A fungal endophyte induces local cell wall-mediated resistance in wheat roots against take-all disease.

Take-all disease, caused by the Ascomycete fungus Gaeumannomyces tritici, is one of the most important root diseases of wheat worldwide. The fungus invades the roots and destroys the vascular tissue, hindering the uptake of water and nutrients. Closely related non-pathogenic species in the Magnaporthaceae family, such as Gaeumannomyces hyphopodioides, occur naturally in arable and grassland soils and have previously been reported to reduce take-all disease in field studies. However, the mechanism of take-all protection has remained unknown. Here, we demonstrate that take-all control is achieved via local but not systemic host changes in response to prior G. hyphopodioides root colonisation. A time-course wheat RNA sequencing analysis revealed extensive transcriptional reprogramming in G. hyphopodioides-colonised tissues, characterised by a striking downregulation of key cell wall-related genes, including genes encoding cellulose synthases (CESA), and xyloglucan endotransglucosylase/hydrolases (XTH). In addition, we characterise the root infection biologies of G. tritici and G. hyphopodioides in wheat. We investigate the ultrastructure of previously described "subepidermal vesicles" (SEVs), dark swollen fungal cells produced in wheat roots by non-pathogenic G. hyphopodioides, but not by pathogenic G. tritici. We show that G. hyphopodioides SEVs share key characteristics of fungal resting structures, containing a greater number of putative lipid bodies and a significantly thickened cell wall compared to infection hyphae. We hypothesise that SEVs are fungal resting structures formed due to halted hyphal growth in the root cortex, perhaps as a stress response to locally induced wheat defence responses. In the absence of take-all resistant wheat cultivars or non-virulent G. tritici strains, studying closely related non-pathogenic G. hyphopodioides provides a much needed avenue to elucidate take-all resistance mechanisms in wheat.

Maintenance of X chromosome inactivation after T cell activation requires NF-κB signaling.

X chromosome inactivation (XCI) balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of X-inactive specific transcript (Xist) RNA and heterochromatic modifications on the inactive X chromosome (Xi), which are involved in maintenance of XCI, and these modifications return to the Xi after stimulation. Here, we examined allele-specific gene expression and epigenomic profiles of the Xi in T cells. We found that the Xi in unstimulated T cells is largely dosage compensated and enriched with the repressive H3K27me3 modification but not the H2AK119-ubiquitin (Ub) mark. Upon T cell stimulation mediated by both CD3 and CD28, the Xi accumulated H2AK119-Ub at gene regions of previous H3K27me3 enrichment. T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of the TCR, was required for Xist RNA localization to the Xi. Disruption of NF-κB signaling in mouse and human T cells using genetic deletion, chemical inhibitors, and patients with immunodeficiencies prevented Xist/XIST RNA accumulation at the Xi and altered X-linked gene expression. Our findings reveal a previously undescribed connection between NF-κB signaling pathways, which affects XCI maintenance in T cells in females.

Selective Use of Positive-Pressure Ventilation for Preoxygenation During Air Medical Rapid Sequence Intubation.

BACKGROUND: Preoxygenation is critical to safe performance of rapid sequence intubation (RSI). The use of positive-pressure ventilation (PPV) has been advocated during preoxygenation but may increase the risk of aspiration. OBJECTIVE: To explore the risk-benefit analysis of using PPV during air medical RSI. METHODS: We performed a retrospective analysis of the Air Methods Airway Registry using patient data from over 175 bases across the U.S. over a 5-year period. Patients were separated into normoxemic (SpO2 ≥93%) and hypoxemic (SpO2 <93%) and compared in regard to demographics, clinical data, and use of PPV. Primary outcomes were first-attempt intubation success (FAS) and FAS without desaturation (FASWD). Chi-square, t-test, and logistical regression were used to analyze the data. RESULTS: There were 9778 patients who underwent intubations during the study period. FAS was 92% (8966 patients). FASWD was 90% (8775 patients). Mean SpO2 was 94.9%. There were 42% (4118 patients) of patients who received PPV prior to intubation and 1% (94) aspirated during RSI. Multivariate logistical regression showed an association between use of PPV and reduced intubation success for normoxemic patients but improved intubation success for hypoxemic patients. The use of PPV was associated with higher risk of aspiration events (p = 0.007). CONCLUSION: The use of PPV during preoxygenation prior to RSI appears beneficial for hypoxemic but not normoxemic patients due to lower intubation success and increased aspiration risk with PPV. This data supports selective use of PPV prior to the initial intubation attempt in patients undergoing RSI.

