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Nanophotonic materials offer spectral and directional control over thermal emission, but in high-temperature oxidizing environments, their stability remains low. This limits their applications in technologies such as solid-state energy conversion and thermal barrier coatings. Here we show an epitaxial heterostructure of perovskite BaZr

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Purpose:The oral proteasome inhibitor oprozomib has shown preclinical antitumor activity. Here, we report phase Ib/II study results investigating single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.Patients and Methods:The primary objectives were to determine the MTD, safety, and tolerability of oprozomib (phase Ib) as well as overall response rate (ORR; phase II). Oprozomib was administered once daily on days 1, 2, 8, and 9 (2/7 schedule) or days 1 to 5 (5/14 schedule) of a 14-day cycle.Results:In patients with multiple myeloma or Waldenström macroglobulinemia (n = 71), the determined MTDs were 300 mg/day (2/7 schedule) and 240 mg/day (5/14 schedule). Median oprozomib treatment duration for patients with multiple myeloma was 11.4 weeks (2/7 schedule, 240/300 mg/day), 5.4 weeks (5/14, 240 mg/day), and 10.1 weeks (5/14, 150/180 mg/day). For patients with Waldenström macroglobulinemia, these values were 34.6 weeks (2/7 schedule, 240/300 mg/day) and 8.1 weeks (5/14 schedule, 240 mg/day). The most common grade ≥3 adverse events (AE) in phase Ib included gastrointestinal and hematologic AEs. Three AE-related deaths in phase II prompted enrollment into 2/7 and 5/14 step-up dosing schedules (240/300 mg/day and 150/180 mg/day, respectively). In phase II, ORRs in 95 response-eligible multiple myeloma patients were 41.0%, 28.1%, and 25.0% in the 2/7, 240/300-mg/day; 5/14, 150/180-mg/day; and 5/14, 240-mg/day cohorts, respectively. ORRs in 31 response-eligible Waldenström macroglobulinemia patients were 71.4% and 47.1% for the 2/7 and 5/14 cohorts, respectively.Conclusions:This study demonstrated promising efficacy of single-agent oprozomib in patients with relapsed multiple myeloma and Waldenström macroglobulinemia.

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

A variety of organisms have been shown to have altered physiology or developed pathology due to gene transfer, but mammals have never been shown to do so. Here, we show that circulating tumor DNA (ct) can promote cell-specific horizontal gene transfer (HGT) between human cancer cells and explain the mechanisms behind this phenomenon. Once ctDNA enters the host cell, it migrates to the nucleus and integrates into the cell’s genome, thereby transferring its genetic information. We determine that retrotransposons of the ERVL, SINE, and LINE families are necessary for cell targeting and the integration of ctDNA into host DNA. Using chemically synthesized retrotransposons, we found that AluSp and MER11C reproduced multiple myeloma’s (MM) ctDNA’s cell targeting and integration into MM cells. We also discovered that ctDNA might, as a result of HGT, influence the treatment response of multiple myeloma and pancreatic cancer models. Overall, this is the first study to show that retrotransposon-directed HGT can promote genetic material transfer in cancer. There is, however, a broader impact of our findings than just cancer since cell-free DNA has also been found in physiological and other pathological conditions as well. Furthermore, with the discovery of transposons-mediated tissue-specific targeting, a new avenue for the delivery of genes and therapies will emerge.

Clean-catch urine (CCU) samples are frequently contaminated. Our aim was to determine if cleaning with 0.1% chlorhexidine before CCU is a safe and feasible method to reduce contamination.Prospective interventional pilot study. Children 1-24 months underwent perigenital skin cleaning with 0.1% chlorhexidine. Primary outcome was contamination rate, and secondary outcomes were parent and clinician satisfaction with the procedure.Twelve of 54 urine samples were contaminated (22%, 95% CI 13-35). Over 90% of parents and clinicians were either 'satisfied' or 'very satisfied'. No adverse events were recorded.Cleaning with chlorhexidine solution before CCU is safe and feasible.

