While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by
, no single factor predicts the extent of lung damage in CF. To elucidate other causes, we studied ...the autoantibody profile in CF and rheumatoid arthritis (RA) patients, given the similar association of airway inflammation and autoimmunity in RA. Even though we observed that bactericidal permeability-increasing protein (BPI), carbamylated proteins, and citrullinated proteins all localized to the neutrophil extracellular traps (NETs), which are implicated in the development of autoimmunity, our study demonstrates striking autoantibody specificity in CF. Particularly, CF patients developed anti-BPI autoantibodies but hardly any anti-citrullinated protein autoantibodies (ACPA). In contrast, ACPA-positive RA patients exhibited no reactivity with BPI. Interestingly, anti-carbamylated protein autoantibodies (ACarPA) were found in both cohorts but did not cross-react with BPI. Contrary to ACPA and ACarPA, anti-BPI autoantibodies recognized the BPI C-terminus in the absence of posttranslational modifications. In fact, we discovered that
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-mediated NET formation results in BPI cleavage by
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elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of
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on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function.
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of ...hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.
Assessing the consumption of assimilative capacity (AC) caused by wastewater discharge is an effective guide in the development of sustainable water use. Conventional studies only considered each ...economic sector's direct wastewater discharge as their consumption of AC, and ignored the indirect consumption of AC caused by the material-product flow network. In response to this problem, the concept of gray water footprint (GWF) was introduced to access the consumption of AC. An accounting method was also provided for GWF based on the input–output analysis (IOA) to deal with the indirect GWF connections between economic sectors. In a case study the GWF accounting method for China's Haihe River Basin was implemented. The results found that the total GWF was 3.35 × 1010 m3, of which 60.0% was for inhabitants and 40.0% was for exports. The GWF was larger than gross river flow and groundwater flow, highlighting an AC gap. This gap was consistent with the basin's water quality situation. The top three sectors with the largest GWFs were agriculture, wood (including paper and others), and chemical industry. The results showed that wastewater treatment helped to decrease the GWF by approximately 39%, which demonstrates the important effects of wastewater treatment and the need to improve wastewater treatment in these sectors. This study provides insights using assimilation capacity in the Haihe River Basin's current water challenge and is a reference for other basin studies.
•A new approach to assess the consumption of assimilative capacity is presented.•Case study in the Haihe River showed the largest gray water footprint in agriculture.•Consumption observed in agriculture was largely driven by other sectors indirectly.•Wastewater treatment is an effective way in sustaining assimilative capacity.
The age profile of populations fundamentally affects their conservation status. Yet, age is frequently difficult to assess in wild animals. Here, we assessed the use of DNA methylation of homologous ...genes to establish the age structure of a rare and elusive wild mammal: the Bechstein's bat (Myotis bechsteinii). We collected 62 wing punches from individuals whose ages were known as a result of a long‐term banding study. DNA methylation was measured at seven CpG sites from three genes, which have previously shown age‐associated changes in humans and laboratory mice. All CpG sites from the tested genes showed a significant relationship between DNA methylation and age, both individually and in combination (multiple linear regression R2 = 0.58, p < 0.001). Despite slight approximation around estimates, the approach is sufficiently precise to place animals into practically useful age cohorts. This method is of considerable practical benefit as it can reliably age individual bats. It is also much faster than traditional capture–mark–recapture techniques, with the potential to collect information on the age structure of an entire colony from a single sampling session to better inform conservation actions for Bechstein's bats. By identifying three genes where DNA methylation correlates with age across distantly related species, this study also suggests that the technique can potentially be applied across a wide range of mammals.
From copy rooms to boardrooms, many Americans have succumbed to the siren song of insider trading. As U.S. companies have gone international, so too have corporate secrets ripe for exploitation. With ...the growth of overseas derivatives based on U.S. stock, foreigners are able to engage in insider trading to a similar extent as Americans.
But in 'Morrison v. National Australia Bank', the Supreme Court limited the reach of the statutory insider-trading prohibition to transactions taking place in U.S. territory or transactions in securities listed on U.S. exchanges. Neither condition applies to overseas insider trading using derivatives. However, courts have reasoned that when the trader's broker hedges by buying stock on a U.S. exchange, that transaction can be attributed to the trader, thus bringing the scheme within 'Morrison'.
This hedging theory depends on the acts of third parties-the brokers- to create insider-trading liability, thus giving arbitrary windfalls to blameworthy traders and creating both evidentiary and legal hurdles for U.S. enforcement. Because 'Morrison' has backed courts into this unworkable corner, it should not govern in insider-trading cases.
There is a fix: the Dodd-Frank Wall Street Reform and Consumer Protection Act abrogated 'Morrison' for enforcement actions, albeit imperfectly. By abandoning the theory in favor of Dodd-Frank's pragmatic standard, courts can more nimbly and forcefully protect U.S. markets from foreign fraud.
