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No study has assessed the durability of pulmonary vein isolation (PVI) with radiofrequency (RF) and cryoballoon (CB) in patients with persistent atrial fibrillation. These data are especially lacking for those with significantly diseased left atria (LA). The goals of this study were to assess PVI durability in patients with significant LA disease and to compare reconnection rates between RF and CB. Forty-four patients (mean age 63 years; 34 (77%) male; median time since atrial fibrillation diagnosis 22.5 months; median indexed LA volume 36 mL/m2) were randomized 1:1 to RF or CB PVI. A redo procedure using ultra-high-density electroanatomic mapping was mandated at 2 months, where PV reconnections were identified and reisolated. Thirty-eight patients underwent both procedures (CB n = 17; RF n = 21). Index RF procedures were longer (median 158 minutes vs 97 minutes; P <.001) but required less fluoroscopy (9.5 minutes vs 23 minutes; P <.001). At the index RF procedure, a median of 47% of LA myocardium had voltage < 0.5 mV, suggesting that half of the mapped LA comprised scar. PV reconnection was observed in 73 of 152 PVs (48.0%) and was more frequent with CB (58.8%) than with RF (39.3%) (P =.022). Reconnection of at least 1 PV was detected in >75% of patients. Significantly more ablation was required during the redo procedure to reisolate PVs in the CB arm (median 10.8 minutes vs 1.2 minutes; P <.001). PVI durability may be poor in those with significant LA scarring and dilatation, even with modern thermal ablation technologies. RF resulted in significantly better PVI durability than did CB in this complex population. [ABSTRACT FROM AUTHOR]

Priority effects occur when the order of species arrival affects subsequent ecological processes. The order that pollinator species visit flowers may affect pollination through a priority effect, whereby the first visitor reduces or modifies the contribution of subsequent visits. We observed floral visitation to blueberry flowers from honeybees, stingless bees or a mixture of both species and investigated how (i) initial visits differed in duration to later visits; and (ii) how visit sequences from different pollinator taxa influenced fruit weight. Stingless bees visited blueberry flowers for significantly longer than honeybees and maintained their floral visit duration, irrespective of the number of preceding visits. In contrast, honeybee visit duration declined significantly with an increasing number of preceding visits. Fruit weight was positively associated with longer floral visit duration by honeybees but not from stingless bee or mixed species visitation. Fruit from mixed species visits were heavier overall than single species visits, because of a strong priority effect. An initial visit by a stingless bee fully pollinated the flower, limiting the pollination contribution of future visitors. However, after an initial honeybee visit, flowers were not fully pollinated and additional visitation had an additive effect upon fruit weight. Blueberries from flowers visited first by stingless bees were 60% heavier than those visited first by honeybees when total floral visitation was short (∼1 min). However, when total visitation time was long (∼ 8 min), blueberry fruit were 24% heavier when initial visits were from honeybees. Our findings highlight that the initial floral visit can have a disproportionate effect on pollination outcomes. Considering priority effects alongside traditional measures of pollinator effectiveness will provide a greater mechanistic understanding of how pollinator communities influence plant reproductive success. [ABSTRACT FROM AUTHOR]

Preliminary evidence supporting the importance of assessing employee attitudes throughout the enterprise resource planning implementation process is provided.

The Waste Treatment and Immobilization Plant (WTP) will process and stabilize nuclear waste stored in tanks on the Hanford Site. At the WTP, the tank waste will be combined with glass-forming chemicals to make a melter feed slurry that can be vitrified in joule-heated melters. Technetium-99 (99Tc), a long-lived radionuclide present in tank waste, is semi-volatile from a glass melt at elevated temperatures. A small laboratory-scale melter system has been designed by PNNL to operate under radioactive conditions, giving it the ability to vitrify actual tank waste and gain information about melter feed processability and the partitioning of components of interest. This study describes two runs performed in a duplicate system with non-radioactive simulants of Hanford tanks 241-AP-107 and 241-AN-105 to gain insight into the relationship between the retentions of 99Tc and its non-radioactive surrogate Re while also investigating the effects of increasing the reducing agent such as sucrose during vitrification on processing and the retention of semi-volatile components in the glass product. The results from these runs align with the general trends of greater retention in the glass of Re compared to 99Tc and the improved retention in the glass of Re with increased reducing agent. [ABSTRACT FROM AUTHOR]