Lattice distortion in high-entropy alloys is postulated to have major effects on their thermophysical properties. There are limited studies that have looked at the effect of lattice distortion on entropy-stabilized oxides. In this study, lattice distortion in the entropy-stabilized oxide, MgCoNiCuZnO5, is explored as a function of temperature. This work uses molecular dynamics (MD) to identify the explicit distances that each atom and atom type distorts from its parent rocksalt crystal structure. Our goal in this work is to understand how the manipulation of the interatomic potential parameters used to define the structure can effectively change the lattice distortion in this system. The results show that lattice distortion increases with temperature and that it can be increased or decreased by changing the atomic composition, the equiatomic ratio, or by judiciously replacing some atoms with alternative elements. Such optimization can potentially modify thermophysical properties of the alloy.

Clathrin-mediated endocytosis (CME) is the main mechanism by which mammalian cells control their cell surface proteome. Proper operation of the pivotal CME cargo-adaptor AP2 requires membrane-localised FCHO. Here, live-cell eTIRF-SIM shows that FCHO marks sites of clathrin-coated pit (CCP) initiation, which mature into uniform sized CCPs comprising a central patch of AP2 and clathrin corralled by an FCHO/Eps15 ring. We dissect the network of interactions between the FCHO interdomain-linker and AP2, which concentrates, orients, tethers and partially destabilizes closed AP2 at the plasma membrane. AP2’s subsequent membrane deposition drives its opening, which triggers FCHO displacement through steric competition with PtdIns4,5P2, clathrin, cargo and CME accessory factors. FCHO can now relocate toward a CCP's outer edge to engage and activate further AP2s to drive CCP growth/maturation.

This review sought to highlight the current paradigms and emerging treatment options for two common and serious problems after congenital cardiac surgery: low cardiac output syndrome (LCOS) and vasoplegia. Low cardiac output syndrome and vasoplegia remain prevalent after congenital cardiac surgery. Recent studies on adjunctive agents for LCOS have not shown consistent improvements in patient outcomes. Recent studies of targeted vasoconstrictors, adjunctive nitric oxide antagonists, and perioperative corticosteroids have limitations precluding their routine use in pediatric patients after congenital cardiac surgery. The treatment of LCOS is predicated on approaches that improve cardiac output by augmentation of heart rate, contractility, preload, and minimization of afterload. Strategies that minimize tissue oxygen demand can also be helpful to restore matching of tissue oxygen delivery and demand. The hallmark of vasoplegia treatment is augmentation of systemic vascular tone. A variety of emerging therapies are under investigation for their role in LCOS and vasoplegia after congenital cardiac surgery, but none are ready for routine use.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

The Toronto Addis Ababa Academic Collaboration in Emergency Medicine (TAAAC-EM) is an educational global health partnership established 10 years ago to support the growth of EM in Ethiopia. In-person global health partnership activities were disrupted by the COVID-19 pandemic. We describe our five-step process for transitioning our global health partnership to a virtual space. Each step was conducted in collaboration between the University of Toronto and Addis Ababa University EM physicians: (1) risk identification and needs assessment, (2) discussing mitigation strategies, (3) crafting and piloting an approach, (4) revising based on pilot results, 5) implementation with continuous evaluation and revision. Teaching was modified iteratively in response to feedback. Our experience shows that virtual teaching, while not a replacement for in-person engagement, can be a valuable tool both to supplement partnership activities when travel is not possible, and to enhance global health partnerships long term. This approach can also inform the transition of other forms of medical education to the virtual space.RéSUMé: La Toronto Addis-Ababa collaboration universitaire en médecine d’urgence (TAAAC-EM) est un partenariat mondial en éducation à la santé établi il y a 10 ans pour soutenir la croissance de la médecine d’urgence en Éthiopie. Les activités du partenariat mondiale pour la santé en personne ont été perturbées par la pandémie de COVID-19. Nous décrivons notre processus en cinq étapes pour la transition de notre partenariat mondial pour la santé vers un espace virtuel. Chaque étape a été menée en collaboration entre les médecins d’urgences de l’Université de Toronto et de l’Université d’Addis-Ababa : 1) identification des risques et évaluation des besoins, 2) discussion des stratégies d’atténuation, 3) élaboration et pilotage d’une approche, 4) révision basée sur les résultats des projets pilotes, 5) mise en œuvre avec évaluation et révision continues. L’enseignement a été modifié de manière itérative en réponse aux commentaires. Notre expérience montre que l’enseignement virtuel, bien qu’il ne remplace pas l’engagement en personne, peut être un outil précieux à la fois pour compléter les activités de partenariat lorsque les déplacements ne sont pas possibles, et pour renforcer les partenariats mondiaux pour la santé à long terme. Cette approche peut également faire apprendre la transition d’autres formes de formation médicale vers l’espace virtuel.

