fungus Trichoderma koningiopsis YIM PH30002.

A new compound named koninginin W (1) and four known polyketides (2-5) were isolated from endophytic fungus Trichoderma koningiopsis YIM PH30002 of Panax notoginseng. The structures of 1 - 5, including absolute configuration of 1, were elucidated on the detailed analysis of the HR-ESI-MS, 1D and 2D NMR, and X-ray crystallographic data. Koninginin W (1) presented weak antibacterial activity against Escherichia coli, Bacillus subtilis and Salmonella typhimurium.

Long focusing range and self-healing Bessel vortex beam generator: publisher's note.

This publisher's note contains corrections to Opt. Lett.45, 2580 (2020).OPLEDP0146-959210.1364/OL.391232.

Long focusing range and self-healing Bessel vortex beam generator.

Here a continuous axial-spiral phase microplate (CAsPP), based on combining a logarithmic axicon and a spiral phase plate, was proposed for generating high-quality higher-order Bessel vortex beams. The novel optical component implemented via femtosecond laser direct writing possesses compact geometry and unique optical properties. The CAsPP with a diameter of 80 µm possesses a controllable long focus ranging from 50 to 600 µm and exhibits a good self-healing ability after free transmission of about 45 µm. Unique optical properties were demonstrated in both experiments and simulations, which were well matched to each other. This Letter provides new opportunities for applications in integrated optics, optical trapping, laser machining, and information reconstruction.

Chitiniphilus eburneus sp. nov., a novel chitinolytic bacterium isolated from sludge.

A novel Gram-stain-negative, curved rod-shaped, motile and non-endospore-forming strain, designated HX-2-15T, was isolated from activated sludge of agricultural chemical plant in Nanjing, Jiangsu province, PR China (32° 03' N, 118° 46' E) . Growth was observed at 15-37 °C (optimum between 25 and 30 °C), at pH 6.0-8.0 (optimum at pH 7.0) and with 0-3.0 % (w/v) NaCl (optimum at 0.5 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain showed closest affiliation to Chitiniphilus shinanonensis SAY3T, with a sequence similarity of 99.0 %. The predominant cellular fatty acids were C16:0, C17:0 cyclo and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). The major quinone was ubiquinone Q-8 . The polar lipid profile was composed of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, three unidentified phospholipids, one unidentified lipid and one unidentified aminophosphoglycolipid . The genomic DNA G+C content of the strain was 63.6 mol%. The ANI and dDDH values obtained between the genomes of HX-2-15T and C. shinanonensis SAY3T were 85.3 and 29.3 % respectively. On the basis of data from phenotypic, chemotaxonomic and genotypic analysis, strain HX-2-15T represents a novel species of the genus Chitiniphilus, for which the name Chitiniphilus eburneus sp. nov. is proposed. The type strain is HX-2-15T (=KCTC 72286T=CCTCC AB 2019178T).

Photoactive NO hybrids with pseudo-zero-order release kinetics for antimicrobial applications.

Bacterial infection is a major threat to the health and life of humans due to the development of drug resistance, which is related to biofilm formation. Nitric oxide (NO) has emerged as an important factor in regulating biofilm formation. In order to harness the potential benefits of NO and develop effective antibacterial agents, we designed and synthesized a new class of NO hybrids in which the active scaffold benzothienoazepine was tagged with a nitroso group and further conjugated with quaternary ammoniums or phosphoniums. The temporal release of NO from these hybrids can be achieved by photoactivation. Interestingly, the NO release follows a pseudo-zero-order kinetics, which is easily determined by measuring the fluorescent benzothienoazepine or NO. Compared to the positive control ciprofloxacin, the NO hybrid with triphenyl phosphonium (TPP) exhibited more effective activity against S. aureus biofilm in darkness. Irradiation of the NO hybrid led to higher inhibition against S. aureus biofilm compared to the parental NO hybrid in darkness or the corresponding NO-released product, indicating the combined effect of NO and the NO-released product. Therefore, this new class of NO hybrids includes very promising antimicrobial agents and this work provides a new way for the design of highly effective antimicrobial agents.

Novel 3,6-Dihydroxypicolinic Acid Decarboxylase-Mediated Picolinic Acid Catabolism in Alcaligenes faecalis JQ135.