Establishing a Core Outcome Set for Creatine Transporter Deficiency and Guanidinoacetate Methyltransferase Deficiency.

Creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies are rare inborn errors of creatine metabolism, resulting in cerebral creatine deficiency. Patients commonly exhibit intellectual and developmental disabilities, often accompanied by behavior problems, delayed speech, seizures, and motor impairments. There is currently no efficacious treatment for CTD, while the current management for GAMT requires lifelong treatment with a protein restricted diet and intake of high amounts of oral supplements. Efforts to develop effective, sustainable treatments for these disorders are limited by the lack of clinical and patient-derived meaningful outcomes. A core outcome set (COS) can facilitate consensus about outcomes for inclusion in studies. Unfortunately, patient and caregiver perspectives have historically been overlooked in the COS development process, thus limiting their input into the outcome selection. We partnered with caregivers and health professionals to establish the first COS for CTD and GAMT. The COS developed includes seven outcomes ("Adaptive Functioning", "Cognitive Functioning", "Emotional Dysregulation", "MRS Brain Creatine", "Seizure/Convulsions", "Expressive Communication", and "Fine Motor Functions") for both CTD and GAMT, and an additional outcome for GAMT ("Serum/Plasma Guanidinoacetate") that are important to stakeholders and consequently should be considered for measurement in every clinical trial. Caregivers were valued partners throughout the COS development process, which increased community engagement and facilitated caregiver empowerment. We expect this COS will ensure a patient-centered approach for accelerating drug development for CTD and GAMT, make clinical trial results comparable, minimize bias in clinical trial outcome selection, and promote efficient use of resources. 1-sentence take home message: A core outcome set for creatine transporter (CTD) and guanidinoacetate methyltransferase (GAMT) deficiencies was created through a multiphase process in partnership with caregivers and health professionals.

Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway.

Synthetic small interfering RNAs conjugated to trivalent N-acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs. An alternative siRNA design that can incorporate chemical modifications through straightforward synthesis without compromising potency will significantly advance the field. Here, we report a facile synthesis of GalNAc ligand-containing single-stranded loop hairpin RNAs (loopmeRNAs) with clinically relevant chemical modifications. We evaluated the efficiency of novel loopmeRNA designs in vivo and correlated their structure-activity relationship with the support of in vitro metabolism data. Sequences and chemical modifications in the loop region of the loopmeRNA design were optimized for maximal potency. Our studies demonstrate that loopmeRNAs can efficiently silence expression of target genes with comparable efficacy to conventional double-stranded siRNAs but reduced environmental and regulatory burdens.

Approach and withdrawal from cognitively effortful activities: Development, validation, and transdiagnostic clinical utility of a cognitive motivation scale.

BACKGROUND: Deficits in cognition and motivation predict functioning in depressive and psychotic disorders. However, experimental tasks of cognitive motivation are inconsistently correlated with functioning, time-intensive, and not intuitive in clinical practice. We aimed to develop and validate a self-report instrument to assess motivation processes pertinent to engagement with cognitive activities in daily life. METHOD: Following item generation, scale dimensionality, reliability, and validity were evaluated iteratively over Studies 1-3 with online general adult participants (n1 = 205; n2 = 235; n3 = 181). The 20-item Cognitive Motivation scale was also validated in a Study 3 sub-sample reporting high levels of depressive symptoms (n = 74) and Study 4 early psychosis outpatients (n = 25). RESULTS: Two-factor model of cognitive approach and cognitive withdrawal, each with good internal consistency, convergent validity, discriminant validity was supported. Cognitive withdrawal showed stronger associations with cognitive difficulties, depressive symptoms, and functional impairments than traditional motivation scale. Participants reporting high depression levels showed more severe difficulties with cognitive motivation than participants reporting low depression levels. In early psychosis outpatients, correlations with functioning and cognitive effort expenditure provided support for scale validity. LIMITATIONS: Cross-sectional data collection restricted evaluation of repeated administration psychometric properties. Scale validation was mostly established in online community samples and a small patient sample during the COVID-19 pandemic, thereby limiting generalizability of clinical applications. CONCLUSIONS: Cognitive Motivation scale is a promising tool for future intervention trials seeking to target motivational processes associated with functioning in the general population and potentially across patient groups with amotivation symptoms.