Functional thin film superlattices with stability in extreme environments can lead to transformative performance in optical and thermal applications such as thermophotovoltaics. In this work, key issues associated with defects that prevent layer-by-layer growth in epitaxial, low-miscibility oxide superlattices are investigated. Layer protrusions, approximately 8 nm wide and 3 nm thick, arise from a strain relaxation mechanism in 8 nm bilayer superlattices of Ba(Zr0.5Hf0.5)O3/MgO and propagate through the subsequent superlattice layers forming an inverted pyramid structure that is spatially phase offset from the matrix. The density and size of these defects scales with the number of interfaces in the sample, indicating that surface roughness during growth is a significant factor in the formation of these defects. In situ high temperature transmission electron microscopy (1000 °C, in vacuo) measurement reveals that phase decomposition of Ba(Zr0.5Hf0.5)O3 and decoherence of the superlattice is nucleated by these defects. This work highlights that achieving optimum growth conditions is imperative to the synthesis of single-crystalline superlattices with sharp interfaces for optimized performance in extreme environments.

To assess the growth trajectory of preterm small-for-gestational-age (SGA) neonates compared to preterm non-small-for-gestational age neonates in the neonatal intensive care unit and special care nursery.We conducted a retrospective cohort study at a large tertiary hospital in Victoria, Australia, examining neonates ≤34 weeks' gestation admitted to the neonatal intensive care unit or special care nursery between 2013 and 2017. We categorized neonates according to their birth weight centile:10th centile (small-for-gestational age) and ≥10th centile (non-small-for-gestational age). Growth trajectory was tracked based on serial weights obtained in the neonatal intensive care unit and special care nursery, usingOf the 910 babies included, 88 were small-for-gestational age and 822 were appropriate-for gestational age. Both groups had a reduction in their weightPreterm SGA babies experience a smaller reduction in their weight trajectory compared to their appropriately grown counterparts in the neonatal intensive care unit or special care nursery.

INTRODUCTION AND OBJECTIVE:We previously reported on the single slice T1 mapping of human bladder using a pair of spoiled gradient recalled echo (SPGR) images acquired at different flip angles. Her...

INTRODUCTION AND OBJECTIVE:Intravesical therapy is critical for bladder cancer and a secondary option for interstitial cystitis and overactive bladder patient's refractory to oral treatment. Althou...

BackgroundUrinary tract infection (UTI) is a common childhood infection. Many febrile children require a urine sample to diagnose or exclude UTI. Collecting urine from young children can be time-consuming, unsuccessful or contaminated. Cost-effectiveness of each collection method in the emergency department is unknown.ObjectiveTo determine the cost-effectiveness of urine collection methods for precontinent children.MethodsA cost-effectiveness analysis was conducted comparing non-invasive (urine bag, clean catch and 5 min voiding stimulation for clean catch) and invasive (catheterisation and suprapubic aspirate (SPA)) collection methods, for children aged 0–24 months in the emergency department. Costs included equipment, staff time and hospital bed occupancy. If initial collection attempts were unsuccessful subsequent collection using catheterisation was assumed. The final outcome was a definitive sample incorporating progressive dipstick, culture and contamination results. Average costs and outcomes were calculated for initial collection attempts and obtaining a definitive sample. One-way and probabilistic sensitivity analyses were performed.ResultsFor initial collection attempts, catheterisation had the lowest cost per successful collection (GBP£25.98) compared with SPA (£37.80), voiding stimulation (£41.32), clean catch (£52.84) and urine bag (£92.60). For definitive collection, catheterisation had the lowest cost per definitive sample (£49.39) compared with SPA (£51.84), voiding stimulation (£52.25), clean catch (£64.82) and urine bag (£112.28). Time occupying a hospital bed was the most significant determinant of cost.ConclusionCatheterisation is the most cost-effective urine collection method, and voiding stimulation is the most cost-effective non-invasive method. Urine bags are the most expensive method. Although clinical factors influence choice of method, considering cost-effectiveness for this common procedure has potential for significant aggregate savings.

