The lipid kinase PI4KB, which generates phosphatidylinositol 4‐phosphate (PI4P), is a key enzyme in regulating membrane transport and is also hijacked by multiple picornaviruses to mediate viral ...replication. PI4KB can interact with multiple protein binding partners, which are differentially manipulated by picornaviruses to facilitate replication. The protein c10orf76 is a PI4KB‐associated protein that increases PI4P levels at the Golgi and is essential for the viral replication of specific enteroviruses. We used hydrogen–deuterium exchange mass spectrometry to characterize the c10orf76‐PI4KB complex and reveal that binding is mediated by the kinase linker of PI4KB, with formation of the heterodimeric complex modulated by PKA‐dependent phosphorylation. Complex‐disrupting mutations demonstrate that PI4KB is required for membrane recruitment of c10orf76 to the Golgi, and that an intact c10orf76‐PI4KB complex is required for the replication of c10orf76‐dependent enteroviruses. Intriguingly, c10orf76 also contributed to proper Arf1 activation at the Golgi, providing a putative mechanism for the c10orf76‐dependent increase in PI4P levels at the Golgi.
Synopsis
Enteroviruses hijack host PI4KB and GBF1 to build replication organelles. This study reveals that the direct interaction between c10orf76 and PI4KB is required for c10orf76 recruitment to the Golgi and the replication of c10orf76‐dependent enteroviruses.
c10orf76 is localized to the Golgi through a direct interaction with the kinase linker of PI4KB.
c10orf76 regulates GBF1 and active Arf1 dynamics that control Golgi PI4P levels.
Enteroviruses that rely on c10orf76 for replication depend on formation of the c10orf76‐PI4KB complex.
Enteroviruses hijack host PI4KB and GBF1 to build replication organelles. This study reveals that the direct interaction between c10orf76 and PI4KB is required for c10orf76 recruitment to the Golgi and the replication of c10orf76‐dependent enteroviruses.
Previous studies reported decreased mortality in patients with carbapenemase-producing Klebsiella pneumoniae bloodstream infections (BSIs) treated with combination therapy but included ...carbapenem-susceptible and -intermediate isolates, as per revised CLSI breakpoints. Here, we assessed outcomes in patients with BSIs caused by phenotypically carbapenem-resistant K. pneumoniae (CRKP) according to the number of in vitro active agents received and whether an extended-spectrum beta-lactam (BL) antibiotic, including meropenem, or an extended-spectrum cephalosporin was administered. We retrospectively reviewed CRKP BSIs at two New York City hospitals from 2006 to 2013, where all isolates had meropenem or imipenem MICs of ≥4 μg/ml. Univariate and multivariable models were created to identify factors associated with mortality. Of 141 CRKP BSI episodes, 23% were treated with a single active agent (SAA), 26% were treated with an SAA plus BL, 28% were treated with multiple active agents (MAA), and 23% were treated with MAA plus BL. Ninety percent of isolates had meropenem MICs of ≥16 μg/ml. Thirty-day mortality was 33% overall and did not significantly differ across the four treatment groups in a multivariable model (P = 0.4); mortality was significantly associated with a Pitt bacteremia score of ≥4 (odds ratio OR, 7.7; 95% confidence interval CI, 3.2 to 18.1; P = 0.1), and immunosuppression was protective (OR, 0.4; 95% CI, 0.2 to 1.0; P = 0.04). Individual treatment characteristics were also not significantly associated with outcome, including use of SAAs versus MAA (26% versus 38%, P = 0.1) or BL versus no BL (26% versus 39%, P = 0.1). In summary, in patients with CRKP BSIs caused by isolates with high carbapenem MICs, the role of combination therapy remains unclear, highlighting the need for prospective studies to identify optimal treatment regimens.
To test the hypothesis that there is no difference in the in vivo maximum wear of enamel opposing monolithic zirconia crowns, enamel opposing porcelain fused to metal crowns and enamel opposing ...enamel.
Thirty patients needing single crowns were randomized to receive either a monolithic zirconia or metal-ceramic crown. Two non-restored opposing teeth in the same quadrants were identified to serve as enamel controls. After cementation, quadrants were scanned for baseline data. Polyvinylsiloxane impressions were obtained and poured in white stone. Patients were recalled at six-months and one-year for re-impression. Stone models were scanned using a tabletop laserscanner to determine maximum wear. Statistical analysis was performed using Mann-Whitney U to determine any significant differences between the wear of enamel against zirconia and metal-ceramic crowns.