The Surgical Risk Preoperative Assessment System accurately predicts postoperative complications in elective surgery using only 8 preoperative variables, but its performance in emergency surgery has not been evaluated. We hypothesized that the Surgical Risk Preoperative Assessment System accurately predicts postoperative complications in emergency surgery and compared its performance to that of the American College of Surgeons Surgical Risk Calculator. We calculated the Surgical Risk Preoperative Assessment System and the American College of Surgeons Surgical Risk Calculator risk estimates in a random sample of 1,010 emergency surgery cases from the American College of Surgeons National Surgical Quality Improvement Program 2014 to 2017 database. Risk estimates were compared with known outcomes. Analyses included the Hosmer-Lemeshow goodness of fit graphs and P values, c-indexes, and Brier scores. Results were similar between the Surgical Risk Preoperative Assessment System and the American College of Surgeons Surgical Risk Calculator for mortality, urinary tract infection, cardiac, venous thromboembolism, and renal complications. The American College of Surgeons Surgical Risk Calculator underestimated morbidity compared with the Surgical Risk Preoperative Assessment System (16.04% American College of Surgeons Surgical Risk Calculator vs 24.88% Surgical Risk Preoperative Assessment System vs 24.3% observed). Both calculators overestimated readmission (7.67% American College of Surgeons Surgical Risk Calculator vs 5.18% Surgical Risk Preoperative Assessment System vs 4.1% observed). Both calculators predicted mortality, urinary tract infection, cardiac, venous thromboembolism, and renal complications well, but readmissions relatively poorly. The Surgical Risk Preoperative Assessment System estimated overall morbidity accurately, while the American College of Surgeons Surgical Risk Calculator underestimated this risk. [ABSTRACT FROM AUTHOR]

Abstract Worldwide, bees have an important role in ecosystem function and the provision of ecosystem services through their role as pollinators. The diversity of bee species in rural landscapes is influenced by the type of landscape features present, and by land-use and management practices. A key challenge is to understand and predict how species vary across the landscape; and the role of functional traits in determining compositional patterns. We systematically sampled wild bees in four types of landscape feature – open farmland, scattered farmland trees, roadside vegetation and streamside vegetation – in rural landscapes in southern Australia. Landscapes were selected to represent wooded or non-wooded combinations of these site types (e.g. roadside vegetation with or without trees), embedded in farmland with different land-uses (e.g. cropping, grazing). The species richness and abundance of bees was greater at sites containing little or no tree cover; and the cumulative richness of species was greater for tree-less sites than for those with trees. In contrast, species evenness was greatest in wooded site types, indicating these were less dominated by abundant generalist species. Open farmland and treeless roadsides had greater functional diversity (based on species traits) than wooded site types. Strong species trait associations were more numerous with open parts of the landscape, reflecting the greater functional diversity of open site types. These results suggest that a suite of the extant bee fauna can exploit large-scale transformation from former extensively wooded ecosystems to open agricultural landscapes. However, not all species are able to exploit modified landscapes and may disappear with further loss of wooded vegetation. Trait-based approaches provide insight into how changes in landscape pattern affect the bee fauna. Failure to adequately cater for multiple functional groups of bees across all landscape features could mean a substantial loss in species that rely on more natural cover, thus affecting ecosystem function. [ABSTRACT FROM AUTHOR]