To assess whether quantitative T1 relaxometry can measure permeability, chronic inflammation and mural thickening of mouse bladder wall. Adult female C57BL6 mice unexposed to radiation (controls) or 40 wk postirradiation of 10 Gy were scanned at 9.4 T before and after instillation (0.1 mL) of aqueous, novel contrast mixture (NCM) containing 4 mM gadobutrol and 5 mM ferumoxytol. Rapid acquisition with refocused echo (RARE) sequence was used with variable repetition times (TR). Pixel-wise maps of T1 relaxation times for the segmented bladder wall layers were generated from voxel-wise, nonlinear least square data fitting of TR-dependent signal intensity acquired with TR array of 0.4–10 s followed by the histology of harvested bladder. Significant differences between precontrast and postcontrast T1 (ΔT1) were noted in urothelium and lamina propria of both groups but only in detrusor of irradiated group ( P < 0.001; 2-way ANOVA). Nearly twofold higher gadobutrol permeability (550 ± 73 vs. 294 ± 160 μM; P < 0.01) derived as per 1/ΔT1 = r1. [C] in urothelium of irradiated group. Inflammation and bladder wall thickening (0.75 ± 0. vs. 0.44 ± 0.08 mm; P < 0.001) predicted by MRI was subsequently confirmed by histology and altered expression of CD45 and zonula occludens-1 (ZO-1) relative to controls. NCM enhanced MRI relies on the retention of large molecular weight ferumoxytol in lumen for negative contrast, while permeation of the non-ionic, small molecular weight gadobutrol through ZO-1 generates positive contrast in bladder wall for virtual measurement of paracellular permeability and assessment of chronic inflammation in thin and distensible bladder wall, which is also defined by its variable shape and location within pelvis.

Aim Clean catch urine (CCU) collection is commonly used in pre-continent children. CCU can be time-consuming and specimens may be contaminated. Our aim was to determine the time taken for CCU attempts and to describe the success of this method in diagnosing or excluding urinary tract infection. Methods Prospective observational study of CCU in pre-continent children aged 2–48 months in the emergency department. Time taken until urine collection, ‘successful’ (voided and caught), ‘missed’ (voided not caught) or the procedure ‘stopped’, were recorded and urine culture results analysed. Results Two hundred and seventeen children (131 (60%) male) were enrolled. There were a total of 247 attempts at CCU. For the first attempt, the median collecting time was 30.5 min (interquartile range (IQR) 11–66). Outcome was ‘successful’ in 64% (95% confidence intervals (CI) 58–70%), ‘missed’ in 16% (95% CI 11–20%) and ‘stopped’ in 20% (95% CI 15–26%). Median time if ‘successful’ was 25 min (IQR 7–46.5), ‘missed’ 27 min (IQR 11.6–59) and 71 min (IQR 42.5–93) when ‘stopped’. One hundred and sixty children had successful CCU collection, 129 were sent for culture. Fifty of 129 (39%) cultures were contaminated. If all urine specimens caught were sent for culture, the estimated yield of an uncontaminated urine specimen was 45%. Contamination was not related to time taken for CCU. Conclusions CCU is time-consuming, frequently unsuccessful and contaminated, resulting in a low overall diagnostic yield. Clinicians could expect a 45% chance of obtaining a definitive urine sample from this method overall.

BackgroundAntibiotic overuse has promoted growing rates of antimicrobial resistance and secondary antibiotic-associated infections such asClostridium difficile(C. difficile). Antimicrobial stewardship programs (ASPs) are effective in reducing antimicrobial use in the inpatient setting; however, the unique environment of the emergency department (ED) lends itself to challenges for successful implementation. Front-line ownership (FLO) methodology has been shown to be a potentially effective strategy for the implementation of inpatient ASPs through an iterative multi-pronged approach driven by front-line providers.ObjectiveTo determine whether a FLO approach to antimicrobial stewardship in the ED can alter antimicrobial usage.MethodsInterventions were driven by ED physicians and facilitated by Infectious Diseases Division physicians from the hospital’s ASP using FLO principles. Measured end points included antibiotic usage in the ED as measured by defined daily doses, and rates of urine culture sent from the ED.ResultsThere was a step-wise significant reduction in the use of azithromycin (p=0.006), ceftriaxone (p=0.045), ciprofloxacin (p=0.034), and moxifloxacin (p=0.008). There was also a significant reduction in rates of urine cultures (pConclusionsFLO offers a promising approach to successful implementation of an ASP in the ED. Future studies would be important to evaluate the generalizability of the FLO approach to ASP development in other EDs and to determine strategies to improve the sustainability of reductions in antimicrobial use.