Sixteen zirconia and 14 metal-ceramic crowns were delivered. There were no statistical differences in mean wear of crown types (p=0.165); enamel antagonists (p=0.235) and enamel controls (p=0.843) after one year.
Monolithic zirconia exhibited comparable wear of enamel compared with metal-ceramic crowns and control enamel after one year.
This study is clinically significant because the use of polished monolithic zirconia demonstrated comparable wear of opposing enamel to metal-ceramic and enamel antagonists.
The Transiting Exoplanet Survey Satellite, TESS, is currently carrying out an all-sky search for small planets transiting bright stars. In the first year of the TESS survey, a steady progress was ...made in achieving the mission’s primary science goal of establishing bulk densities for 50 planets smaller than Neptune. During that year, the TESS’s observations were focused on the southern ecliptic hemisphere, resulting in the discovery of three mini-Neptunes orbiting the star TOI-125, a V = 11.0 K0 dwarf. We present intensive HARPS radial velocity observations, yielding precise mass measurements for TOI-125b, TOI-125c, and TOI-125d. TOI-125b has an orbital period of 4.65 d, a radius of 2.726 ± 0.075 R(E), a mass of 9.50 ± 0.88 M(E), and is near the 2:1 mean motion resonance with TOI-125c at 9.15 d. TOI-125c has a similar radius of 2.759 ± 0.10 R(E) and a mass of 6.63 ± 0.99 M(E), being the puffiest of the three planets. TOI-125d has an orbital period of 19.98 d and a radius of 2.93 ± 0.17 R(E) and mass 13.6 ± 1.2 M(E). For TOI-125b and d, we find unusual high eccentricities of 0.19 ± 0.04 and 0.17(sup +0.08, sub −0.06), respectively. Our analysis also provides upper mass limits for the two low-SNR planet candidates in the system; for TOI-125.04 (R(P) = 1.36 R(E), P = 0.53 d), we find a 2σ upper mass limit of 1.6 M(E), whereas TOI-125.05 (R(P) = 4.2(sup +2.4, sub −1.4 R(E), P = 13.28 d) is unlikely a viable planet candidate with an upper mass limit of 2.7 M(E). We discuss the internal structure of the three confirmed planets, as well as dynamical stability and system architecture for this intriguing exoplanet system.
Patients and clinicians may misinterpret the clinical importance of imaging findings in patients with low back pain, leading to potential harm related to overdiagnosis.
Our aims were to qualitatively ...summarize the characteristics of tested interventions that target the reporting, communication, or clinical interpretation of lumbar imaging findings and determine whether interventions are effective in improving low back pain-related health outcomes, health care use, or health care costs.
PubMed, MEDLINE, CINAHL, EMBASE, PsycINFO, and the Cochrane Library were searched from inception to October 20, 2021.
The search retrieved 4394 articles, nine articles (seven studies) met the inclusion criteria to summarize intervention characteristics. Five of these studies had an adequate design for evaluating intervention effectiveness.
Intervention characteristics were summarized using the Template for Intervention Description and Replication checklist. Effectiveness data were extracted from short, intermediate, and long-term follow-up points. Studies were assessed for risk of bias, and Grading of Recommendations Assessment, Development and Evaluation methodology was used to determine the certainty of the evidence.
Four studies investigated the insertion of prevalence information into imaging reports. Single studies investigated withholding diagnostic information, education, and reassurance. Moderate-quality evidence (from 1 study) suggests that inserting prevalence information into imaging reports probably does not change the overall health care use in the long-term but may reduce opioid prescribing.
The available evidence is limited, and a meta-analysis was not possible.
Further work is required to develop and test interventions that target the reporting, communication, and clinical interpretation of lumbar imaging findings that may reduce overdiagnosis and improve the management of low back pain.
