Deep swarm: Nested particle swarm optimization

A new generation of particle swarm optimization (PSO) has been developed that automatically evolves optimal or near-optimal values for parameters of the PSO algorithm such as population size and neighborhood size, and, if used, parameters of associated neural network(s), such as number of hidden processing elements (PEs). Called Deep Swarm, it is a nested version of PSO, and comprises swarms within a swarm

Stronger but Not Faster : Flipped Classroom Teaching Significantly Improves Resident\u27s Skills but Not Speed

Objective: Flipped classroom teaching is a nontraditional education model where instructional content is delivered outside the classroom. This constructivist approach emphasizes self-direction, active inquiry; the instructor’s role is to foster critical reflection and facilitate the application and understanding of concepts. Our objective was to study the difference in time taken and quality of patch graft angioplasty performed by residents with and without flipped teaching. Methods: The study was set in a skills simulation teaching session overseen by attending surgeons. The intervention consisted of introducing a video outlining the technical aspects of patch graft angioplasty, watched before the session. The first group (2018 postgraduate year [PGY] 1 and 2 residents) was given instructions at the time of the class without a prior educational video or resources (Figs 1 and 2). The second group (2019, 2020 PGY 1 and 2 residents) was asked to watch a 20-minute video on the technical aspects of the procedure before the class. Participants then performed a standardized patch graft closure of a 1 cm arteriotomy using a polytetrafluoroethylene patch. The groups were timed. The quality of the closure was tested by assessing the number of leaks and the quantity of leak of the patch (Fig 3). Bivariate analysis sample t-tests were used for statistical analysis. P value \u3c.05 was considered significant. Pre- and post-session surveys were conducted to assess residents’ experience. Results: Forty-two residents (PGY 1 and 2) were enrolled in the study, 15 in nonintervention group 1 and 27 in intervention group 2, compared with 7 staff vascular surgeons. The mean completion time was 26 minutes (group 1) vs 27 minutes (group 2), P ¼ .6. The staff completion time was 12 minutes, P ¼ .001. The number of major leaks (not needle holes) was 2.0 (group 1) vs 1.6 (group 2), P ¼ .007, none for staff. The total quantity of leak was 42 mL (group 1) vs 15 mL (group 2), P ¼ .0001 (Table I). There was perceived improvement in skill on analyzing pre- and post-session surveys (Table II). Conclusions: A structured educational intervention, watching a video of a procedure before the skills session, did not change the time needed to complete the skill. There was improvement in the technical outcome of the procedure defined by a decrease in the total quantity of leak. Reversed classroom teaching significantly improves resident’s skill, not speed. There was also a perceived improvement in skill by participants. This is a pilot study and further instructional outcomes are being studied

SLC19A1 transports immunoreactive cyclic dinucleotides.

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7. This cyclic dinucleotide (CDN) activates STING8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2'3'-cGAMP produced by malignant cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases

The LEECH Exoplanet Imaging Survey: Limits on Planet Occurrence Rates Under Conservative Assumptions

We present the results of the largest $L^{\prime}$ ($3.8~\mu$m) direct imaging survey for exoplanets to date, the Large Binocular Telescope Interferometer (LBTI) Exozodi Exoplanet Common Hunt (LEECH). We observed 98 stars with spectral types from B to M. Cool planets emit a larger share of their flux in $L^{\prime}$ compared to shorter wavelengths, affording LEECH an advantage in detecting low-mass, old, and cold-start giant planets. We emphasize proximity over youth in our target selection, probing physical separations smaller than other direct imaging surveys. For FGK stars, LEECH outperforms many previous studies, placing tighter constraints on the hot-start planet occurrence frequency interior to $\sim20$ au. For less luminous, cold-start planets, LEECH provides the best constraints on giant-planet frequency interior to $\sim20$ au around FGK stars. Direct imaging survey results depend sensitively on both the choice of evolutionary model (e.g., hot- or cold-start) and assumptions (explicit or implicit) about the shape of the underlying planet distribution, in particular its radial extent. Artificially low limits on the planet occurrence frequency can be derived when the shape of the planet distribution is assumed to extend to very large separations, well beyond typical protoplanetary dust-disk radii ($\lesssim50$ au), and when hot-start models are used exclusively. We place a conservative upper limit on the planet occurrence frequency using cold-start models and planetary population distributions that do not extend beyond typical protoplanetary dust-disk radii. We find that $\lesssim90\%$ of FGK systems can host a 7 to 10 $M_{\mathrm{Jup}}$ planet from 5 to 50 au. This limit leaves open the possibility that planets in this range are common.Comment: 31 pages, 13 figures, accepted to A