Ebstein’s disease of the tricuspid valve is a congenital cardiac anomaly that occurs with an incidence of approximately 1–5 in every 200,000 live newborns, therefore representing 1% of congenital cardiac defects. It is the most common etiology for congenital tricuspid regurgitation in the neonatal period as well as later in life. This chapter will summarize the main aspects related to diagnosis and management of the Ebstein’s disease of the tricuspid valve.

Fellowship examinations are a potentially stressful part of clinical training. While they may feel at the time to be a test of academic fortitude and endurance, they also establish the foundation knowledge essential for a career in paediatrics. We reflect on the important role of the study group in this process, and the far-reaching benefits of peer support and sticking together, for the exam and beyond.

Urinary tract infections (UTIs) are a common and potentially serious bacterial infection of childhood. History and examination findings can be non-specific, so a urine sample is required to diagnose UTI. Sample collection in young precontinent children can be challenging. Bedside dipstick tests are useful for screening, but urine culture is required for diagnostic confirmation. Antibiotic therapy must be guided by local guidelines due to increasing antibiotic resistance. Duration of therapy and indications for imaging remain controversial topics and guidelines lack consensus. This article presents an overview of paediatric UTI diagnosis and management, with highlights of recent advances and evidence updates.

We thank the author(s) for their most informative letter in response to our article [...]

Mastering regulation The mechanistic target of rapamycin complex 1 (mTORC1) is known as the master kinase, acknowledging its key role in integrating multiple signals to regulate cell growth. When nutrients are abundant, heterodimers of Rag, a class of small guanosine triphosphatase, bind to mTORC1 and recruit it to the lysosome. Here, other signaling pathways converge on the mTORC1 complex. Anandapadamanaban et al. determined cryo–electron microscopy and crystal structures of a RagA/RagC heterodimer. The structures, together with dynamic studies, explain the nucleotide states required for binding to mTORC1 and support a mechanism for conformational communication between the RagA and RagC subunits in the heterodimer. RagA/RagC binding causes no conformational change in mTORC1, which is consistent with the idea that mTORC1 must sense additional growth regulators before it is activated. Science , this issue p. 203

Ensuring that the entire Australian population is Vitamin D sufficient is challenging, given the wide range of latitudes spanned by the country, its multicultural population and highly urbanised lifestyle of the majority of its population. Specific issues related to the unique aspects of vitamin D metabolism during pregnancy and infancy further complicate how best to develop a universally safe and effective public health policy to ensure vitamin D adequacy for all. Furthermore, as Australia is considered a “sunny country”, it does not yet have a national vitamin D food supplementation policy. Rickets remains very uncommon in Australian infants and children, however it has been recognised for decades that infants of newly arrived immigrants remain particularly at risk. Yet vitamin D deficiency rickets is entirely preventable, with the caveat that when rickets occurs in the absence of preexisting risk factors and/or is poorly responsive to adequate treatment, consideration needs to be given to genetic forms of rickets.

Renal near-infrared spectroscopy is known to be predictive of acute kidney injury in children following cardiac surgery using a series of complex equations and area under the curve. This study was performed to determine if a greater than or equal to 20% reduction in renal near-infrared spectroscopy for 20 consecutive minutes intraoperatively or within the first 24 postoperative hours is associated with 1) acute kidney injury, 2) increased acute kidney injury biomarkers, or 3) other adverse clinical outcomes in children following cardiac surgery.Prospective single center observational study.Pediatric cardiac ICU.Children less than or equal to age 4 years who underwent cardiac surgery with the use of cardiopulmonary bypass during the study period (June 2011-July 2012).None.A reduction in near-infrared spectroscopy was not associated with acute kidney injury. Nine of 12 patients (75%) with a reduction in renal near-infrared spectroscopy did not develop acute kidney injury. The remaining three patients had mild acute kidney injury (pediatric Risk, Injury, Failure, Loss, End stage-Risk). A reduction in renal near-infrared spectroscopy was associated with the following adverse clinical outcomes: 1) a longer duration of mechanical ventilation (p = 0.05), 2) longer intensive care length of stay (p = 0.05), and 3) longer hospital length of stay (p0.01). A decline in renal near-infrared spectroscopy in combination with an increase in serum interleukin-6 and serum interleukin-8 was associated with a longer intensive care length of stay, and the addition of urine interleukin-18 to this was associated with a longer hospital length of stay.In this cohort, the rate of acute kidney injury was much lower than anticipated thereby limiting the evaluation of a reduction in renal near-infrared spectroscopy as a predictor of acute kidney injury. A greater than or equal to 20% reduction in renal near-infrared spectroscopy was significantly associated with adverse outcomes in children following cardiac surgery. The addition of specific biomarkers to the model was predictive of worse outcomes in these patients. Thus, real-time evaluation of renal near-infrared spectroscopy using the specific levels of change of a 20% reduction for 20 minutes may be useful in predicting prolonged mechanical ventilation and other adverse outcomes in children undergoing cardiac surgery.

Eukaryotic cells coordinate growth with the availability of nutrients through the protein kinase complex mTORC1, which is part of a pathway that is often upregulated in cancer. The mTORC1 complex is activated by association with two types of GTPases, Rags and RHEB. The heterodimeric Rag GTPases are key components in the activation of the mTORC1 pathway in response to amino acids. The Rag heterodimer interacts with the RAPTOR subunit of mTORC1 in a manner dependent on the nucleotide-bound states of its constituent GTPases. We used hydrogen/deuterium exchange mass spectrometry (HDX-MS) to map the interface of RAPTOR with an active Rag heterodimer, and we determined X-ray crystal structures of human Rag heterodimers in several nucleotide-bound states. Our high-resolution crystal structure of an oncogenic mutant heterodimer enabled us to interpret the cryo-EM structure of a complex of mTORC1 with the mutant RagA/C heterodimer. The cryo-EM structure shows that the G-domains from both Rags contact helical repeats of the RAPTOR subunit of mTORC1, but the GTP-bound RagA G domain forms almost all of the interface. The structure suggests how the nucleotide state of RagA is coordinated with the nucleotide state of RagC. The conformation of mTORC1 in a complex with the Rags is nearly identical to the apo mTORC1 complex, suggesting that the primary role of Rag binding is to recruit the mTORC1 complex to the lysosomal surface in the presence of the Ragulator complex. Citation Format: Madhan Anandapadamanaban, Olga Perisic, Alex Berndt, Glenn R Masson, Jonathan Kaufman, Stephen H. McLaughlin, Chris M. Johnson, David M. Sabatini, Roger L. Williams. Structure and dynamics of Rag heterodimers in a complex with mTORC1 [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr IA10.

BICEP Array is a degree-scale Cosmic Microwave Background (CMB) experiment that will search for primordial B-mode polarization while constraining Galactic foregrounds. BICEP Array will be comprised of four receivers to cover a broad frequency range with channels at 30/40, 95, 150 and 220/270 GHz. The first low-frequency receiver will map synchrotron emission at 30 and 40 GHz and will deploy to the South Pole at the end of 2019. In this paper, we give an overview of the BICEP Array science and instrument, with a focus on the detector module. We designed corrugations in the metal frame of the module to suppress unwanted interactions with the antenna-coupled detectors that would otherwise deform the beams of edge pixels. This design reduces the residual beam systematics and temperature-to-polarization leakage due to beam steering and shape mismatch between polarized beam pairs. We report on the simulated performance of single- and wide-band corrugations designed to minimize these effects. Our optimized design alleviates beam differential ellipticity caused by the metal frame to about 7% over 57% bandwidth (25 to 45 GHz), which is close to the level due the bare antenna itself without a metal frame. Initial laboratory measurements are also presented., 12 pages and 14 figures

Summary Drosophila Dpr (21 paralogs) and DIP proteins (11 paralogs) are cell recognition molecules of the immunoglobulin superfamily (IgSF) that form a complex protein interaction network. DIP and Dpr proteins are expressed in a synaptic layer-specific fashion in the visual system. How interactions between these proteins regulate layer-specific synaptic circuitry is not known. Here we establish that DIP-α and its interacting partners Dpr6 and Dpr10 regulate multiple processes, including arborization within layers, synapse number, layer specificity, and cell survival. We demonstrate that heterophilic binding between Dpr6/10 and DIP-α and homophilic binding between DIP-α proteins promote interactions between processes in vivo. Knockin mutants disrupting the DIP/Dpr binding interface reveal a role for these proteins during normal development, while ectopic expression studies support an instructive role for interactions between DIPs and Dprs in circuit development. These studies support an important role for the DIP/Dpr protein interaction network in regulating cell-type-specific connectivity patterns.