Multi-Level Approaches to Fetal Alcohol Spectrum Disorders Prevention Education and Training for Health Professionals.

BACKGROUND: Alcohol-exposed pregnancies, which can lead to fetal alcohol spectrum disorders (FASDs), is one of the most common preventable causes of lifelong intellectual and developmental disabilities in the U.S. Healthcare teams can play a critical role in preventing FASDs; however, they are currently unprepared to do so. Training can remediate this problem. This article explores the different approaches to the education and training of healthcare providers around FASD prevention used by six Centers for Disease Control (CDC)-funded programs, and how they have been adapted to (1) the specific needs of the healthcare professionals and/or the clinical setting and (2) the challenges posed by the COVID-19 pandemic. METHODS: This article offers an in-depth description and comparison of the models utilized by the programs described, detailing the challenges of each model as well as the adaptations made. Interdisciplinary collaboration and review highlights these models and offers a variety of solutions and lessons learned that can be implemented in similar practice settings and/or educational initiatives. RESULTS: Based on organizational structure (i.e., national organization, educational institution, and clinical settings) and program purpose, different methods were employed for FASD education. Some programs were focused on FASD prevention through staff training and alcohol screening and brief intervention/clinical intervention and others were focused on broadscale professional education and awareness. Improvements were made on an ongoing basis as challenges related to COVID-19, staff shortages, and patient and clinician discomfort were identified, resulting in modifications to content and delivery modality (e.g., online forums and use of social media). CONCLUSION: FASD prevention education is wrought with a variety of challenges related to stigma, discomfort, and misinformation, which these programs encountered in a variety of ways.

Bottlebrush Midblocks Promote Colloidal Bridging of Telechelic Polymers.

Telechelic polymers are effective rheological modifiers that bridge between associative constituents to form elastic networks. The performance of linear telechelic chains, however, is controlled by entropic forces and thus suffers from an upper limit on bridge formation. This work overcomes this limitation by utilizing telechelic triblock copolymers containing bottlebrush midblocks. By comparing the rheological properties of emulsions linked by telechelic bottlebrush polymers to those containing linear chains, we determined that telechelic polymers with bottlebrush midblocks form elastic networks more efficiently. These enhanced rheological properties arise from the high stiffness of the bottlebrush midblocks, which offsets the entropic stretching penalty for bridge formation, enabling them to more readily form networks. This molecular-level control over polymer conformation in complex fluids opens avenues for designing highly elastic networks with minimal polymeric additives.

Environmental fate and transport of PFAS in wastewater treatment plant effluent discharged to rapid infiltration basins.

Fate and transport of per- and polyfluoroalkyl substances (PFAS) in wastewater treatment plant (WWTP) effluent discharged to rapid infiltration basins (RIBs) is investigated using data from 26 WWTPs in Michigan, USA. PFAS were found to accumulate in groundwater downgradient from RIBs with median groundwater-effluent enrichment factors for ten commonly detected, terminal-form perfluoroalkyl acids (PFAAs) ranging from 1.3 to 5.2. Maximum contaminant levels for drinking water were exceeded in groundwater at all WWTPs with available PFAS data. Numerical models of unsaturated fluid flow and PFAS transport honoring RIB site properties, such as median vertical separation distance to the water table and a realistic range of area-normalized effluent fluxes, show long-chain PFAS undergo significant delays from air-water interface (AWI) adsorption, requiring up to 15 times longer to reach maximum mass flux to the saturated zone under low-flux conditions, where AWI area is 2.5 times greater. Short-chain PFAS commonly detected in effluent are only minimally affected by AWI adsorption and show little to no attenuation under high-flux conditions. The nonlinear inverse relationship between water content and AWI area highlights the important role of AWI adsorption in modulating unsaturated transport of long-chain PFAS to underlying groundwater due to the broad range of flux rates applied to RIB systems.

Complete Genomic Characterization of Global Pathogens, Respiratory Syncytial Virus (RSV), and Human Norovirus (HuNoV) Using Probe-based Capture Enrichment.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, while human noroviruses (HuNoV) are a leading cause of epidemic and sporadic acute gastroenteritis. Generating full-length genome sequences for these viruses is crucial for understanding viral diversity and tracking emerging variants. However, obtaining high-quality sequencing data is often challenging due to viral strain variability, quality, and low titers. Here, we present a set of comprehensive oligonucleotide probe sets designed from 1,570 RSV and 1,376 HuNoV isolate sequences in GenBank. Using these probe sets and a capture enrichment sequencing workflow, 85 RSV positive nasal swab samples and 55 (49 stool and six human intestinal enteroids) HuNoV positive samples encompassing major subtypes and genotypes were characterized. The Ct values of these samples ranged from 17.0-29.9 for RSV, and from 20.2-34.8 for HuNoV, with some HuNoV having below the detection limit. The mean percentage of post-processing reads mapped to viral genomes was 85.1% for RSV and 40.8% for HuNoV post-capture, compared to 0.08% and 1.15% in pre-capture libraries, respectively. Full-length genomes were>99% complete in all RSV positive samples and >96% complete in 47/55 HuNoV positive samples-a significant improvement over genome recovery from pre-capture libraries. RSV transcriptome (subgenomic mRNAs) sequences were also characterized from this data. Probe-based capture enrichment offers a comprehensive approach for RSV and HuNoV genome sequencing and monitoring emerging variants.

Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics.

Nicotinamide adenine dinucleotide (NAD+) is an essential co-factor in metabolic reactions and co-substrate for signaling enzymes. Failing human hearts display decreased expression of the major NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (Nampt) and lower NAD+ levels, and supplementation with NAD+ precursors is protective in preclinical models. Here we show that Nampt loss in adult cardiomyocytes caused depletion of NAD+ along with marked metabolic derangements, hypertrophic remodeling and sudden cardiac deaths, despite unchanged ejection fraction, endurance and mitochondrial respiratory capacity. These effects were directly attributable to NAD+ loss as all were ameliorated by restoring cardiac NAD+ levels with the NAD+ precursor nicotinamide riboside (NR). Electrocardiograms revealed that loss of myocardial Nampt caused a shortening of QT intervals with spontaneous lethal arrhythmias causing sudden cardiac death. Thus, changes in NAD+ concentration can have a profound influence on cardiac physiology even at levels sufficient to maintain energetics.

Wafer-Scale MgB2 Superconducting Devices.

Progress in superconducting device and detector technologies over the past decade has realized practical applications in quantum computers, detectors for far-infrared telescopes, and optical communications. Superconducting thin-film materials, however, have remained largely unchanged, with aluminum still being the material of choice for superconducting qubits and niobium compounds for high-frequency/high kinetic inductance devices. Magnesium diboride (MgB2), known for its highest transition temperature (Tc = 39 K) among metallic superconductors, is a viable material for elevated temperature and higher frequency superconducting devices moving toward THz frequencies. However, difficulty in synthesizing wafer-scale thin films has prevented implementation of MgB2 devices into the application base of superconducting electronics. Here, we report ultrasmooth (<0.5 nm root-mean-square roughness) and uniform MgB2 thin (<100 nm) films over 100 mm in diameter and present prototype devices fabricated with these films demonstrating key superconducting properties including an internal quality factor over 104 at 4.5 K and high tunable kinetic inductance in the order of tens of pH/sq in a 40 nm thick film. This advancement will enable development of elevated temperature, high-frequency superconducting quantum circuits, and devices.

Improving Specificity for Ovarian Cancer Screening Using a Novel Extracellular Vesicle-Based Blood Test: Performance in a Training and Verification Cohort.

The low incidence of ovarian cancer (OC) dictates that any screening strategy needs to be both highly sensitive and highly specific. This study explored the utility of detecting multiple colocalized proteins or glycosylation epitopes on single tumor-associated extracellular vesicles from blood. The novel Mercy Halo Ovarian Cancer Test (OC Test) uses immunoaffinity capture of tumor-associated extracellular vesicles, followed by proximity-ligation real-time quantitative PCR to detect combinations of up to three biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. A high-grade serous carcinoma (HGSC) case-control training set of EDTA plasma samples from 397 women was used to lock down the test design, the data interpretation algorithm, and the cutoff between cancer and noncancer. Performance was verified and compared with cancer antigen 125 in an independent blinded case-control set of serum samples from 390 women (132 controls, 66 HGSC, 83 non-HGSC OC, and 109 benign). In the verification study, the OC Test showed a specificity of 97.0% (128/132; 95% CI, 92.4%-99.6%), a HGSC sensitivity of 97.0% (64/66; 95% CI, 87.8%-99.2%), and an area under the curve of 0.97 (95% CI, 0.93-0.99) and detected 73.5% (61/83; 95% CI, 62.7%-82.6%) of the non-HGSC OC cases. This test exhibited fewer false positives in subjects with benign ovarian tumors, nonovarian cancers, and inflammatory conditions when compared with cancer antigen 125. The combined sensitivity and specificity of this new test suggests it may have potential in OC screening.

Partisan Bias in Political Judgment.

This article reviews empirical data demonstrating robust ingroup favoritism in political judgment. Partisans display systematic tendencies to seek out, believe, and remember information that supports their political beliefs and affinities. However, the psychological drivers of partisan favoritism have been vigorously debated, as has its consistency with rational inference. We characterize decades-long debates over whether such tendencies violate normative standards of rationality, focusing on the phenomenon of motivated reasoning. In light of evidence that both motivational and cognitive factors contribute to partisan bias, we advocate for a descriptive approach to partisan bias research. Rather than adjudicating the (ir)rationality of partisan favoritism, future research should prioritize the identification and measurement of its predictors and clarify the cognitive mechanisms underlying motivated political reasoning. Ultimately, we argue that political judgment is best evaluated by a standard of ecological rationality based on its practical implications for individual well-being and functional democratic governance.

Stent vs Stent-Less Ileal Conduits After Radical Cystectomy: Is There a Difference in Early Postoperative Outcomes?

INTRODUCTION: Placing ureteral stents at the uretero-ileal anastomosis for radical cystectomy with ileal conduit (RCIC) has long been common practice. Recently, some providers have begun omitting stents. We sought to investigate differences in perioperative and 30-day outcomes between patients who underwent radical cystectomy with ileal conduit (RCIC) with and without stents placed at the uretero-ileal anastomosis. METHODS: We identified RCICs performed between 2019 to 2021 in the National Surgical Quality Improvement Program database and corresponding Cystectomy-Targeted Participant Use File. Baseline demographics, comorbidities, and operative parameters were compared via Pearson's chi-square and t-tests between stented and stent-less RCICs. Outcomes of interest, including rates of urinary tract infections (UTIs), acute kidney injury (AKI), renal failure requiring dialysis, ileoileal anastomotic leaks, ureteral obstruction, urinary leak or fistula formation, reoperations, and 30-day hospital readmissions were compared using Pearson's chi-square. All statistical tests were 2 tailed with P < .05 considered significant. RESULTS: Five Thousand Four Hundred Eighteen RCICs were identified. Four hundred ninety-eight (9.2%) were stent-less. There were no differences in baseline demographics or comorbidities. Significantly fewer stented patients had robotic-assisted operations (23% vs 29%, P < .01). Stented patients had lower rates of urinary leak or fistula formation (3.1% vs 4.8%, P = .04). There was no significant difference in 30-day rates of UTIs, AKIs, renal failure, ileoileal anastomotic leaks, ureteral obstruction, reoperations, and readmissions. Limitations include retrospective design and lack of longitudinal tracking past 30 days. CONCLUSIONS: Stent-less patients had non-inferior outcomes compared to stented patients in most important 30-day outcomes. Our analysis suggests that stents may not be necessary in ileal conduit urinary diversion procedures.

Evidence of longitudinal differences in spring migration strategies of an Arctic-nesting goose.

During spring, migratory birds are required to optimally balance energetic costs of migration across heterogeneous landscapes and weather conditions to survive and reproduce successfully. Therefore, an individual's migratory performance may influence reproductive outcomes. Given large-scale changes in land use, climate, and potential carry-over effects, understanding how individuals migrate in relation to breeding outcomes is critical to predicting how future scenarios may affect populations. We used GPS tracking devices on 56 Greater White-fronted Geese (Anser albifrons) during four spring migrations to examine whether migration characteristics influenced breeding propensity and breeding outcome. We found a strong longitudinal difference in arrival to the breeding areas (18 days earlier), pre-nesting duration (90.9% longer), and incubation initiation dates (9 days earlier) between western- and eastern-Arctic breeding regions, with contrasting effects on breeding outcomes, but no migration characteristic strongly influenced breeding outcome. We found that breeding region influenced whether an individual likely pursued a capital or income breeding strategy. Where individuals fell along the capital-income breeding continuum was influenced by longitude, revealing geographic effects of life-history strategy among conspecifics. Factors that govern breeding outcomes likely occur primarily upon arrival to breeding areas or are related to individual quality and previous breeding outcome, and may not be directly tied to migratory decision-making across broad scales.