Angiotensin-converting enzyme (ACE) inhibitors are one of the most active classes for cardiovascular diseases and hypertension treatment. In this regard, developing active and non-toxic ACE ...inhibitors is still a continuous challenge. Furthermore, the literature survey shows that oxidative stress plays a significant role in the development of hypertension. Herein, glutathione's molecular structure and supramolecular arrangements are evaluated as a potential ACE inhibitor. The tripeptide molecular modeling by density functional theory, the electronic structure by the frontier molecular orbitals, and the molecular electrostatic potential map to understand the biochemical processes inside the cell were analyzed. The supramolecular arrangements were studied by Hirshfeld surfaces, quantum theory of atoms in molecules, and natural bond orbital analyses. They showed distinct patterns of intermolecular interactions in each polymorph, as well as distinct stabilizations of these. Additionally, the molecular docking study presented the interactions between the active site residues of the ACE and glutathione via seven hydrogen bonds. The pharmacophore design indicated that the hydrogen bond acceptors are necessary for the interaction of this ligand with the binding site. The results provide useful information for the development of GSH analogs with higher ACE inhibitor activity.
Rituximab (RTX) has been the hallmark anti-CD20 mAb for the treatment of B cell neoplasms, including B cell chronic lymphocytic leukemia (B-CLL). Recently, a novel humanized anti-CD20 mAb ...obinutuzumab (GA101) has been implemented as first-line CLL therapy. Treatment of CLL patients with RTX is associated with CD20 loss via an FcγR-mediated process, trogocytosis. RTX-induced trogocytosis has been characterized as both the means of resistance to therapy, via loss of cell surface target proteins (antigenic modulation), as well as a process that alters B cell phenotype and function. This study investigates the nature and clinical relevance of GA101-mediated trogocytosis. In this study, we demonstrate that GA101 is a more potent mediator of trogocytosis than RTX in vitro in both normal B cells and B-CLL cells. Qualitative differences in the effector function of these anti-CD20 Abs appear specific to B-CLL cells. GA101-mediated CD19 and CD20 trogocytosis from B-CLL cells is associated with its ability to induce homotypic adhesion (HA). The degree of HA varies between CLL patients and positively correlates with the expression of ZAP-70, a BCR-associated kinase. Deregulation of ZAP-70 using tyrosine kinase inhibitors, gefitinib or ibrutinib, diminishes HA formation and trogocytosis by GA101. Taken together, these findings elucidate the differences in trogocytosis and HA formation mediated by anti-CD20 mAbs RTX and GA101, as well as provide a novel link between ZAP-70 expression and these effector functions.
A novel 4(1H) quinolinone derivative (QBCP) was synthesized and characterized with single crystal X-ray diffraction. Hirshfeld surfaces (HS) analyses were employed as a complementary tool to evaluate ...the crystal intermolecular interactions. The molecular global reactivity parameters of QBCP were studied using HOMO and LUMO energies. In addition, the molecular electrostatic potential (MEP) and the UV-Vis absorption and emission spectra were obtained and analyzed. The supermolecule (SM) approach was employed to build a bulk with 474,552 atoms to simulate the crystalline environment polarization effect on the asymmetric unit of the compound. The nonlinear optical properties were investigated using the density functional method (DFT/CAM-B3LYP) with the Pople's 6-311++G(d,p) basis set. The quantum DFT results of the linear polarizability, the average second-order hyperpolarizability and the third-order nonlinear susceptibility values were computed and analyzed. The results showed that the organic compound (QBCP) has great potential for application as a third-order nonlinear optical material.
Climate warming in the 20th Century has had profound effects on the limnology of High Arctic lakes, including substantial increases in autochthonous primary productivity (APP). Here, we report ...organic carbon and Hg core profiles from two lakes which support the hypothesis that 20th Century increases in sedimentary Hg at these latitudes were largely driven by APP increases, via Hg scavenging by algae and/or suspended detrital algal matter. Hydrocarbons quantitatively released by thermal cracking of algal-derived organic matter (“S2” carbon) were used to reconstruct past APP. Variation of S2 flux accounted for 87−91% of the variance in total Hg flux in the study lakes since 1854. Mercury and S2 carbon were also associated during the pre-Industrial Period, co-varying by as much as 30% during past warm/cool periods. As a test of the hypothesis, predicted values for 20th Century Hg were derived from pre-1900 Hg−S2 relationships. Measured 20th Century Hg was on average only 6−11% higher than that predicted in one lake, and 33% higher in the other. S2-normalization of Hg in the latter lake suggested that 78% of the average increase in 20th Century Hg could be explained by scavenging. These findings suggest that the atmospheric contribution of long-range anthropogenic Hg to High Arctic lakes may have been overestimated by several-fold because of this climate-driven process, and was responsible for no more than 22% of the 20th Century Hg increase in the study lakes.
Prior research has argued that upwardly biased appraised values of residential properties were a contributing factor of the 2008 financial crisis. Subsequent reforms have been enacted to reduce ...appraiser’s financial incentives to submit biased appraisals, but appraisers continue to receive the contract price of pending home sales. This knowledge may lead them to subconsciously interpret and select information to confirm the contract price exposing the economy to future crises. A novel data series of properties that were appraised twice within six months where one appraiser was uninformed of the contract price is used to test how appraisal practices differ when prices are known. Significant differences were found in the property descriptions and the selection, price adjustment, and weighting of comparable transactions for appraisers aware of the contract price. Appraisers aware of contract price were more than twice as likely to reach an appraised value at least equal to contract price; on average their valuations were 4.2%-to-8.3% higher than appraisers unaware of contract prices.
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