Picolinic acid (PA), a typical C-2-carboxylated pyridine derivative, is a metabolite of l-tryptophan and many other aromatic compounds in mammalian and microbial cells. Microorganisms can degrade and utilize PA for growth. However, the precise mechanism of PA metabolism remains unknown. Alcaligenes faecalis strain JQ135 utilizes PA as its carbon and nitrogen source for growth. In this study, we screened a 6-hydroxypicolinic acid (6HPA) degradation-deficient mutant through random transposon mutagenesis. The mutant hydroxylated 6HPA into an intermediate, identified as 3,6-dihydroxypicolinic acid (3,6DHPA), with no further degradation. A novel decarboxylase, PicC, was identified to be responsible for the decarboxylation of 3,6DHPA to 2,5-dihydroxypyridine. Although, PicC belonged to the amidohydrolase 2 family, it shows low similarity (<45%) compared to other reported amidohydrolase 2 family decarboxylases. Moreover, PicC was found to form a monophyletic group in the phylogenetic tree constructed using PicC and related proteins. Further, the genetic deletion and complementation results demonstrated that picC was essential for PA degradation. The PicC was Zn2+-dependent nonoxidative decarboxylase that can specifically catalyze the irreversible decarboxylation of 3,6DHPA to 2,5-dihydroxypyridine. The Km and kcat toward 3,6DHPA were observed to be 13.44 µM and 4.77 s-1, respectively. Site-directed mutagenesis showed that His163 and His216 were essential for PicC activity. This study provides new insights into the microbial metabolism of PA at molecular level.IMPORTANCE Picolinic acid is a natural toxic pyridine derived from l-tryptophan metabolism and other aromatic compounds in mammalian and microbial cells. Microorganisms can degrade and utilize picolinic acid for their growth, and thus a microbial degradation pathway of picolinic acid has been proposed. Picolinic acid is converted into 6-hydroxypicolinic acid, 3,6-dihydroxypicolinic acid, and 2,5-dihydroxypyridine in turn. However, there was no physiological and genetic validation for this pathway. This study demonstrated that 3,6-dihydroxypicolinic acid was an intermediate in picolinic acid catabolism and further identified and characterized a novel amidohydrolase 2 family decarboxylase PicC. PicC was also shown to catalyze the decarboxylation of 3,6-dihydroxypicolinic acid into 2,5-dihydroxypyridine. This study provides a basis for understanding picolinic acid degradation and its underlying molecular mechanism.

Characterization of Genetic Variation in CYP3A4 on the Metabolism of Cabozantinib in Vitro.

Cabozantinib is a multityrosine kinase inhibitor and has a wide range of applications in the clinic, whose metabolism is predominately dependent on CYP3A4. This study was performed to characterize the enzymatic properties of 29 CYP3A4 alleles toward cabozantinib and the functional changes of five selected alleles (the wild-type, CYP3A4.2.8.14 and .15) toward cabozantinib in the presence of ketoconazole. Cabozantinib, 1-100 µM, with/without the presence of ketoconazole and CYP3A4 enzymes in the incubation system went through 30 min incubation at 37 °C, and the concentrations of cabozantinib N-oxide were quantified by UPLC-MS/MS to calculate the corresponding kinetic parameters of each variant. Collectively, without the presence of ketoconazole, most variants displayed defective enzymatic activities in different degrees, and only CYP3A4.14 and .15 showed significantly augmented enzymatic activities. With the presence of ketoconazole, five tested CYP3A4 alleles, even CYP3A4.14 and .15, exhibited obvious reductions in intrinsic clearance. Besides, we compared cabozantinib with regorafenib in relative clearance to confirm that CYP3A4 has the property of substrate specificity. As the first study of CYP3A4 genetic polymorphisms toward cabozantinib, our observations can provide prediction of an individual's capability in response to cabozantinib and guidance for medication and treatment of cabozantinib.

Speech-based markers for posttraumatic stress disorder in US veterans.

BACKGROUND: The diagnosis of posttraumatic stress disorder (PTSD) is usually based on clinical interviews or self-report measures. Both approaches are subject to under- and over-reporting of symptoms. An objective test is lacking. We have developed a classifier of PTSD based on objective speech-marker features that discriminate PTSD cases from controls. METHODS: Speech samples were obtained from warzone-exposed veterans, 52 cases with PTSD and 77 controls, assessed with the Clinician-Administered PTSD Scale. Individuals with major depressive disorder (MDD) were excluded. Audio recordings of clinical interviews were used to obtain 40,526 speech features which were input to a random forest (RF) algorithm. RESULTS: The selected RF used 18 speech features and the receiver operating characteristic curve had an area under the curve (AUC) of 0.954. At a probability of PTSD cut point of 0.423, Youden's index was 0.787, and overall correct classification rate was 89.1%. The probability of PTSD was higher for markers that indicated slower, more monotonous speech, less change in tonality, and less activation. Depression symptoms, alcohol use disorder, and TBI did not meet statistical tests to be considered confounders. CONCLUSIONS: This study demonstrates that a speech-based algorithm can objectively differentiate PTSD cases from controls. The RF classifier had a high AUC. Further validation in an independent sample and appraisal of the classifier to identify those with MDD only compared with those with PTSD comorbid with MDD is required.

Prevalence of psychiatric morbidity in United States military spouses: The Millennium Cohort Family Study.

BACKGROUND: Approximately half of US service members are married, equating to 1.1 million military spouses, yet the prevalence of psychiatric morbidity among military spouses remains understudied. We assessed the prevalence and correlates of eight mental health conditions in spouses of service members with 2-5 years of service. METHOD: We employed baseline data from the Millennium Cohort Family Study, a 21-year longitudinal survey following 9,872 military-affiliated married couples representing all US service branches and active duty, Reserve, and National Guard components. Couples were surveyed between 2011 and 2013, a period of high military operational activity associated with Operation Iraqi Freedom and Operation Enduring Freedom. Primary outcomes included depression, anxiety, posttraumatic stress disorder (PTSD), panic, alcohol misuse, insomnia, somatization, and binge eating, all assessed with validated self-report questionnaires. RESULTS: A total of 35.90% of military spouses met criteria for at least one psychiatric condition. The most commonly endorsed conditions were moderate-to-severe somatization symptoms (17.63%) and moderate-to-severe insomnia (15.65%). PTSD, anxiety, depression, panic, alcohol misuse, and binge eating were endorsed by 9.20%, 6.65%, 6.05%, 7.07%, 8.16%, and 5.23% of spouses, respectively. Having a partner who deployed with combat resulted in higher prevalence of anxiety, insomnia, and somatization. Spouses had lower prevalence of PTSD, alcohol misuse, and insomnia but higher rates of panic and binge eating than service members. Both members of a couple rarely endorsed having the same psychiatric problem. CONCLUSIONS: One third of junior military spouses screened positive for one or more psychiatric conditions, underscoring the need for high-quality prevention and treatment services.

Investigation of an "alternate water supply system" in enzymatic hydrolysis in the processive endocellulase Cel7A from Rasamsonia emersonii by molecular dynamics simulation.

Cel7A from Rasamsonia emersonii is one of the processive endocellulases classified under family 7 glycoside hydrolase. Molecular dynamics simulations were carried out to obtain the optimized sliding and hydrolyzing conformations, in which the reducing ends of sugar chains are located on different sites. Hydrogen bonds are investigated to clarify the interactions between protein and substrate in either conformation. Nine hydrogen bonding interactions are identified in the sliding conformation, and six similar interactions are also found correspondingly in the hydrolyzing conformation. In addition, four strong hydrophobic interactions are also determined. The domain cross-correlation map analysis shows movement correlation of protein including autocorrelation between residues. The root mean square fluctuations analysis represents the various flexibilities of different fragment in the two conformations. Comparing the two conformations reveals the water-supply mechanism of selective hydrolysis of cellulose in Cel7A. The mechanism can be described as follow. When the reducing end of substrate slides from the unhydrolyzing site (sliding conformation) to the hydrolyzing site (hydrolyzing conformation), His225 is pushed down and rotated, the rotation leads to the movement of Glu209 with the interstrand hydrogen bonding in ß-sheet. It further makes Asp211 close to the hydrolysis center and provides a water molecule bounding on its carboxyl in the previous unhydrolyzing site. After the hydrolysis takes place and the product is excluded from the enzyme, the Asp211 comes back to its initial position. In summary, Asp211 acts as an elevator to transport outer water molecules into the hydrolysis site for every other glycosidic bond.

Predictors of PTSD 40 years after combat: Findings from the National Vietnam Veterans longitudinal study.

BACKGROUND: Few studies have longitudinally examined predictors of posttraumatic stress disorder (PTSD) in a nationally representative sample of US veterans. We examined predictors of warzone-related PTSD over a 25-year span using data from the National Vietnam Veterans Longitudinal Study (NVVLS). METHODS: The NVVLS is a follow-up study of Vietnam theater veterans (N = 699) previously assessed in the National Vietnam Veterans Readjustment Study (NVVRS), a large national-probability study conducted in the late 1980s. We examined the ability of 22 premilitary, warzone, and postmilitary variables to predict current warzone-related PTSD symptom severity and PTSD symptom change in male theater veterans participating in the NVVLS. Data included a self-report Health Questionnaire survey and a computer-assisted telephone Health Interview Survey. Primary outcomes were self-reported PTSD symptoms assessed by the PTSD Checklist for DSM-5 (PCL 5) and Mississippi PTSD Scale (M-PTSD). RESULTS: Predictors of current PTSD symptoms most robust in hierarchical multivariable models were African-American race, lower education level, negative homecoming reception, lower current social support, and greater past-year stress. PTSD symptoms remained largely stable over time, and symptom exacerbation was predicted by African-American race, lower education level, younger age at entry into Vietnam, greater combat exposure, lower current social support, and greater past-year stressors. CONCLUSIONS: Findings confirm the robustness of a select set of risk factors for warzone-related PTSD, establishing that these factors can predict PTSD symptom severity and symptom change up to 40 years postdeployment.

Three-dimensional reconstruction of nonplanar ultrasound fields using Radon transform and the schlieren imaging method.

This paper introduces a numerical method of reconstructing three-dimensional (3D) ultrasound fields from their two-dimensional back-projections to understand the intensity distribution of nonplanar waves. The horizontal planes for line-focused ultrasound fields were roughly elliptical, whereas those for point-focused ultrasound fields were nearly circular. Experimental and simulated results indicated that the ultrasound intensity at the central axis can be calibrated from the light intensity by 3D reconstruction of the ultrasound field. The difference between the measured ultrasound intensity for nonplanar waves in schlieren imaging and the simulation results were discussed. From this work, the 3D ultrasound field becomes possible to be reconstructed.

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid ß (Aß) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. Aß is the proteolytic product from its precursor amyloid precursor protein (APP) by ß- and γ- secretase. An optional cleavage by α-secretase happens inside the Aß domain. ADAM17 is supposed to be the regulated α-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP α fragment and reduction of Aß generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed.