Activating Nitrogen for Electrochemical Ammonia Synthesis via an Electrified Transition-Metal Dichalcogenide Catalyst.

The complex interplay between local chemistry, the solvent microenvironment, and electrified interfaces frequently present in electrocatalytic reactions has motivated the development of quantum chemical methods that can accurately model these effects. Here, we predict the thermodynamics of the nitrogen reduction reaction (NRR) at sulfur vacancies in 1T'-phase MoS2 and highlight how the realistic treatment of potential within grand canonical density functional theory (GC-DFT) seamlessly captures the multiple competing effects of applied potential on a catalyst interface interacting with solvated molecules. In the canonical approach, the computational hydrogen electrode is widely used and predicts that adsorbed N2 structure properties are potential-independent. In contrast, GC-DFT calculations show that reductive potentials activate N2 toward electroreduction by controlling its back-bonding strength and lengthening the N-N triple bond while decreasing its bond order. Similar trends are observed for another classic back-bonding ligand in CO, suggesting that this mechanism may be broadly relevant to other electrochemistries involving back-bonded adsorbates. Furthermore, reductive potentials are required to make the subsequent N2 hydrogenation steps favorable but simultaneously destabilizes the N2 adsorbed structure resulting in a trade-off between the favorability of N2 adsorption and the subsequent reaction steps. We show that GC-DFT facilitates modeling all these phenomena and that together they can have important implications in predicting electrocatalyst selectivity for the NRR and potentially other reactions.

Evaluation of a Combinatorial Immunotherapy Regimen That Can Cure Mice Bearing MYCN-Driven High-Risk Neuroblastoma That Resists Current Clinical Therapy.

Background: Incorporating GD2-targeting monoclonal antibody into post-consolidation maintenance therapy has improved survival for children with high-risk neuroblastoma. However, ~50% of patients do not respond to, or relapse following, initial treatment. Here, we evaluated additional anti-GD2-based immunotherapy to better treat high-risk neuroblastoma in mice to develop a regimen for patients with therapy-resistant neuroblastoma. Methods: We determined the components of a combined regimen needed to cure mice of established MYCN-amplified, GD2-expressing, murine 9464D-GD2 neuroblastomas. Results: First, we demonstrate that 9464D-GD2 is nonresponsive to a preferred salvage regimen: anti-GD2 with temozolomide and irinotecan. Second, we have previously shown that adding agonist anti-CD40 mAb and CpG to a regimen of radiotherapy, anti-GD2/IL2 immunocytokine and anti-CTLA-4, cured a substantial fraction of mice bearing small 9464D-GD2 tumors; here, we further characterize this regimen by showing that radiotherapy and hu14.18-IL2 are necessary components, while anti-CTLA-4, anti-CD40, or CpG can individually be removed, and CpG and anti-CTLA-4 can be removed together, while maintaining efficacy. Conclusions: We have developed and characterized a regimen that can cure mice of a high-risk neuroblastoma that is refractory to the current clinical regimen for relapsed/refractory disease. Ongoing preclinical work is directed towards ways to potentially translate these findings to a regimen appropriate for clinical testing.

Effects of passive ankle exoskeletons on neuromuscular function during exaggerated standing sway.

Wearable robotic exoskeletons designed to assist human movement should integrate with the neuromusculoskeletal system. This means assisting movement while not perturbing motor control. We sought to test if passive ankle exoskeletons, which have been shown to successfully assist human gait, affect neuromuscular control of an exaggerated anterior-posterior standing sway task. Participants actively swayed while wearing an ankle exoskeleton that provided 0, 42 or 85 Nm rad-1 of additional stiffness to the ankle joint in resistance to dorsiflexion. Sway amplitude was controlled via biofeedback to elicit similar ankle angle displacements across conditions. With greater exoskeleton stiffness, participants swayed at lower sway-cycle frequencies and slower centre of pressure speeds. Furthermore, increasing exoskeleton stiffness resulted in longer operating lengths of the medial gastrocnemius and overall reduced plantar flexor muscle activation. For the soleus, there was also a temporal shift in the cross-correlation of its electromyogram with the centre of pressure displacement, meaning that muscle activation peaked later than anterior sway displacement. Together, these data suggest that assistive ankle exoskeletons influence neuromuscular control of ankle-based sway tasks. Changes in fascicle lengths could influence afferent feedback signals and the short-range stiffness of ankle muscles, while shifts in muscle activation timing suggest changes in neural control. The observed neuromuscular adaptations to exoskeleton assistance demonstrate the potential implications for standing balance and overall movement control, prompting future investigations.