Stingless bees (Meliponini) are important pollinators throughout the world's tropical and subtropical regions. Understanding their thermal tolerance is key to predicting their resilience to changing climates and increasingly frequent extreme heat events. We examined critical thermal maxima (CT max), survival during 1–8 h heat periods, chill coma recovery and thermal preference for Australian meliponine species that occupy different climates across their ranges: Tetragonula carbonaria (tropical to temperate regions), T. hockingsi (tropical and subtropical regions only) and Austroplebeia australis (widely distributed including arid regions). We found interspecific differences in thermal tolerance consistent with differences in the climate variability observed in each species' range. Foragers of A. australis had a faster chill coma recovery (288 s) than foragers of T. hockingsi (1059 s) and T. carbonaria (872 s). Austroplebeia australis also had the highest CT max of 44.5 °C, while the CT max of the two Tetragonula species was ∼43.1 °C. After a 1-h heat exposure, T. carbonaria foragers experienced 95% mortality at 42 °C, and 100% at 45 °C. Surprisingly, larvae and pupae of both Tetragonula species were more resistant to heat exposure than foragers. Within an enclosed temperature gradient apparatus (17–38 °C), no clear preference was found for foragers; however, they were most frequently observed at ∼18 °C. Results indicate that in some regions of Australia, meliponines already experience periodic heat events exceeding their thermal maxima. Employing effective management strategies (such as nest site insulation and habitat preservation) may be crucial to colony survival under continued climate change. • Across species and life stages, heat stress became lethal at 40–45 °C. • Larvae and pupae of the two Tetragonula species were more resistant to heat stress than adults. • Austroplebeia survived at greater temperature extremes than Tetragonula. • Critical thermal maxima for these species are already exceeded during contemporary heat events in eastern Australia. [ABSTRACT FROM AUTHOR]

Background: More advanced atrial fibrillation (AF) is associated with lower success rates after pulmonary vein isolation (PVI), and the optimal ablation strategy is uncertain.Objectives: To assess the impact of additional linear ablation (lines) compared to PVI alone.Methods: In this multicenter randomized controlled trial, 122 patients (mean age 61.9 ± 10.5 years; left atrial diameter 43 ± 6 mm) with persistent AF (PeAF) or sustained (>12 hours) paroxysmal AF (SusPAF) with risk factors for atrial substrate were included and followed up for 12 months. Patients were randomized to PVI-only or PVI + lines (left atrial roof line, mitral isthmus line, and tricuspid isthmus line) group. Holter monitoring was performed at 3, 6, and 12 months and according to symptoms. The primary outcome was atrial tachyarrhythmia recurrence lasting ≥30 seconds.Results: Baseline characteristics were comparable between groups; 61% had PeAF and 39% SusPAF. Successful PVI was achieved for 98% of pulmonary veins, and bidirectional block was obtained in 90% of lines. The primary end point occurred in 38% of the PVI + lines group and 32% of the PVI-only group (P = .50), which was consistent in both PeAF (36% vs 28%; P = .45) and SusPAF (42% vs 39%; P = .86). Compared with the PVI-only group, the PVI + lines group had higher procedure duration (209 ± 52 minutes vs 172 ± 44 minutes; P < .001), ablation time (4352 ± 1084 seconds vs 2503 ± 1061 seconds; P < .001), and radiation exposure (Dose-area product 3992 ± 6496 Gy·cm(2) vs 2106 ± 1679 Gy·cm(2); P = .03). Quality of life (disease-specific Atrial Fibrillation Effect on Quality of Life questionnaire and mental component scale of the Short Form 36 Health Survey) improved significantly during the study but did not differ between groups.Conclusion: Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation, increases procedure duration and radiation dose, but provides no additional clinical benefit. [ABSTRACT FROM AUTHOR]

