Biologically produced monometallic palladium nanoparticles (bio-Pd) have been shown to catalyze the dehalogenation of environmental contaminants, but fail to efficiently catalyze the degradation of ...other important recalcitrant halogenated compounds. This study represents the first report of biologically produced bimetallic Pd/Au nanoparticle catalysts. The obtained catalysts were tested for the dechlorination of diclofenac and trichlorethylene. When aqueous bivalent Pd(II) and trivalent Au(III) ions were both added to concentrations of 50 mg L–1 and reduced simultaneously by Shewanella oneidensis in the presence of H2, the resulting cell-associated bimetallic nanoparticles (bio-Pd/Au) were able to dehalogenate 78% of the initially added diclofenac after 24 h; in comparison, no dehalogenation was observed using monometallic bio-Pd or bio-Au. Other catalyst-synthesis strategies did not show improved dehalogenation of TCE and diclofenac compared with bio-Pd. Synchrotron-based X-ray diffraction, (scanning) transmission electron microscopy and energy dispersive X-ray spectroscopy indicated that the simultaneous reduction of Pd and Au supported on cells of S. oneidensis resulted in the formation of a unique bimetallic crystalline structure. This study demonstrates that the catalytic activity and functionality of possibly environmentally more benign biosupported Pd-catalysts can be improved by coprecipitation with Au.
Immunomodulatory monoclonal IgG1 antibodies developed for cancer and autoimmune disease have an inherent risk of systemic release of pro-inflammatory cytokines. In vitro cytokine release assays are ...currently used to predict cytokine release syndrome (CRS) risk, but the validation of these preclinical tools suffers from the limited number of characterized CRS-inducing IgG1 antibodies and the poor understanding of the mechanisms regulating cytokine release. Here, we incubated human whole blood from naïve healthy volunteers with four monoclonal IgG1 antibodies with different proven or predicted capacity to elicit CRS in clinic and measured cytokine release using a multiplex assay. We found that, in contrast to anti-CD52 antibodies (Campath-1H homolog) that elicited high level of multiple inflammatory cytokines from human blood cells in vitro, other IgG1 antibodies with CRS-inducing potential consistently induced release of a single tested cytokine, interferon (IFN)-γ, with a smaller magnitude than Campath. IFN-γ expression was observed as early as 2-4 h after incubation, mediated by natural killer cells, and dependent upon tumor necrosis factor and FcγRIII. Importantly, the magnitude of the IFN-γ response elicited by IgG1 antibodies with CRS-inducing potential was determined by donor FcγRIIIa-V158F polymorphism. Overall, our results highlight the importance of FcγRIIIa-dependent IFN-γ release in preclinical cytokine release assay for the prediction of CRS risk associated with therapeutic IgG1 antibodies.
This article investigates the sales force socialization process, wherein newly hired salespeople often face failureprone environments. Drawing from the learned helplessness paradigm, the authors ...hypothesize that cumulative periods of sales performance failure are associated with sales-oriented behavior intentions. In addition, the authors examine the influence of leadership, expecting core transformational leadership to have a diminishing effect as unmet sales goals accumulate. Study 1 finds support for these hypotheses using panel survey data from 221 new hires during six months of a furniture retailer's sales force socialization process. Then, aiming to uncover the underlying mechanism driving salesperson helplessness and a managerial approach that has a sustained impact, the authors conduct Study 2, a scenario-based experiment focused on the business-to-business insurance industry. The authors find that perceived task difficulty mediates the focal relationship and that error management enables core transformational leadership to have a lasting effect such that new hires have the lowest sales-oriented behavior intentions when transformational sales managers encourage them to make errors during their interactions with customers and to actively learn from their failures.
Inflammation has been recognized as essential for restorative regeneration. Here, we analyzed the sequential processes during onset of liver injury and subsequent regeneration based on time-resolved ...transcriptional regulatory networks (TRNs) to understand the relationship between inflammation, mature organ function, and regeneration. Genome-wide expression and TRN analysis were performed time dependently in mouse liver after acute injury by CCl
4
(2 h, 8 h, 1, 2, 4, 6, 8, 16 days), as well as lipopolysaccharide (LPS, 24 h) and compared to publicly available data after tunicamycin exposure (mouse, 6 h), hepatocellular carcinoma (HCC, mouse), and human chronic liver disease (non-alcoholic fatty liver, HBV infection and HCC). Spatiotemporal investigation differentiated lobular zones for signaling and transcription factor expression. Acute CCl
4
intoxication induced expression of gene clusters enriched for inflammation and stress signaling that peaked between 2 and 24 h, accompanied by a decrease of mature liver functions, particularly metabolic genes. Metabolism decreased not only in pericentral hepatocytes that underwent CCl
4
-induced necrosis, but extended to the surviving periportal hepatocytes. Proliferation and tissue restorative TRNs occurred only later reaching a maximum at 48 h. The same upstream regulators (e.g. inhibited RXR function) were implicated in increased inflammation and suppressed metabolism. The concomitant inflammation/metabolism TRN occurred similarly after acute LPS and tunicamycin challenges, in chronic mouse models and also in human liver diseases. Downregulation of metabolic genes occurs concomitantly to induce inflammation-associated genes as an early response and appears to be initiated by similar upstream regulators in acute and chronic liver diseases in humans and mice. In the acute setting, proliferation and restorative regeneration associated TRNs peak only later when metabolism is already suppressed.
Introduction and hypothesis
Native tissue vaginal repairs are associated with relatively high levels of recurrence. Systematic reviews have noted that preoperative pelvic floor muscle strength was ...associated with increased risk of recurrence in the short term.
Methods
This is a retrospective review of patients who underwent a primary reconstructive surgery for anterior compartment vaginal prolapse between 2001 and 2015. Patients were divided into “absent,” “weak” and “good” preoperative PFM strength (aPFM, wPFM and gPFM, respectively) based on a modified Oxford scale. Failure rates were determined by a composite of subjective and objective anatomic outcomes. Subjects who underwent re-operations or procedures for recurrent prolapse of the anterior compartment were considered failures. A
p
value < 0.05 was considered statistically significant.
Results
Two hundred ninety-nine patients were included. The aPFM (
n
= 36), wPFM (
n
= 115) and gPFM (
n
= 148) groups had similar descriptive statistics, except subjects in the aPFM and wPFM groups were significantly older than the gPFM group (
p
= 0.008). All groups underwent similar reconstructive surgeries. Average length of follow-up of 143.9 weeks (41 to 717 weeks) was similar among the three groups (
p
= 0.472). For the primary outcome of composite failure, aPFM had significantly more anterior vaginal wall recurrences than both the wPFM and gPFM groups, 13.89% vs. 3.48% and 4.05%, respectively (
p
= 0.033).
Conclusions
Patients with preoperative absent pelvic floor muscle strength (nonfunctioning PFM) had a significantly higher anterior vaginal wall recurrence rate than those with weak or good pelvic floor muscle strength.
Autophagy-related proteins (Atgs) drive the lysosome-mediated degradation pathway, autophagy, to enable the clearance of dysfunctional cellular components and maintain homeostasis. In humans, this ...process is driven by the mammalian Atg8 (mAtg8) family of proteins comprising the LC3 and GABARAP subfamilies. The mAtg8 proteins play essential roles in the formation and maturation of autophagosomes and the capture of specific cargo through binding to the conserved LC3-interacting region (LIR) sequence within target proteins. Modulation of interactions of mAtg8 with its target proteins via small-molecule ligands would enable further interrogation of their function. Here we describe unbiased fragment and DNA-encoded library (DEL) screening approaches for discovering LC3 small-molecule ligands. Both strategies resulted in compounds that bind to LC3, with the fragment hits favoring a conserved hydrophobic pocket in mATG8 proteins, as detailed by LC3A-fragment complex crystal structures. Our findings demonstrate that the malleable LIR-binding surface can be readily targeted by fragments; however, rational design of additional interactions to drive increased affinity proved challenging. DEL libraries, which combine small, fragment-like building blocks into larger scaffolds, yielded higher-affinity binders and revealed an unexpected potential for reversible, covalent ligands. Moreover, DEL hits identified possible vectors for synthesizing fluorescent probes or bivalent molecules for engineering autophagic degradation of specific targets.
As engineering projects grow in complexity, estimating the required engineering effort during the development phase of a project has become more art than science. Predictions of required engineering ...effort are based on empirical models fitted to historical data with additional subjective factors, such as "team cohesion," applied based on the judgment of the user of the model. Recent work has shown that information quality theory can be used to estimate the engineering effort necessary to develop system requirements by evaluating the change in requirements uncertainty during the requirements engineering process. This paper builds upon that foundation by generalizing the information quality theory to apply to the variety of system engineering artifacts generated during the development phase of a program. The generalized form of information quality theory is implemented in a model for application to the system architecture definition process. Engineering effort required for system architecture definition on four programs is used to evaluate both the performance of the model and the performance of the system architecture definition teams. The results of the model and program evaluations show clear benefits in reducing the engineering effort required to define a system's architecture when there is reuse from previous programs. The results of the evaluation also show the architecture definition team benefits from "momentum" and performs more efficiently if the team has completed a system's architecture definition on a recent program.
The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize ...the patient in future antibiotic development and potential market entry rewards.
To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics).
Retrospective cohort.
619 U.S. hospitals.
Adult inpatients.
Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections.
Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 2631 episodes of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and
complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage.
Residual confounding.
Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization.
U.S. Food and Drug Administration; NIH Intramural Research Program.
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