Intake of carbohydrates that provide a large glycemic response has been hypothesized to increase the risk of NIDDM, whereas dietary fiber is suspected to reduce incidence. These hypotheses have not ...been evaluated prospectively. We examined the relationship between diet and risk of NIDDM in a cohort of 42,759 men without NIDDM or cardiovascular disease, who were 40-75 years of age in 1986. Diet was assessed at baseline by a validated semiquantitative food frequency questionnaire. During years of follow-up, 523 incident cases of NIDDM were documented. The dietary glycemic index (an indicator of carbohydrate's ability to raise blood glucose levels) was positively associated with risk of NIDDM after adjustment for age, BMI, smoking, physical activity family history of diabetes, alcohol consumption, cereal fiber, and total energy intake. Comparing the highest and lowest quintiles, the relative risk (RR) of NIDDM was 1.37 (95% CI, 1.02-1.83, P trend = 0.03). Cereal fiber was inversely associated with risk of NIDDM (RR= 0.70; 95% CI, 0.51-0.96, P trend =0.007; for 8.1 g/day vs. 3.2 g/day). The combination of a high glycemic load and a low cereal fiber intake further increased the risk of NIDDM (RR
We present our analysis of Kepler observations of 29 RR Lyrae stars, based on 138 d of observation. We report precise pulsation periods for all stars. Nine of these stars had incorrect or unknown ...periods in the literature. 14 of the stars exhibit both amplitude and phase Blazhko modulations, with Blazhko periods ranging from 27.7 to more than 200 d. For V445 Lyr, a longer secondary variation is also observed in addition to its 53.2-d Blazhko period. The unprecedented precision of the Kepler photometry has led to the discovery of the the smallest modulations detected so far. Moreover, additional frequencies beyond the well-known harmonics and Blazhko multiplets have been found. These frequencies are located around the half-integer multiples of the main pulsation frequency for at least three stars. In four stars, these frequencies are close to the first and/or second overtone modes. The amplitudes of these periodicities seem to vary over the Blazhko cycle. V350 Lyr, a non-Blazhko star in our sample, is the first example of a double-mode RR Lyrae star that pulsates in its fundamental and second overtone modes.
Aims.
L 98-59 (TIC 307210830, TOI-175) is a nearby M3 dwarf around which TESS revealed three small transiting planets (0.80, 1.35, 1.57 Earth radii) in a compact configuration with orbital periods ...shorter than 7.5 days. Here we aim to measure the masses of the known transiting planets in this system using precise radial velocity (RV) measurements taken with the HARPS spectrograph.
Methods.
We considered both trained and untrained Gaussian process regression models of stellar activity, which are modeled simultaneously with the planetary signals. Our RV analysis was then supplemented with dynamical simulations to provide strong constraints on the planets’ orbital eccentricities by requiring long-term stability.
Results.
We measure the planet masses of the two outermost planets to be 2.42 ± 0.35 and 2.31 ± 0.46 Earth masses, which confirms the bulk terrestrial composition of the former and eludes to a significant radius fraction in an extended gaseous envelope for the latter. We are able to place an upper limit on the mass of the smallest, innermost planet of <1.01 Earth masses with 95% confidence. Our RV plus dynamical stability analysis places strong constraints on the orbital eccentricities and reveals that each planet’s orbit likely has
e
< 0.1.
Conclusions.
L 98-59 is likely a compact system of two rocky planets plus a third outer planet with a lower bulk density possibly indicative of the planet having retained a modest atmosphere. The system offers a unique laboratory for studies of planet formation, dynamical stability, and comparative atmospheric planetology as the two outer planets are attractive targets for atmospheric characterization through transmission spectroscopy. Continued RV monitoring will help refine the characterization of the innermost planet and potentially reveal additional planets in the system at wider separations.
Context. Small planets transiting bright nearby stars are essential to our understanding of the formation and evolution of exoplanetary systems. However, few constitute prime targets for atmospheric ...characterization, and even fewer are part of multiple star systems. Aims. This work aims to validate TOI-4336 A b, a sub-Neptune-sized exoplanet candidate identified by the TESS space-based transit survey around a nearby M dwarf. Methods. We validated the planetary nature of TOI-4336 A b through the global analysis of TESS and follow-up multi-band high-precision photometric data from ground-based telescopes, medium- and high-resolution spectroscopy of the host star, high-resolution speckle imaging, and archival images. Results. The newly discovered exoplanet TOI-4336 A b has a radius of 2.1 ± 0.1 R ⊕ . Its host star is an M3.5-dwarf star with a mass of 0.33 ± 0.01 M ⊙ and a radius of 0.33 ± 0.02 R ⊙ , and is a member of a hierarchical triple M-dwarf system 22 pc away from the Sun. The planet’s orbital period of 16.3 days places it at the inner edge of the habitable zone of its host star, which is the brightest of the inner binary pair. The parameters of the system make TOI-4336 A b an extremely promising target for the detailed atmospheric characterization of a temperate sub-Neptune by transit transmission spectroscopy with JWST.
Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with ...Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin–tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35–1.94 and adjusted OR 0.92; 95% CI 0.50–1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.
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