Changes in Perceived Emotions in Facial Paralysis Patients After Depressor Anguli Oris Excision.

OBJECTIVES: Depressor anguli oris (DAO) excision can improve clinician-graded, objective, and patient-reported smile outcomes in patients with nonflaccid facial paralysis (NFFP). However, no prior research has studied changes in perceived emotions after surgery. This study quantifies changes in perceived emotions with smiling after DAO excision in the largest case series presented to date. METHODS: Prospectively collected data from patients with NFFP who underwent DAO excision at a tertiary care facial nerve center were reviewed. Patient-reported, clinician-graded, and objective smile metrics were compared before and after surgery. Videos of faces at rest and while smiling were analyzed by artificial intelligence-derived facial expression analysis software to quantify perceived emotions. RESULTS: Sixty-eight patients underwent isolated DAO excision between August 2021 and August 2023. Patients conveyed significantly more perceived happiness with smile and at rest after surgery (p < 0.001 and p = 0.012, respectively). DAO excision improved oral commissure excursion (p < 0.001), dental show (p < 0.001), and smile angle (p < 0.001) symmetry. Patients reported significant improvements in smiling and social function after surgery. CONCLUSIONS: This study demonstrates DAO excision increases perceived happiness conveyed by patients with NFFP while smiling and at rest. It confirms improved objective, clinician-graded, and patient-reported smile outcomes after surgery. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2024.

Evaluation of environmental features that support breastfeeding: A photovoice study.

The United Kingdom (UK) has some of the lowest breastfeeding rates in the world, and Stoke-on-Trent has some of the lowest breastfeeding rates and highest infant mortality rates in the UK. Vicarious experience of formula feeding, formula feeding culture, and a lack of physical environments to support breastfeeding are known barriers to uptake and maintenance. Improving physical environments and increasing the visibility of breastfeeding in public would help to challenge these barriers. This research employs a participatory approach to understand the facilitators and barriers to breastfeeding in public. Nine breastfeeding peer supporters were recruited as co-researcher for a photovoice study. Co-researchers collated images of features in environments which they felt either supported or acted as a barrier to public breastfeeding. An analysis workshop was held to review the data collected and produce collaboratively agreed findings. Various environmental features were highlighted as facilitators to breastfeeding including family rooms, welcoming signage, supportive staff members, and displays of information about breastfeeding. In addition, poorly designed family rooms, lack of inclusivity within breastfeeding spaces, breastfeeding spaces within toilets and a lack of information were barriers to public breastfeeding. This research illustrates that while some environments are well designed to support breastfeeding many others are not. Environments often lack basic provision and/or make token gestures towards breastfeeding support, such as welcome signage, without providing the infrastructure needed to support breastfeeding. More education about breastfeeding friendly spaces and resources for putting this information into practice are needed for environment owners, managers, and policy makers.

Surgical Management of Overgrowth Syndrome With Bilateral Vision-Threatening Ptosis.

We describe the first case reported in ophthalmological literature of the surgical management of a 17-month-old boy with bilateral vision-threatening ptosis, tarsomegaly, ectropion, and euryblepharon secondary to suspected overgrowth syndrome. We elaborate on the major challenges associated with surgical management including the natural and asymmetric growth of oversized tissue, the high likelihood of scarring and formation of disorganized tissue, and risks of frequent intubation in these patients who may have lesions that compromise critical structures such as the airway. Ultimately, surgical intervention is encouraged primarily if vision or ocular health is threatened and secondarily to achieve good cosmesis.

A survey of preferences and expectations for surgical interventions targeting atonic seizures in Lennox-Gastaut syndrome.

PURPOSE: To assess preferences and outcome expectations for vagus nerve stimulation (VNS) and corpus callosotomy (CC) surgeries in the treatment of atonic seizure in Lennox-Gastaut syndrome (LGS). METHODS: A total of 260 surveys were collected from patients are caregivers of LGS patients via Research Electronic Data Capture (REDCap). RESULTS: Respondents reported an average acceptable atonic seizure reduction rate of 55.9% following VNS and 74.7% following CC. 21.3% (n = 50) were willing to be randomized. Respondents reported low willingness for randomization and a higher seizure reduction expectation with CC. CONCLUSION: Our findings guide surgical approaches for clinicians to consider patient preference in order to design future studies comparing effectiveness between these two procedures.

Benchmarking of X-Ray Fluorescence Microscopy with Ion Beam Implanted Samples Showing Detection Sensitivity of Hundreds of Atoms.

Single impurities in insulators are now often used for quantum sensors and single photon sources, while nanoscale semiconductor doping features are being constructed for electrical contacts in quantum technology devices, implying that new methods for sensitive, non-destructive imaging of single- or few-atom structures are needed. X-ray fluorescence (XRF) can provide nanoscale imaging with chemical specificity, and features comprising as few as 100 000 atoms have been detected without any need for specialized or destructive sample preparation. Presently, the ultimate limits of sensitivity of XRF are unknown - here, gallium dopants in silicon are investigated using a high brilliance, synchrotron source collimated to a small spot. It is demonstrated that with a single-pixel integration time of 1 s, the sensitivity is sufficient to identify a single isolated feature of only 3000 Ga impurities (a mass of just 350 zg). With increased integration (25 s), 650 impurities can be detected. The results are quantified using a calibration sample consisting of precisely controlled numbers of implanted atoms in nanometer-sized structures. The results show that such features can now be mapped quantitatively when calibration samples are used, and suggest that, in the near future, planned upgrades to XRF facilities might achieve single-atom sensitivity.

A high internal heat flux and large core in a warm neptune exoplanet.

Interactions between exoplanetary atmospheres and internal properties have long been hypothesized to be drivers of the inflation mechanisms of gaseous planets and apparent atmospheric chemical disequilibrium conditions1. However, transmission spectra of exoplanets has been limited in its ability to observational confirm these theories due to the limited wavelength coverage of HST and inferences of single molecules, mostly H2O (ref. 2). In this work, we present the panchromatic transmission spectrum of the approximately 750 K, low-density, Neptune-sized exoplanet WASP-107b using a combination of HST WFC3, JWST NIRCam and MIRI. From this spectrum, we detect spectroscopic features due to H2O (21σ), CH4 (5σ), CO (7σ), CO2 (29σ), SO2 (9σ), and NH3 (6σ). The presence of these molecules enable constraints on the atmospheric metal enrichment (M/H is 10-18× Solar3), vertical mixing strength (log10Kzz = 8.4-9.0 cm2s-1), and internal temperature (>345 K). The high internal temperature is suggestive of tidally-driven inflation4 acting upon a Neptunelike internal structure, which can naturally explain the planet's large radius and low density. These findings suggest that eccentricity driven tidal heating is a critical process governing atmospheric chemistry and interior structure inferences for a majority of the cool (<1,000K) super-Earth-to-Saturn mass exoplanet population.

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response.

C. elegans numr-1/2 (nuclear-localized metal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts for numr-1p::GFP activation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activates numr-1/2 strongly in the alimentary canal but is distinct from metal exposure, because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism in C. elegans as genetic disruption and RNAi screening of homologues did not induce numr-1/2 in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to induce numr-1/2. ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect on numr-1/2, suggesting a dimer requirement. Chetomin inhibits C. elegans growth at low micromolar levels, and loss of numr-1/2 increases sensitivity; C. elegans and Chaetomiaceae fungi inhabit similar environments raising the possibility that numr-1/2 functions as a defense mechanism. There is no direct orthologue of numr-1/2 in humans, but RNaseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.

Genetic impact of external Targhee sires at the U.S. Sheep Experiment Station: a case study of introgression.

Sheep breeders requested that the U.S. Sheep Experiment Station (USSES) to participate in national genetic evaluation through the National Sheep Improvement Program (NSIP). The reasons included the need for (1) a comparison of the productivity of industry and United States Department of Agriculture (USDA) lines, (2) transparency of USDA flocks, (3) genetic ties for NSIP by sampling of industry flocks, and (4) development of premium genetic lines for public release. In response, USSES began to incorporate external sires from NSIP participating flocks into the USSES Targhee flock. Our objective, based on a pedigree analysis, was to test if introgression of external genetics into the flock was achieved. The pedigree included 13,189 animals with mean maximum generations, mean complete generations, and mean equivalent complete generations of 4.2, 1.8, and 2.6, respectively. The mean generation interval was 3.1 yr. The reference population was defined as lambs born from 2021 to 2023 (n = 792). Two additional populations were defined as the current mature ewe flock (n = 123) and the current mature rams (n = 14). The Genetic Conservation Index averaged 7.7 for the full population and 25.7 for the reference population. Overall inbreeding was 0.003 for the full population and 0.006 for the reference population. The rate of inbreeding was 0.0003 per generation. Average relatedness was 0.015 for the full population and 0.018 for the reference population. The effective number of founders, effective number of ancestors, and founder genome equivalents contributing to the reference population were 60, 39, and 19.1, respectively. The ratio of the effective number of founders to the effective number of ancestors was 1.5, indicating the presence of genetic bottlenecks. Measures of effective population size ranged from 102 to 547. Of the 704 offspring produced by external sires, 17 ram lambs and 132 ewe lambs were retained for breeding. The USSES sires produced 299 offspring with 2 ram lambs and 51 ewe lambs retained. Incorporating external sires resulted in a cumulative percentage of genetic variance of 48.8, 49.1, and 44.2 of external genetics for the reference population, current mature ewe flock, and current mature rams, respectively. Stakeholder needs were addressed by introgression of external sires and participation in NSIP, but future selection practices need to be modified to maintain a minimum of 50% USSES core genetics in the flock.

Haloperidol-Induced Neuroleptic Malignant Syndrome: A Case Report.

Neuroleptic malignant syndrome (NMS) is a severe reaction to antipsychotic medications characterized by fever, muscle rigidity, altered mental status, and autonomic dysfunction. Here, we describe the case of a 58-year-old female who presented with altered mental status two days after open reduction and internal fixation of the hip. A rapid response team was called when the patient appeared agitated with increased respiratory demand. After being intubated and moved to the ICU, she became febrile and rigid. A preliminary diagnosis of metabolic encephalopathy of unknown origin was made. Before being transported to the ICU, the patient was given multiple haloperidol doses in addition to her continued at-home medication, paroxetine, for major depressive disorder. The differential diagnosis included a workup for NMS, serotonin syndrome, and infectious processes. Once NMS was determined as the most likely etiology, all antipsychotic and serotonergic medications were discontinued. Then dantrolene and amantadine were administered, which resulted in clinically significant improvement. This case report demonstrates the importance of early identification of and intervention for NMS.

Buprenorphine prescribing and treatment accessibility in response to regulation changes due to the COVID-19 public health emergency.

BACKGROUND: In 2021, over 80,000 fatal overdoses occurred in the United States. Since 2020, the federal government has enacted multiple regulatory changes around buprenorphine prescribing for opioid use disorder (OUD) to increase access to buprenorphine. This study aims to explore trends in buprenorphine treatment initiation pre- and post-public health emergency to evaluate changes in the context of X-waiver relaxations and telehealth allowances. METHODS: In a cross-sectional study, all RI residents who filled a buprenorphine prescription at a pharmacy in Rhode Island (RI), Massachusetts, and Connecticut between January 2017 and December 2023 were obtained from the RI Prescription Drug Monitoring Program (PDMP). The study excluded buprenorphine products not approved for OUD treatment from the analysis. Identified individuals had initiated buprenorphine for OUD during the study period if they did not have a prior prescription or if they had >30 days without buprenorphine exposure between their prescriptions. Spearman's rank correlation tests were used to identify significant associations between outcomes and regulation changes. RESULTS: The average number of patients dispensed buprenorphine did not significantly change over the study period, however the average number of initiates significantly decreased (ρ = -0.38255, p = .0003). The average number of providers prescribing CII-CV substances in RI has increased 3.4 % over the study period. The average percentage of prescribers in the PDMP prescribing buprenorphine for OUD doubled (ρ = 0.96075, p < .0001). CONCLUSION: Though efforts have been made to increase buprenorphine initiation, buprenorphine initiates remain well below pre-PHE levels. Efforts must continue to eliminate existing barriers to treatment and improve access to individuals seeking treatment.

Emerging roles for ABC transporters as virulence factors in uropathogenic Escherichia coli.

Urinary tract infections (UTI) account for a substantial financial burden globally. Over 75% of UTIs are caused by uropathogenic Escherichia coli (UPEC), which have demonstrated an extraordinarily rapid growth rate in vivo. This rapid growth rate appears paradoxical given that urine and the human urinary tract are relatively nutrient-restricted. Thus, we lack a fundamental understanding of how uropathogens propel growth in the host to fuel pathogenesis. Here, we used large in silico, in vivo, and in vitro screens to better understand the role of UPEC transport mechanisms and their contributions to uropathogenesis. In silico analysis of annotated transport systems indicated that the ATP-binding cassette (ABC) family of transporters was most conserved among uropathogenic bacterial species, suggesting their importance. Consistent with in silico predictions, we determined that the ABC family contributed significantly to fitness and virulence in the urinary tract: these were overrepresented as fitness factors in vivo (37.2%), liquid media (52.3%), and organ agar (66.2%). We characterized 12 transport systems that were most frequently defective in screening experiments by generating in-frame deletions. These mutant constructs were tested in urovirulence phenotypic assays and produced differences in motility and growth rate. However, deletion of multiple transport systems was required to achieve substantial fitness defects in the cochallenge murine model. This is likely due to genetic compensation among transport systems, highlighting the centrality of ABC transporters in these organisms. Therefore, these nutrient uptake systems play a concerted, critical role in pathogenesis and are broadly applicable candidate targets for therapeutic intervention.

Magnet-in-ferroelectric crystals exhibiting photomultiferroicity.

Growing crystallographically incommensurate and dissimilar organic materials is fundamentally intriguing but challenging for the prominent cross-correlation phenomenon enabling unique magnetic, electronic, and optical functionalities. Here, we report the growth of molecular layered magnet-in-ferroelectric crystals, demonstrating photomanipulation of interfacial ferroic coupling. The heterocrystals exhibit striking photomagnetization and magnetoelectricity, resulting in photomultiferroic coupling and complete change of their color while inheriting ferroelectricity and magnetism from the parent phases. Under a light illumination, ferromagnetic resonance shifts of 910 Oe are observed in heterocrystals while showing a magnetization change of 0.015 emu/g. In addition, a noticeable magnetization change (8% of magnetization at a 1,000 Oe external field) in the vicinity of ferro-to-paraelectric transition is observed. The mechanistic electric-field-dependent studies suggest the photoinduced ferroelectric field effect responsible for the tailoring of photo-piezo-magnetism. The crystallographic analyses further evidence the lattice coupling of a magnet-in-ferroelectric heterocrystal system.

The effect of experts on attitude change in public-facing political science: Scientific communication on term limits in the United States.

How can scientists best inform the public and change attitudes? Does the message or the messenger matter more? We test the effect of scientific expert messengers and messages in a preregistered, nationally representative survey experiment in the United States. Consistent with our hypotheses, scientists can move public attitudes in areas where knowledge is based on a non-ideological misperception to a greater extent than the same science-based message from another source. Although we focus on political science as a field and Congressional term limits in the United States as a topic area, our findings have broader implications for science communication with policymaking relevance given the persistence of misperceptions among the public across all natural and social science research fields.

Intracranial Mapping of Response Latencies and Task Effects for Spoken Syllable Processing in the Human Brain.

Prior lesion, noninvasive-imaging, and intracranial-electroencephalography (iEEG) studies have documented hierarchical, parallel, and distributed characteristics of human speech processing. Yet, there have not been direct, intracranial observations of the latency with which regions outside the temporal lobe respond to speech, or how these responses are impacted by task demands. We leveraged human intracranial recordings via stereo-EEG to measure responses from diverse forebrain sites during (i) passive listening to /bi/ and /pi/ syllables, and (ii) active listening requiring /bi/-versus-/pi/ categorization. We find that neural response latency increases from a few tens of ms in Heschl's gyrus (HG) to several tens of ms in superior temporal gyrus (STG), superior temporal sulcus (STS), and early parietal areas, and hundreds of ms in later parietal areas, insula, frontal cortex, hippocampus, and amygdala. These data also suggest parallel flow of speech information dorsally and ventrally, from HG to parietal areas and from HG to STG and STS, respectively. Latency data also reveal areas in parietal cortex, frontal cortex, hippocampus, and amygdala that are not responsive to the stimuli during passive listening but are responsive during categorization. Furthermore, multiple regions-spanning auditory, parietal, frontal, and insular cortices, and hippocampus and amygdala-show greater neural response amplitudes during active versus passive listening (a task-related effect). Overall, these results are consistent with hierarchical processing of speech at a macro level and parallel streams of information flow in temporal and parietal regions. These data also reveal regions where the speech code is stimulus-faithful and those that encode task-relevant representations.