High contrast imaging at the LBT: the LEECH exoplanet imaging survey

In Spring 2013, the LEECH (LBTI Exozodi Exoplanet Common Hunt) survey began its $\sim$130-night campaign from the Large Binocular Telescope (LBT) atop Mt Graham, Arizona. This survey benefits from the many technological achievements of the LBT, including two 8.4-meter mirrors on a single fixed mount, dual adaptive secondary mirrors for high Strehl performance, and a cold beam combiner to dramatically reduce the telescope's overall background emissivity. LEECH neatly complements other high-contrast planet imaging efforts by observing stars at L' (3.8 $\mu$m), as opposed to the shorter wavelength near-infrared bands (1-2.4 $\mu$m) of other surveys. This portion of the spectrum offers deep mass sensitivity, especially around nearby adolescent ($\sim$0.1-1 Gyr) stars. LEECH's contrast is competitive with other extreme adaptive optics systems, while providing an alternative survey strategy. Additionally, LEECH is characterizing known exoplanetary systems with observations from 3-5$\mu$m in preparation for JWST.Comment: 12 pages, 5 figures. Proceedings of the SPIE, 9148-2

(p)ppGpp and c-di-AMP Homeostasis Is Controlled by CbpB in Listeria monocytogenes

The facultative intracellular pathogen Listeria monocytogenes, like many related Firmicutes, uses the nucleotide second messenger cyclic di-AMP (c-di-AMP) to adapt to changes in nutrient availability, osmotic stress, and the presence of cell wall-acting antibiotics. In rich medium, c-di-AMP is essential; however, mutations in cbpB, the gene encoding c-di-AMP binding protein B, suppress essentiality. In this study, we identified that the reason for cbpB-dependent essentiality is through induction of the stringent response by RelA. RelA is a bifunctional RelA/SpoT homolog (RSH) that modulates levels of (p)ppGpp, a secondary messenger that orchestrates the stringent response through multiple allosteric interactions. We performed a forward genetic suppressor screen on bacteria lacking c-di-AMP to identify genomic mutations that rescued growth while cbpB was constitutively expressed and identified mutations in the synthetase domain of RelA. The synthetase domain of RelA was also identified as an interacting partner of CbpB in a yeast-2-hybrid screen. Biochemical analyses confirmed that free CbpB activates RelA while c-di-AMP inhibits its activation. We solved the crystal structure of CbpB bound and unbound to c-di-AMP and provide insight into the region important for c-di-AMP binding and RelA activation. The results of this study show that CbpB completes a homeostatic regulatory circuit between c-di-AMP and (p)ppGpp in Listeria monocytogenes.</div

Comparing different definitions of prediabetes with subsequent risk of diabetes: an individual participant data meta-analysis involving 76 513 individuals and 8208 cases of incident diabetes

Objective: There are currently five widely used definition of prediabetes. We compared the ability of these to predict 5-year conversion to diabetes and investigated whether there were other cut-points identifying risk of progression to diabetes that may be more useful. Research design and methods: We conducted an individual participant meta-analysis using longitudinal data included in the Obesity, Diabetes and Cardiovascular Disease Collaboration. Cox regression models were used to obtain study-specific HRs for incident diabetes associated with each prediabetes definition. Harrell's C-statistics were used to estimate how well each prediabetes definition discriminated 5-year risk of diabetes. Spline and receiver operating characteristic curve (ROC) analyses were used to identify alternative cut-points. Results: Sixteen studies, with 76 513 participants and 8208 incident diabetes cases, were available. Compared with normoglycemia, current prediabetes definitions were associated with four to eight times higher diabetes risk (HRs (95% CIs): 3.78 (3.11 to 4.60) to 8.36 (4.88 to 14.33)) and all definitions discriminated 5-year diabetes risk with good accuracy (C-statistics 0.79-0.81). Cut-points identified through spline analysis were fasting plasma glucose (FPG) 5.1 mmol/L and glycated hemoglobin (HbA1c) 5.0% (31 mmol/mol) and cut-points identified through ROC analysis were FPG 5.6 mmol/L, 2-hour postload glucose 7.0 mmol/L and HbA1c 5.6% (38 mmol/mol). Conclusions: In terms of identifying individuals at greatest risk of developing diabetes within 5 years, using prediabetes definitions that have lower values produced non-significant gain. Therefore, deciding which definition to use will ultimately depend on the goal for identifying individuals at risk of diabetes.This work was supported by the National Health and Medical Research Council of Australia (grant number 1103242). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contract nos. HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I. ES was supported by NIH/NIDDK grant K24DK106414. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN2682018000031, HHSN2682018000041, HHSN2682018000051, HHSN2682018000061 and HHSN2682018000071 from the National Heart, Lung, and Blood Institute (NHLBI). The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The Melbourne Collaborative Cohort Study (MCCS) recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. The Multi-Ethnic Study of Atherosclerosis was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The Population Study of Women in Gothenburg (PSWG) was financed in part by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement ALFGBG-720201. VIVA Study received grants 95/0029 and 06/90270 from the Instituto de Salud Carlos III, Spain.S

Endomembrane targeting of human OAS1 p46 augments antiviral activity

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity