Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection.

Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.

Molecular evidence of anteroposterior patterning in adult echinoderms.

The origin of the pentaradial body plan of echinoderms from a bilateral ancestor is one of the most enduring zoological puzzles1,2. Because echinoderms are defined by morphological novelty, even the most basic axial comparisons with their bilaterian relatives are problematic. To revisit this classical question, we used conserved anteroposterior axial molecular markers to determine whether the highly derived adult body plan of echinoderms masks underlying patterning similarities with other deuterostomes. We investigated the expression of a suite of conserved transcription factors with well-established roles in the establishment of anteroposterior polarity in deuterostomes3-5 and other bilaterians6-8 using RNA tomography and in situ hybridization in the sea star Patiria miniata. The relative spatial expression of these markers in P. miniata ambulacral ectoderm shows similarity with other deuterostomes, with the midline of each ray representing the most anterior territory and the most lateral parts exhibiting a more posterior identity. Strikingly, there is no ectodermal territory in the sea star that expresses the characteristic bilaterian trunk genetic patterning programme. This finding suggests that from the perspective of ectoderm patterning, echinoderms are mostly head-like animals and provides a developmental rationale for the re-evaluation of the events that led to the evolution of the derived adult body plan of echinoderms.

Candidate Cancer Driver Mutations in Distal Regulatory Elements and Long-Range Chromatin Interaction Networks.

A comprehensive catalog of cancer driver mutations is essential for understanding tumorigenesis and developing therapies. Exome-sequencing studies have mapped many protein-coding drivers, yet few non-coding drivers are known because genome-wide discovery is challenging. We developed a driver discovery method, ActiveDriverWGS, and analyzed 120,788 cis-regulatory modules (CRMs) across 1,844 whole tumor genomes from the ICGC-TCGA PCAWG project. We found 30 CRMs with enriched SNVs and indels (FDR < 0.05). These frequently mutated regulatory elements (FMREs) were ubiquitously active in human tissues, showed long-range chromatin interactions and mRNA abundance associations with target genes, and were enriched in motif-rewiring mutations and structural variants. Genomic deletion of one FMRE in human cells caused proliferative deficiencies and transcriptional deregulation of cancer genes CCNB1IP1, CDH1, and CDKN2B, validating observations in FMRE-mutated tumors. Pathway analysis revealed further sub-significant FMREs at cancer genes and processes, indicating an unexplored landscape of infrequent driver mutations in the non-coding genome.

Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Normal Fermi Surface in the Nodal Superconductor CeCoIn_{5} Revealed via Thermal Conductivity.

The thermal conductivity of heavy-fermion superconductor CeCoIn_{5} was measured with a magnetic field rotating in the tetragonal a-b plane, with the heat current in the antinodal direction, J|| [100]. We observe a sharp resonance in thermal conductivity for the magnetic field at an angle Θ≈12°, measured from the heat current direction [100]. This resonance corresponds to the reported resonance at an angle Θ^{'}≈33° from the direction of the heat current applied along the nodal direction, J||[110]. Both resonances, therefore, occur when the magnetic field is applied in the same crystallographic orientation in the two experiments, regardless of the direction of the heat current, proving conclusively that these resonances are due to the structure of the Fermi surface of CeCoIn_{5}. We argue that the uncondensed Landau quasiparticles, emerging with field, are responsible for the observed resonance. We support our experimental results with density-functional-theory model calculations of the density of states in a rotating magnetic field. Our calculations, using a model Fermi surface of CeCoIn_{5}, reveal several sharp peaks as a function of the field direction. Our study demonstrates that the thermal-conductivity measurement in rotating magnetic field can probe the normal parts of the Fermi surface deep inside the superconducting state.

Mohs micrographic surgery for the treatment of invasive melanoma: A systematic review with meta-analyses.

BACKGROUND: The use of Mohs micrographic surgery (MMS) in melanoma treatment has divided opinion and evidence-based guidelines are lacking. OBJECTIVES: This systematic review aimed to analyse clinical outcomes for patients with invasive melanomas treated with Mohs rather than wide local excision (WLE). METHODS: Embase, MEDLINE and Cochrane databases (to 30 August 2023) were searched for studies using Mohs to treat invasive melanoma. Outcomes of interest were local recurrence and death from melanoma. RESULTS: Thirty-five articles involving 41,499 patients with invasive melanoma treated with Mohs were identified. Sixteen studies compared Mohs with WLE and 19 were Mohs-only, non-comparative studies. Patients treated with Mohs differed significantly from those undergoing WLE, in particular Mohs patients were older and had thinner melanomas. Two comparative studies using the same data source reported adjusted hazard ratios for melanoma-specific death and both showed no significant difference between Mohs and WLE-treated patients; 0.87 (95% CI 0.55-1.35) and 1.20 (95% CI 0.71-20.36). There was also no statistically significant difference in local recurrence risk; the unadjusted risk ratio for patients treated with Mohs was 0.46 (95% CI 0.14-1.51 p = 0.20) with moderate heterogeneity (I2 = 62%). No studies reported multivariable analyses for risk of local recurrence. Many studies generated from relatively few and often overlapping data sets have reported the use of Mohs to treat patients with invasive melanoma. Fewer studies were comparative between Mohs and WLE and these reported substantially different baseline risks of recurrence and death from melanoma between the groups. Mohs has generally been used for thinner melanomas in older patients; therefore, comparisons based on univariable analyses are likely to have been misleading. CONCLUSIONS: On the basis of currently available data, it is not possible to reliably assess whether outcomes differ if invasive melanomas with comparable features are treated with Mohs or WLE, and randomized trial evidence will be required for reliable conclusions to be reached.

When and why is red blood cell genotyping applicable in transfusion medicine: a systematic review of the literature.

This review aims to provide a better understanding of when and why red blood cell (RBC) genotyping is applicable in transfusion medicine. Articles published within the last 8 years in peer-reviewed journals were reviewed in a systematic manner. RBC genotyping has many applications in transfusion medicine including predicting a patient's antigen profile when serologic methods cannot be used, such as in a recently transfused patient, in the presence of autoantibody, or when serologic reagents are not available. RBC genotyping is used in prenatal care to determine zygosity and guide the administration of Rh immune globulin in pregnant women to prevent hemolytic disease of the fetus and newborn. In donor testing, RBC genotyping is used for resolving ABO/D discrepancies for better donor retention or for identifying donors negative for high-prevalence antigens to increase blood availability and compatibility for patients requiring rare blood. RBC genotyping is helpful to immunohematology reference laboratory staff performing complex antibody workups and is recommended for determining the antigen profiles of patients and prospective donors for accurate matching for C, E, and K in multiply transfused patients. Such testing is also used to determine patients or donors with variant alleles in the Rh blood group system. Information from this testing aides in complex antibody identification as well as sourcing rare allele-matched RBC units. While RBC genotyping is useful in transfusion medicine, there are limitations to its implementation in transfusion services, including test availability, turn-around time, and cost.

Suture Augmentation of a Four-Strand Semitendinosus Graft Improves Time-Zero Biomechanical Properties.

PURPOSE: To compare the time-zero biomechanical properties of hamstring graft preparations with or without suture augmentation for anterior cruciate ligament reconstruction (ACLR) in a full-construct cadaveric model. METHODS: Hamstring grafts were harvested from 24 fresh frozen human cadavers and prepared in 1 of 3 ways: quadrupled SemiTendinosus (SemiT), and quadrupled SemiT with suture augmentation (SemiT+2.0-mm tape or SemiT+1.3-mm tape; n = 8 per group). Adjustable loop suspensory implants and cortical buttons were used for fixation on a porcine tibia and acrylic block. Testing included force-controlled cyclic loading at 250 N and 400 N followed by load to failure. RESULTS: The 2 suture augmentation groups had less total elongation and increased stiffness compared to the nonsuture-augmented group (P = .025). The SemiT+2.0-mm tape group had 36% less total elongation and 34% increased stiffness compared to SemiT+1.3mm tape (P < .001). CONCLUSIONS: Suture augmentation improves construct biomechanics at time zero following hamstring tendon ACLR. Augmentation with 2.0-mm tape suture improves construct biomechanics compared to 1.3-mm tape suture. CLINICAL RELEVANCE: Independent suture augmentation of a quadrupled SemiT graft improves ACLR construct biomechanics. Outcomes were improved with augmentation using 2.0-mm tape suture compared to 1.3-mm tape suture.

Cleft Laterality Dental Arch Relationship Outcomes for Children with Unilateral Cleft Lip and Palate in New Zealand.

OBJECTIVES: To investigate cleft laterality dental arch relationship outcomes of children with non-syndromic complete unilateral cleft lip and palate (UCLP) in New Zealand. DESIGN: A retrospective nationwide study. SETTINGS: Virtual 3D orthodontic study models collected prior to undertaking secondary alveolar bone grafting. PARTICIPANTS: A total of 104 patients with UCLP (L = 80: R = 24). OUTCOME MEASURES: Four calibrated assessors used the GOSLON Yardstick and 100 mm Visual Analogue Scale (VAS) to score the randomised models on 2 separate assessment sessions. Weighted Kappa were used to determine the intra/inter-rater reliability for the GOSLON and correlations for the VAS. RESULTS: Intra-rater reliability ranged from 0.57-0.88 (GOSLON) and 0.45-0.93 (VAS). Inter-rater reliability ranged from 0.62-0.86 (GOSLON) and 0.64-0.93 (VAS).GOSLON scores for the left UCLP were 31.2% for good/very good; 26.3% for fair; 42.5% for poor/very poor while the right UCLP scored 8.3% for good/very good; 37.5% for fair; 54.2% for poor/very poor. The mean VAS for left and right UCLP were 53.4 (sd 22.5) and 44.6 (sd 17.1) respectively. Neither the GOSLON nor VAS differences reached statistical significance (both P = .08). CONCLUSIONS: From a clinical perspective right UCLP had worse dental arch relationship outcomes, however, these differences failed to reach statistical significance. Further studies using larger sample sizes are required to determine if cleft laterality is an important consideration when investigating UCLP dental arch outcomes.

Managing the risks associated with technological disruption in the road transport system: a control structure modelling approach.

Road transport is experiencing disruptive change from new first-of-a-kind technologies. While such technologies offer safety and operational benefits, they also pose new risks. It is critical to proactively identify risks during the design, development and testing of new technologies. The Systems Theoretic Accident Model and Processes (STAMP) method analyses the dynamic structure in place to manage safety risks. This study applied STAMP to develop a control structure model for emerging technologies in the Australian road transport system and identified control gaps. The control structure shows the actors responsible for managing risks associated with first-of-a-kind technologies and the existing control and feedback mechanisms. Gaps identified related to controls (e.g. legislation) and feedback mechanisms (e.g. monitoring for behavioural adaptation). The study provides an example of how STAMP can be used to identify control structure gaps requiring attention to support the safe introduction of new technologies.

This paper considers emerging risks associated with new technologies in the road transport system. It demonstrates a novel approach using STAMP to identify gaps in control and feedback mechanisms within the existing control structure which should be addressed to mitigate risk.

Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Absence of Spontaneous Magnetic Fields due to Time-Reversal Symmetry Breaking in Bulk Superconducting UTe_{2}.

We have investigated the low-temperature local magnetic properties in the bulk of molten salt-flux (MSF)-grown single crystals of the candidate odd-parity superconductor UTe_{2} by zero-field muon spin relaxation (µSR). In contrast to previous µSR studies of UTe_{2} single crystals grown by a chemical vapor transport method, we find no evidence of magnetic clusters or electronic moments fluctuating slow enough to cause a discernible relaxation of the zero-field µSR asymmetry spectrum. Consequently, our measurements on MSF-grown single crystals rule out the generation of spontaneous magnetic fields in the bulk that would occur near impurities or lattice defects if the superconducting state of UTe_{2} breaks time-reversal symmetry. This result suggests that UTe_{2} is characterized by a single-component superconducting order parameter.

Quality-adjusted survival in women with gynecologic malignancies receiving IMRT after surgery: A Ppatient Rreported Ooutcome study of NRG oncology's RTOG 1203.

INTRODUCTION: NRG/RTOG 1203 compared 3-D conformal radiotherapy (3D CRT) to intensity-modulated radiotherapy (IMRT) in patients with endometrial or cervical cancer requiring post-operative radiotherapy after hysterectomy. The purpose of this study was to report the first quality-adjusted survival analysis comparing the two treatments. METHODS: NRG/RTOG 1203 randomized patients having undergone hysterectomy to either 3DCRT or IMRT. Stratification factors included RT dose, chemotherapy, and disease site. The EQ-5D, both index and visual analog scale (VAS), were obtained at baseline, 5 weeks after the start of RT, 4-6 weeks post RT and 1 and 3-years post RT. EQ-5D index and VAS scores along with quality-adjusted survival (QAS) were compared between treatment arms using the t-test at a two-sided significance level of 0.05. RESULTS: NRG/RTOG 1203 enrolled 289 patients of which 236 consented to participate in the patient reported outcome (PRO) assessments. QAS was higher in women treated with IMRT, 1374 vs 1333 days (p = 0.5) compared to patients treated with 3DCRT, but this difference was not statistically different. Patients treated with IMRT had less of a decline in VAS score 5 weeks post RT, -5.04, compared to patients treated with 3DCRT, -7.48, although not statistically significant (p = 0.38). CONCLUSION: This is the first report of the use of the EQ-5D comparing two radiotherapy techniques in the treatment of gynecologic malignancies after surgery. While there were no significant differences in QAS and VAS scores between patients who received IMRT vs. 3DCRT, RTOG 1203 was not powered to show statistical differences in these secondary endpoints.

KPT-330 Prevents Aortic Valve Calcification via a Novel C/EBPß Signaling Pathway.

[Figure: see text].

Protocolized screening and detection of occult alcohol use before and after liver transplant: Lessons learned from a quality improvement initiative.

INTRODUCTION: Detection of alcohol (ETOH) use with biomarkers provides an opportunity to intervene and treat patients with alcohol use disorder before and after liver transplant (LT). We describe our center's experience using urine ethyl glucuronide (EtG) and serum phosphatidylethanol (PEth) in alcohol screening protocols. METHODS: Single-center, retrospective review of patients presenting for LT evaluation, patients waitlisted for LT for alcohol-associated liver disease (ALD), and patients who received a LT for ALD over a 12-month period, from October 1, 2019 through September 30, 2020. Patients were followed from waitlisting to LT, or for up to 12 months post-LT. We monitored protocol adherence to screening for ETOH use- defined as completion of all possible tests over the follow-up period- at the initial LT visit, while on the LT waitlist and after LT. RESULTS: During the study period, 227 patients were evaluated for LT (median age 57 years, 58% male, 78% white, 54.2% ALD). Thirty-one patients with ALD were placed on the waitlist, and 38 patients underwent LT for ALD during this time period. Protocolized adherence to screening for alcohol use was higher for PEth for all LT evaluation patients (191 [84.1%] vs. 146 [67%] eligible patients, p < .001), in patients with ALD waitlisted for LT (22 [71%] vs. 14 (48%] eligible patients, p = .04) and after LT for ALD, 20 (33 [86.8%] vs. 20 [52.6%] eligible patients, p < .01). Few patients with a positive test in any group completed chemical dependency treatment. CONCLUSIONS: When screening for ETOH use in pre- and post-LT patients, protocol adherence is higher using PEth compared to EtG. While protocolized biomarker screening can detect recurrent ETOH use in this population, engagement of patients into chemical dependency treatment remains challenging.

Forecasting emergent risks in advanced AI systems: an analysis of a future road transport management system.

Artificial Intelligence (AI) is being increasingly implemented within road transport systems worldwide. Next generation of AI, Artificial General Intelligence (AGI) is imminent, and is anticipated to be more powerful than current AI. AGI systems will have a broad range of abilities and be able to perform multiple cognitive tasks akin to humans that will likely produce many expected benefits, but also potential risks. This study applied the EAST Broken Links approach to forecast the functioning of an AGI system tasked with managing a road transport system and identify potential risks. In total, 363 risks were identified that could have adverse impacts on the stated goals of safety, efficiency, environmental sustainability, and economic performance of the road system. Further, risks beyond the stated goals were identified; removal from human control, mismanaging public relations, and self-preservation. A diverse set of systemic controls will be required when designing, implementing, and operating future advanced technologies.Practitioner summary: This study demonstrated the utility of HFE methods for formally considering risks associated with the design, implementation, and operation of future technologies. This study has implications for AGI research, design, and development to ensure safe and ethical AGI implementation.

On-Chip Preconcentration Microchip Capillary Electrophoresis Based CE-PRM-LIVE for High-Throughput Selectivity Profiling of Deubiquitinase Inhibitors.

The family of deubiquitinases (DUBs) comprises ∼100 enzymes that cleave ubiquitin from substrate proteins and thereby regulate key aspects of human physiology. DUBs have recently emerged as disease-relevant and chemically tractable, although currently there are no approved DUB-targeting drugs and most preclinical small molecules are low-potency and/or multitargeted. We paired a novel capillary electrophoresis microchip containing an integrated, "on-chip" C18 bed (SPE-ZipChip) with a TMT version of our recently described PRM-LIVE acquisition scheme on a timsTOF Pro mass spectrometer to facilitate rapid activity-based protein profiling of DUB inhibitors. We demonstrate the ability of the SPE-ZipChip to improve proteome coverage of complex samples as well as the quantitation integrity of CE-PRM-LIVE for TMT labeled samples. These technologies provide a platform to accurately quantify competitive binding of covalent and reversible inhibitors in a multiplexed assay that spans 49 endogenous DUBs in less than 15 min.

Diet and irritable bowel syndrome: an update from a UK consensus meeting.

There has been a renewed interest in the role of dietary therapies to manage irritable bowel syndrome (IBS), with diet high on the agenda for patients. Currently, interest has focussed on the use of traditional dietary advice (TDA), a gluten-free diet (GFD) and the low FODMAP diet (LFD). A consensus meeting was held to assess the role of these dietary therapies in IBS, in Sheffield, United Kingdom.Evidence for TDA is from case control studies and clinical experience. Randomised controlled trials (RCT) have demonstrated the benefit of soluble fibre in IBS. No studies have assessed TDA in comparison to a habitual or sham diet. There have been a number of RCTs demonstrating the efficacy of a GFD at short-term follow-up, with a lack of long-term outcomes. Whilst gluten may lead to symptom generation in IBS, other components of wheat may also play an important role, with recent interest in the role of fructans, wheat germ agglutinins, as well as alpha amylase trypsin inhibitors. There is good evidence for the use of a LFD at short-term follow-up, with emerging evidence demonstrating its efficacy at long-term follow-up. There is overlap between the LFD and GFD with IBS patients self-initiating gluten or wheat reduction as part of their LFD. Currently, there is a lack of evidence to suggest superiority of one diet over another, although TDA is more acceptable to patients.In view of this evidence, our consensus group recommends that dietary therapies for IBS should be offered by dietitians who first assess dietary triggers and then tailor the intervention according to patient choice. Given the lack of dietetic services, novel approaches such as employing group clinics and online webinars may maximise capacity and accessibility for patients. Further research is also required to assess the comparative efficacy of dietary therapies to other management strategies available to manage IBS.

Trapping Alkaline Earth Rydberg Atoms Optical Tweezer Arrays.

Neutral atom qubits with Rydberg-mediated interactions are a leading platform for developing large-scale coherent quantum systems. In the majority of experiments to date, the Rydberg states are not trapped by the same potential that confines ground state atoms, resulting in atom loss and constraints on the achievable interaction time. In this Letter, we demonstrate that the Rydberg states of an alkaline earth atom, ytterbium, can be stably trapped by the same red-detuned optical tweezer that also confines the ground state, by leveraging the polarizability of the Yb^{+} ion core. Using the previously unobserved ^{3}S_{1} series, we demonstrate trapped Rydberg atom lifetimes exceeding 100 µs, and observe no evidence of auto- or photoionization from the trap light for these states. We measure a coherence time of T_{2}=59 µs between two Rydberg levels, exceeding the 28 µs lifetime of untrapped Rydberg atoms under the same conditions. These results are promising for extending the interaction time of Rydberg atom arrays for quantum simulation and computing, and are vital to capitalize on the extended Rydberg lifetimes in circular states or cryogenic environments.

Quantitative Proteomics Links the LRRC59 Interactome to mRNA Translation on the ER Membrane.

Protein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination of numerous cellular components. Together, resident ER membrane proteins, cytoplasmic translation factors, and both integral membrane and cytosolic RNA-binding proteins operate in concert with membrane-associated ribosomes to facilitate ER-localized translation. Little is known, however, regarding the spatial organization of ER-localized translation. This question is of growing significance as it is now known that ER-bound ribosomes contribute to secretory, integral membrane, and cytosolic protein synthesis alike. To explore this question, we utilized quantitative proximity proteomics to identify neighboring protein networks for the candidate ribosome interactors SEC61ß (subunit of the protein translocase), RPN1 (oligosaccharyltransferase subunit), SEC62 (translocation integral membrane protein), and LRRC59 (ribosome binding integral membrane protein). Biotin labeling time course studies of the four BioID reporters revealed distinct labeling patterns that intensified but only modestly diversified as a function of labeling time, suggesting that the ER membrane is organized into discrete protein interaction domains. Whereas SEC61ß and RPN1 reporters identified translocon-associated networks, SEC62 and LRRC59 reporters revealed divergent protein interactomes. Notably, the SEC62 interactome is enriched in redox-linked proteins and ER luminal chaperones, with the latter likely representing proximity to an ER luminal chaperone reflux pathway. In contrast, the LRRC59 interactome is highly enriched in SRP pathway components, translation factors, and ER-localized RNA-binding proteins, uncovering a functional link between LRRC59 and mRNA translation regulation. Importantly, analysis of the LRRC59 interactome by native immunoprecipitation identified similar protein and functional enrichments. Moreover, [35S]-methionine incorporation assays revealed that siRNA silencing of LRRC59 expression reduced steady state translation levels on the ER by ca. 50%, and also impacted steady state translation levels in the cytosol compartment. Collectively, these data reveal a functional domain organization for the ER and identify a key role for LRRC59 in the organization and regulation of local translation.