Objectives: Animal studies suggest that RSV increases nasopharyngeal (NP) bacterial colonization facilitating bacterial infections. We investigated the influence of antibiotic treatment and colonization with potentially pathogenic bacteria on inflammatory markers and disease severity in RSV-infected in infants.Methods: Healthy young infants hospitalized with RSV bronchiolitis (n = 136) and age-matched healthy controls (n = 23) were enrolled and NP samples cultured for potentially pathogenic bacteria including: Gram-positive bacteria (GPB): Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic Streptococcus; and Gram-negative bacteria (GNB): Moraxella catarrhalis and Haemophilus influenzae. Clinical parameters and plasma IL-8, IL-6 and TNF-α concentrations were compared according to the bacterial class and antibiotic treatment.Results: Antibiotic treatment decreased by 10-fold NP bacterial recovery. Eighty-one percent of RSV infants who did not receive antibiotics before sample collection were colonized with pathogenic bacteria. Overall, GNB were identified in 21% of patients versus 4% of controls who were mostly colonized with GPB. Additionally, in RSV patients NP white blood cell counts (p = 0.026), and blood neutrophils (p = 0.02) were higher in those colonized with potentially pathogenic bacteria versus respiratory flora. RSV patients colonized with GNB had higher plasma IL-8 (p = 0.01) and IL-6 (p < 0.01) concentrations than controls, and required longer duration of oxygen (p = 0.049).Conclusions: Infants with RSV bronchiolitis colonized with potentially pathogenic bacteria had increased numbers of mucosal and systemic inflammatory cells. Specifically, colonization with GNB was associated with higher concentrations of proinflammatory cytokines and a trend towards increased disease severity. [ABSTRACT FROM AUTHOR]

Background Electrogram fractionation and atrial fibrosis are both thought to be pathophysiological hallmarks of evolving persistence of atrial fibrillation (AF), but recent studies in humans have shown that they do not colocalize. The interrelationship and relative roles of fractionation and fibrotic change in AF persistence therefore remain unclear. Objective The aim of the study was to examine the hypothesis that electrogram fractionation with increasing persistence of AF results from localized conduction slowing or block due to changes in atrial connexin distribution in the absence of fibrotic change. Methods Of 12 goats, atrial burst pacemakers maintained AF in 9 goats for up to 3 consecutive 4-week periods. After each 4-week period, 3 goats underwent epicardial mapping studies of the right atrium and examination of the atrial myocardium for immunodetection of connexins 43 and 40 (Cx43 and Cx40) and quantification of connective tissue. Results Despite refractoriness returning to normal in between each 4-week period of AF, there was a cumulative increase in the prevalence of fractionated atrial electrograms during both atrial pacing (control and 1, 2, and 3 months period of AF 0.3%, 1.3% ± 1.5%, 10.6% ± 2%, and 17% ± 5%, respectively; analysis of variance, P < .05) and AF (0.3% ± 0.1%, 2.3% ± 1.2%, 14% ± 2%, and 23% ± 3%; P < .05) caused by colocalized areas of conduction block during both pacing (local conduction velocity <10 cm/s: 0.1% ± 0.1%, 0.3% ± 0.6%, 6.5% ± 3%, and 6.9% ± 4%; P < .05) and AF (1.5% ± 0.5%, 2.7% ± 1.1%, 10.1% ± 1.2%, and 13.6% ± 0.4%; P < .05), associated with an increase in the heterogeneity of Cx40 and lateralization of Cx43 (lateralization scores: 1.75 ± 0.89, 1.44 ± 0.31, 2.85 ± 0.96, and 2.94 ± 0.31; P < .02), but not associated with change in connective tissue content or net conduction velocity. Conclusion Electrogram fractionation with increasing persistence of AF results from slow localized conduction or block associated with changes in atrial connexin distribution in the absence of fibrotic change. [ABSTRACT FROM AUTHOR]

Abstract: Objective: A subset of children with scald burns develops respiratory failure despite no direct injury to the lungs. We examined these patients in an effort to elucidate the etiology of the respiratory failure. Methods: The charts of pediatric patients with greater than 10% total body surface area (TBSA) scald burns were reviewed. Age, weight, burn distribution, percentage of TBSA burned, resuscitation volumes, Injury Severity Score, evidence of abuse, length of stay, days in the intensive care unit, and time and duration of intubation were recorded. Results: Two hundred thirty-two patients met our inclusion criteria. Of these, 220 patients did not require intubation, and 12 of the patients did. No patient older than 3 years or with burns less than 15% TBSA required intubation. Fluid over resuscitation was not directly associated with respiratory failure requiring mechanical ventilation. Conclusions: We report the largest published series of patients with scald burns requiring mechanical ventilation in the absence of direct airway injury. Five percent of pediatric patients required mechanical ventilation after scald injury. We believe that a combination of causes including fluid resuscitation, young patient age, small patient size, and possible activation of the systemic inflammatory immune response may be responsible for the respiratory failure. [Copyright &y& Elsevier]

Abstract: Objective: The objective of this study is to provide updated prevalence information on hepatitis C, hepatitis B, and human immunodeficiency virus (HIV) among patients in a high-volume emergency department (ED) located in a medium-sized, Midwestern city. Background: This study provides updated information regarding the prevalence of the blood-borne pathogens hepatitis C, hepatitis B, and HIV among ED patients. Prior studies of this type have focused on large inner-city populations with high incidence rates of blood-borne diseases. These studies have limited applicability to other common ED settings. Methods: A convenience sample of 404 patients was selected using blood previously drawn independent of the study. Patient-identifying information was unlinked from study results, which allowed waiver of informed consent from the Institutional Review Board. This blood was then tested for hepatitis C, hepatitis B, and HIV. Results: Prevalence of hepatitis C antibody was 4.0%, relative to the overall US population prevalence of 1.8%. Hepatitis BsAg was present in 0.7% and HIV prevalence was 0.8%. There were no coinfections; therefore, there was a combined prevalence of blood-borne pathogens of 5.5%. Conclusions: The combined prevalence of blood-borne pathogens of 5.5% supports previous recommendations of universal precautions, particularly in settings where the overall prevalence may be underestimated. [Copyright &y& Elsevier]

Background: Little is known about the effects of investigators' financial disclosures on potential research participants.Methods: We conducted a vignette trial in which 470 participants in a telephone survey were randomly assigned to receive a simulated informed consent document that contained 1 of 2 financial disclosures (per capita payments to the research institution or equity ownership by the investigator) or no disclosure. The main outcome measures were trust in medical research and willingness to participate in a hypothetical clinical trial.Results: Participants in the equity group reported less willingness to participate than participants in the per capita payments group (P = .01) and the no disclosure group (P = .03). Trust in the investigator was highest in the per capita payments group and lowest in the equity group (P < .001). Trust among participants who received no disclosure was also greater than trust among participants in the equity group (P = .04) but did not differ significantly from trust among participants in the per capita payments group (P = .15). Participants in the equity group made 3 times as many negative comments as participants in the per capita payments group; and 10 participants in the equity group spontaneously said they would not participate in the hypothetical trial because of the financial interest, compared with only 1 such participant from the other groups.Conclusions: Although investigators' financial disclosures in research do not substantially affect willingness to participate, potential research participants are more troubled by equity interests than by per capita payments. [ABSTRACT FROM AUTHOR]

Detection methods of Shiga toxin-producing Escherichia coli (STEC) in cattle feces varied in using enrichment media containing different antibiotic combinations. To examine efficacy of a new detection method for STEC, three O157:H7 (ATCC 43889, 43890, and 43895) and 41 non-O157:H7 (members of the O1, O15, O26, O86, O103, O111, O125, O127, O128, O136, O146, O153, O158, O165, O166, and O169 serogroups) isolates were tested. These isolates were grown in tryptic soy broth for 6 h, and their concentrations were determined before inoculation of tubes containing 1 g of cattle feces (sterile [experiment 1; evaluating growth] and fresh [experiment 2; evaluating enrichment]) to simulate the high and low levels of STEC shedding by cattle (105 versus 10² CFU/g feces, respectively). Eight STEC isolates (the three O157:H7 and five non-O157:H7 selected at random) were tested at a very low level (10 CFU/g feces). The feces were incubated in 50 ml of brain heart infusion broth containing potassium tellurite, novobiocin, and vancomycin (2.5, 20, and 40 mg/liter, respectively) and cefixime (50 µg/liter) at 37°C for 12 h and tested for STEC (VTEC [verotoxin-producing E. coli]-Screen assay [agglutination immunoassay]). Potential STEC isolates were recovered, characterized biochemically, serotyped, and tested for toxin production using Vero (African green monkey kidney) cell toxicity assay and agglutination immunoassay. In both experiments, all the STEC isolates used for fecal inoculation were recovered at the concentrations tested. Our medium supported growth of and enrichment for a wide range of STEC isolates. [ABSTRACT FROM AUTHOR]

The anaphase-promoting complex (APC) regulates the eukaryotic cell cycle by targeting specific proteins for proteasomal degradation. Its activity must be strictly controlled to ensure proper cell cycle progression. The co-activator proteins Cdc20 and Cdh1 are required for APC activity and are important regulatory targets. Recently, budding yeast Acm1 was identified as a Cdh1 binding partner and APCCdh1 inhibitor. Acm1 disappears in late mitosis when APCCdh1 becomes active and contains conserved degron-like sequences common to APC substrates, suggesting it could be both an inhibitor and substrate. Surprisingly, we found that Acm1 proteolysis is independent of APC. A major determinant of Acm1 stability is phosphorylation at consensus cyclin-dependent kinase sites. Acm1 is a substrate of Cdc28 cyclin-dependent kinase and Cdcl4 phosphatase both in vivo and in vitro. Mutation of Cdc28 phosphorylation sites or conditional inactivation of Cdc28 destabilizes Acm1. In contrast, inactivation of Cdc14 prevents Acm1 dephosphorylation and proteolysis. Cdc28 stabilizes Acm1 in part by promoting binding of the 14-3-3 proteins Bmh1 and Bmh2. We conclude that the opposing actions of Cdc28 and Cdc14 are primary factors limiting Acm1 to the interval from G1/S to late mitosis and are capable of establishing APC-independent expression patterns similar to APC substrates. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: This study explored how state managed-care patient protection laws affect health insurers’ criteria for medical necessity, using bariatric surgery for weight reduction as a case in point. Methods: Six states and three national insurers were selected for in-depth case studies to represent a range of market, demographic, and legal conditions. In each state, 10–12 qualitative interviews were conducted in 2002 with insurers, regulators, providers, and healthcare attorneys, for a total of 71 interview subjects. Results: Denials of coverage for bariatric surgery are a frequent source of appeals to external review, and external reviewers frequently overturn these denials. However, few insurers feel pressured to approve most or all requests for coverage because external review decisions do not set binding precedents. Instead, insurers continue to assert their own criteria for medical necessity, relying on the insurance contract’s general definition of medical necessity. Some insurers, however, specifically exclude all weight reduction surgery because of the difficulty of defending case-by-case denials on appeal. Conclusions: Unlike most areas of medicine, in which health insurers have greatly scaled back their past efforts to scrutinize medical necessity, for bariatric surgery, many insurers continue to apply a more stringent standard for medical necessity than the one that independent practicing physicians use. [Copyright &y& Elsevier]

Abstract To determine the nature and extent of the emerging field of "health law" scholarship in China, we retrieved 2956 publications about various aspects of health law published up through 2014 in 268 journals from the "Chinese Social Science Citation Index" and from the list of Chinese "Core Journals" maintained by the Peking University Library. By bibliometric analysis, we observed some interesting results which were different from our expectations. The collaboration network among Chinese health law (CHL) authors was relatively small, loose, unstable and early in its development. Kan Tian and Lixin Yang were leading authors, Renmin University of China was the primary institution, and Beijing was the predominant region studying Chinese health law (CHL). Kan Tian ranked 1st in the collaboration network and Lixin Yang published the most number of articles on CHL. Comprehensive universities made up the majority of institutions studying CHL, while medical colleges did not focus on health law research, possibly due to medical schools focusing mainly on clinical education and not attaching as much importance to social and humanistic aspects of medicine. Food safety, health administration, and the general principles of civil law were the main areas of focus in CHL research, which is basically in line with what we expected. Highlights • This paper presents the first ever bibliometric analysis of Chinese health law literature, and it employs a social network analysis. • TFocusing on the period 1978 to 2014, the network of Chinese Health Law scholarship was relatively small and loosely connected. • The main areas of focus in Chinese Health Law research included food safety, health administration, and the general principles of civil law. [ABSTRACT FROM AUTHOR]

Identifies two additional subunits, Mnd2 and Swm1, in anaphase-promoting complex (APC) from budding yeast. Yeast methods and strain construction; Demonstration that swm1 and Mnd2 are functional components of the yeast APC; APC subunit interaction assay; Identification of two unknown proteins co-purifying with yeast APC.

Cdc14 phosphatases are related structurally and mechanistically to protein tyrosine phosphatases (PTPs) but evolved a unique specificity for phosphoSer-Pro-X-Lys/Arg sites primarily deposited by cyclin-dependent kinases. This specialization is widely conserved in eukaryotes. The evolutionary reconfiguration of the Cdc14 active site to selectively accommodate phosphoSer-Pro likely required modification to the canonical PTP catalytic cycle. While studying Saccharomyces cerevisiae Cdc14, we discovered a short sequence in the disordered C terminus, distal to the catalytic domain, which mimics an optimal substrate. Kinetic analyses demonstrated this pseudosubstrate binds the active site and strongly stimulates rate-limiting phosphoenzyme hydrolysis, and we named it “substrate-like catalytic enhancer” (SLiCE). The SLiCE motif is found in all Dikarya fungal Cdc14 orthologs and contains an invariant glutamine, which we propose is positioned via substrate-like contacts to assist orientation of the hydrolytic water, similar to a conserved active site glutamine in other PTPs that Cdc14 lacks. AlphaFold2 predictions revealed vertebrate Cdc14 orthologs contain a conserved C-terminal alpha helix bound to the active site. Although apparently unrelated to the fungal sequence, this motif also makes substratelike contacts and has an invariant glutamine in the catalytic pocket. Altering these residues in human Cdc14A and Cdc14B demonstrated that it functions by the same mechanism as the fungal motif. However, the fungal and vertebrate SLiCE motifs were not functionally interchangeable, illuminating potential active site differences during catalysis. Finally, we show that the fungal SLiCE motif is a target for phosphoregulation of Cdc14 activity. Our study uncovered evolution of an unusual stimulatory pseudosubstrate motif in Cdc14 phosphatases. [ABSTRACT FROM AUTHOR]

The death receptor ligand TRAIL has shown remarkable promise as an anticancer agent. However, TRAIL signaling also activates NF-κB, which induces the antiapoptotic regulators Mcl-1 and cIAP2, thus compromising its efficacy. In this issue of Cancer Cell, El-Deiry and colleagues explore pathways that disrupt TRAIL-induced survival signaling and show that the Myc oncoprotein and the Raf kinase inhibitor Sorafenib sensitize otherwise TRAIL-resistant colon cancer cells by effectively reducing NF-κB-mediated transcription of Mcl-1. These findings suggest that combining TRAIL with agents that disrupt NF-κB regulation or binding or those that directly destabilize or disable Mcl-1 will have therapeutic benefit. [Copyright &y& Elsevier]

Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear. We sought to evaluate suppression of the TLR4 and the antiviral retinoic acid–inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand polyinosinic-polycytidylic acid-low-molecular-weight/LyoVec and LPS to evaluate IFN-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). Suppression of either IFN-α or TNF-α production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n = 33 of 103 [32%]) were more likely to have prolonged (≥7 days) multiple-organ dysfunction syndrome (30.3% vs 8.6%; P =.004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4%; P =.001) compared with those with single- or no pathway suppression. Suppression of both RIG-I and TLR4 signaling pathways, essential for respective antiviral and antibacterial responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial coinfection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring. [ABSTRACT FROM AUTHOR]