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Peripheral neuropathy (PN) and peripheral arterial disease (PAD) are life-limiting comorbidities among adults with lower-limb loss that may not be adequately addressed in current care models. The objective of this study was to evaluate underreporting of PN and PAD among adults with lower-limb loss. We conducted a secondary analysis of a cross-sectional dataset of community-dwelling adults with unilateral lower-limb loss seen in an outpatient Limb Loss Clinic (n = 196; mean age = 56.7 ± 14.4 years; 73.5% male). Individuals participated in standardized clinical examinations including Semmes-Weinstein monofilament testing to assess for PN and pedal pulse palpation to assess for PAD. Bivariate regression was performed to identify key variables for subsequent stepwise logistic regression to discern risk factors. Clinical examination results indicated 16.8% (n = 33) of participants had suspected PN alone, 15.8% (n = 31) had suspected PAD alone, and 23.0% (n = 45) had suspected PN and PAD. More than half of participants with clinical examination findings of PN or PAD failed to self-report the condition (57.7% and 86.8%, respectively). Among adults with lower-limb loss with suspected PN, participants with dysvascular amputations were at lower risk of underreporting (odds ratio [OR] = 0.2, 95% CI: 0.1-0.6). For those with suspected PAD, those who reported more medication prescriptions were at lower risk of underreporting (OR = 0.8, 95% CI: 0.7-1.0). Adults with lower-limb loss underreport PN and PAD per a medical history checklist, which may indicate underdiagnosis or lack of patient awareness. Routine assessment is highly recommended in this population and may be especially critical among individuals with non-dysvascular etiology.

ABSTRACT In the United States Army initial entry training (IET) environment, stress fractures are common musculoskeletal injuries. Due to the repetitive physical demands placed on soldiers, stress fractures are particularly common in individuals matriculating through basic combat training (BCT) and advanced individual training (AIT). Within the Army medical department, the clinical definitions of stress fractures vary widely among providers who are directly responsible for diagnosing these injuries. The use of diversified definitions of stress fractures in patient evaluations, treatment, communication measures, and injury data collection negatively affect patient dispositions and soldier training outcomes. This report identifies discrepancies in clinical definitions of stress fractures and the implications for the Army regarding the lack of a standardized definition for stress fractures. [ABSTRACT FROM AUTHOR]

Background: Most schwannomas are isolated tumours occurring in otherwise healthy people. However, bilateral vestibular schwannomas (BVS) or multiple non-vestibular schwannomas indicate an underlying genetic predisposition. This is most commonly NF2 -related schwannomatosis (SWN), but when BVS are absent, this can also indicate SMARCB1 -related or LZTR1 -related SWN., Methods: We assessed the variant detection rates for the three major SWN genes ( NF2 , LZTR1 and SMARCB1 ) in 154 people, from 150 families, who had at least one non-vestibular schwannoma, but who did not meet clinical criteria for NF2 -related SWN at the time of genetic testing., Results: We found that 17 (11%) people from 13 families had a germline SMARCB1 variant and 19 (12%) unrelated individuals had a germline LZTR1 variant. 19 people had an NF2 variant, but 18 of these were mosaic and 17 were only detected when 2 tumours were available for testing. The overall detection rate was 25% using blood alone, but increased to 36% when tumour analysis was included. Another 12 people had a germline variant of uncertain significance (VUS)., Conclusions: There were similar proportions of LZTR1 , SMARCB1 or mosaic NF2 . However, since an NF2 variant was detected in tumours from 103 people, it is likely that further cases of mosaicism would be detected if more people had additional tumours available for analysis. In addition, if further evidence becomes available to show that the VUSs are pathogenic, this would significantly increase the proportion of people with a genetic diagnosis. Our results indicate the importance of comprehensive genetic testing and improved variant classification., Competing Interests: Competing interests: GE has received consultancy fees from AstraZeneca, Springworks and Everything Genetic., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent calls to address racism in bioethics reflect a sense of urgency to mitigate the lethal effects of a lack of action. While the field was catalyzed largely in response to pivotal events deeply rooted in racism and other structures of oppression embedded in research and health care, it has failed to center racial justice in its scholarship, pedagogy, advocacy, and practice, and neglected to integrate anti-racism as a central consideration. Academic bioethics programs play a key role in determining the field's norms and practices, including methodologies, funding priorities, and professional networks that bear on equity, inclusion, and epistemic justice. This article describes recommendations from the Racial Equity, Diversity, and Inclusion (REDI) Task Force commissioned by the Association of Bioethics Program Directors to prioritize and strengthen anti-racist practices in bioethics programmatic endeavors and to evaluate and develop specific goals to advance REDI.

Collaboration between the arts and health sectors is gaining momentum. Artists are contributing significantly to public health efforts such as vaccine confidence campaigns. Artists and the arts are well positioned to contribute to the social conditions needed to build trust in the health sector. Health professionals, organizations, and institutions should recognize not only the power that can be derived from the insights, artefacts, and expertise of artists and the arts to create the conditions that make trust possible. The health sector must also recognize that, while it can gain much from partnership with artists, artists risk much-namely, the public's trust-when they are in such partnerships. This essay unpacks these claims and considers the care and ethical considerations that must be brought to these partnerships to yield constructive pathways for ethical collaboration as well as for both establishing public trust and continuing to hold the health care profession accountable for becoming more trustworthy., (© 2023 The Hastings Center.)

The electrochemical nitrate (NO 3 - ) reduction reaction (NO 3 RR) to ammonia (NH 3 ) represents a sustainable approach for denitrification to balance global nitrogen cycles and an alternative to traditional thermal Haber-Bosch processes. Here, we present a supramolecular strategy for promoting NH 3 production in water from NO 3 RR by integrating two-dimensional (2D) molecular cobalt porphyrin (CoTPP) units into a three-dimensional (3D) porous organic cage architecture. The porphyrin box CoPB-C8 enhances electrochemical active site exposure, facilitates substrate-catalyst interactions, and improves catalyst stability, leading to turnover numbers and frequencies for NH 3 production exceeding 200,000 and 56 s -1 , respectively. These values represent a 15-fold increase in NO 3 RR activity and 200-mV improvement in overpotential for the 3D CoPB-C8 box structure compared to its 2D CoTPP counterpart. Synthetic tuning of peripheral alkyl substituents highlights the importance of supramolecular porosity and cavity size on electrochemical NO 3 RR activity. These findings establish the incorporation of 2D molecular units into 3D confined space microenvironments as an effective supramolecular design strategy for enhancing electrocatalysis., (© 2023 Wiley-VCH GmbH.)

Megalibraries are centimeter-scale chips containing millions of materials synthesized in parallel using scanning probe lithography. As such, they stand to accelerate how materials are discovered for applications spanning catalysis, optics, and more. However, a long-standing challenge is the availability of substrates compatible with megalibrary synthesis, which limits the structural and functional design space that can be explored. To address this challenge, thermally removable polystyrene films were developed as universal substrate coatings that decouple lithography-enabled nanoparticle synthesis from the underlying substrate chemistry, thus providing consistent lithography parameters on diverse substrates. Multi-spray inking of the scanning probe arrays with polymer solutions containing metal salts allows patterning of >56 million nanoreactors designed to vary in composition and size. These are subsequently converted to inorganic nanoparticles via reductive thermal annealing, which also removes the polystyrene to deposit the megalibrary. Megalibraries with mono-, bi-, and trimetallic materials were synthesized, and nanoparticle size was controlled between 5 and 35 nm by modulating the lithography speed. Importantly, the polystyrene coating can be used on conventional substrates like Si/SiO x , as well as substrates typically more difficult to pattern on, such as glassy carbon, diamond, TiO 2, BN, W, or SiC. Finally, high-throughput materials discovery is performed in the context of photocatalytic degradation of organic pollutants using Au-Pd-Cu nanoparticle megalibraries on TiO 2 substrates with 2,250,000 unique composition/size combinations. The megalibrary was screened within 1 h by developing fluorescent thin-film coatings on top of the megalibrary as proxies for catalytic turnover, revealing Au 0.53 Pd 0.38 Cu 0.09 -TiO 2 as the most active photocatalyst composition.

We present a supramolecular approach to catalyzing photochemical CO 2 reduction through second-sphere porosity and charge effects. An iron porphyrin box (PB) bearing 24 cationic groups, FePB-2(P), was made via post-synthetic modification of an alkyne-functionalized supramolecular synthon. FePB-2(P) promotes the photochemical CO 2 reduction reaction (CO 2 RR) with 97 % selectivity for CO product, achieving turnover numbers (TON) exceeding 7000 and initial turnover frequencies (TOF max ) reaching 1400 min -1 . The cooperativity between porosity and charge results in a 41-fold increase in activity relative to the parent Fe tetraphenylporphyrin (FeTPP) catalyst, which is far greater than analogs that augment catalysis through porosity (FePB-3(N), 4-fold increase) or charge (Fe p-tetramethylanilinium porphyrin (Fe-p-TMA), 6-fold increase) alone. This work establishes that synergistic pendants in the secondary coordination sphere can be leveraged as a design element to augment catalysis at primary active sites within confined spaces., (© 2022 Wiley-VCH GmbH.)

This paper offers a novel understanding of collective responsibility for AI outcomes that can help resolve the "problem of many hands" and "responsibility gaps" when it comes to AI failure, especially in the context of lethal autonomous weapon systems., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Smith.)

Schwannomatosis comprises a group of hereditary tumor predisposition syndromes characterized by, usually benign, multiple nerve sheath tumors, which frequently cause severe pain that does not typically respond to drug treatments. The most common schwannomatosis-associated gene is NF2, but SMARCB1 and LZTR1 are also associated. There are still many cases in which no pathogenic variants (PVs) have been identified, suggesting the existence of as yet unidentified genetic risk factors. In this study, we performed extended genetic screening of 75 unrelated schwannomatosis patients without identified germline PVs in NF2, LZTR1, or SMARCB1. Screening of the coding region of DGCR8, COQ6, CDKN2A, and CDKN2B was carried out, based on previous reports that point to these genes as potential candidate genes for schwannomatosis. Deletions or duplications in CDKN2A, CDKN2B, and adjacent chromosome 9 region were assessed by multiplex ligation-dependent probe amplification analysis. Sequencing analysis of a patient with multiple schwannomas and melanomas identified a novel duplication in the coding region of CDKN2A, disrupting both p14ARF and p16INK4a. Our results suggest that none of these genes are major contributors to schwannomatosis risk but the possibility remains that they may have a role in more complex mechanisms for tumor predisposition., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Medical documentation is an important component of healthcare delivery and represents a significant portion of physician assistant educational efforts. Assessing proficiency in documentation is challenging, often relying on the subjective evaluation of documents. This study presents a novel approach using video-recorded provider-patient interactions and an interactive scoring rubric. Sixty-five participants, representing three cohorts, completed medical documentation with each document receiving accuracy scores from three independent scorers. Using this approach, the consistency of two versions of a provider-patient encounter with the same chief complaint but variable details was demonstrated (p = 0.239). Inter-scorer reliability using this method was maintained across participants with an average variation of 1.21 points on a 54-point scale between three independent scorers. Applying this method to evaluate educational preparedness, a statistically significant increase in accuracy was identified in cohorts approaching the completion of didactic education (p < 0.05). The method presented here provides a reliable platform to access medical documentation accuracy across educational levels and documentation styles.

Nature uses proteins as building blocks to create three-dimensional (3D) structural components (like spiderwebs and tissue) that are recycled within a closed loop. Furthermore, it is difficult to replicate the mechanical properties of these 3D architectures within synthetic systems. In the absence of biological machinery, protein-based materials can be difficult to process and can have a limited range of mechanical properties. Herein, we present an additive manufacturing workflow to fabricate tough, protein-based composite hydrogels and bioplastics with a range of mechanical properties. Briefly, methacrylated bovine-serum-albumin-based aqueous resins were 3D-printed using a commercial vat photopolymerization system. The printed structures were then treated with tannic acid to introduce additional non-covalent interactions and form tough hydrogels. The hydrogel material could be sutured and withstand mechanical load, even after immersion in water for 24 h. Additionally, a denaturing thermal cure could be used to virtually eliminate rehydration of the material and form a bioplastic. To highlight the functionality of this material, a bioplastic screw was 3D-printed and driven into wood without damage to the screw. Moreover, the 3D-printed constructs enzymatically degraded up to 85% after 30 days in pepsin solution. Thus, these protein-based 3D-printed constructs show great potential for biomedical devices that degrade in situ .

Missense variants in the NF2 gene result in variable NF2 disease presentation. Clinical classification of missense variants often represents a challenge, due to lack of evidence for pathogenicity and function. This study provides a summary of NF2 missense variants, with variant classifications based on currently available evidence. NF2 missense variants were collated from pathology-associated databases and existing literature. Association for Clinical Genomic Sciences Best Practice Guidelines (2020) were followed in the application of evidence for variant interpretation and classification. The majority of NF2 missense variants remain classified as variants of uncertain significance. However, NF2 missense variants identified in gnomAD occurred at a consistent rate across the gene, while variants compiled from pathology-associated databases displayed differing rates of variation by exon of NF2. The highest rate of NF2 disease-associated variants was observed in exon 7, while lower rates were observed toward the C-terminus of the NF2 protein, merlin. Further phenotypic information associated with variants, alongside variant-specific functional analysis, is necessary for more definitive variant interpretation. Our data identified differences in frequency of NF2 missense variants by exon between gnomAD population data and NF2 disease-associated variants, suggesting a potential genotype-phenotype correlation; further work is necessary to substantiate this., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

As a field concerned with ethical issues in health and health care, particularly how structures, policies, and practices unfairly advantage some and disadvantage others, bioethics has a moral obligation to address the long-standing challenges that racism has posed to the overall health and well-being of Black, Indigenous, and Latinx people and other people of color. Arguably, the premature death and disease disproportionately affecting Black Americans and the well-documented association of such death and illness with racism are issues that have not gained due attention in bioethics. This multiauthored report highlights the intergenerational work of mostly Black scholars and aims to create an agenda for bioethics that addresses anti-Black racism and the ways in which this form of racism threatens the actualization of justice in health and health care, not only for Black people and other minoritized groups but also for all people. This special report contains five major sections representing different approaches to scholarship, including theoretical, empirical, and narrative forms. The first section features two target articles focused on anti-Black racism and health care settings, with each article accompanied by two commentaries. The second section includes four essays thematically centered around anti-Black racism and health equity research and practice. Section three features four essays that explore anti-Black racism and bioethics. The next section consists of four essays framing a braver, bolder, and broader bioethics. We conclude with a powerful tribute to the late Marian Gray Secundy, a bioethics luminary, friend, colleague, role model, and mentor, and a tie that binds together many bioethics scholars who prioritize social justice in their scholarship and praxis., (© 2022 The Hastings Center.)

This essay takes as its starting point the claim that addressing anti-Black racism is essential to the work of bioethics in the United States. The essay examines whether and how racism has been addressed in the field's central reference work, the Encyclopedia of Bioethics, throughout its four editions-in 1978, 1995, 2004, and 2014. With consideration of each edition's stated purpose and editorial framing, we find that the subject of racism is obscured by the Encyclopedia's inattention to African American approaches to bioethics, to racism as a bioethics issue, and specifically, to racism as a matter of justice. This essay suggests questions for guiding reflection necessary for giving racism its due in the field of bioethics., (© 2022 The Hastings Center.)

Health justice seeks, both conceptually and in practice, to strengthen community engagement and empowerment as an integral means of addressing health disparities. In this essay, we explore the nature of communities and their roles in health care/public health. We propose that an ethical  principle of respect for communities  is a requisite part of health justice. It is this respect for communities that ethically grounds health justice's calls for greater community engagement and empowerment. Conceptions of health justice, we claim, will gain ethical power and coherence as this principle is more clearly recognized and further developed.

Importance: The major North American professional sports leagues were among the first to return to full-scale sport activity during the coronavirus disease 2019 (COVID-19) pandemic. Given the unknown incidence of adverse cardiac sequelae after COVID-19 infection in athletes, these leagues implemented a conservative return-to-play (RTP) cardiac testing program aligned with American College of Cardiology recommendations for all athletes testing positive for COVID-19., Objective: To assess the prevalence of detectable inflammatory heart disease in professional athletes with prior COVID-19 infection, using current RTP screening recommendations., Design, Setting, and Participants: This cross-sectional study reviewed RTP cardiac testing performed between May and October 2020 on professional athletes who had tested positive for COVID-19. The professional sports leagues (Major League Soccer, Major League Baseball, National Hockey League, National Football League, and the men's and women's National Basketball Association) implemented mandatory cardiac screening requirements for all players who had tested positive for COVID-19 prior to resumption of team-organized sports activities., Exposures: Troponin testing, electrocardiography (ECG), and resting echocardiography were performed after a positive COVID-19 test result. Interleague, deidentified cardiac data were pooled for collective analysis. Those with abnormal screening test results were referred for additional testing, including cardiac magnetic resonance imaging and/or stress echocardiography., Main Outcomes and Measures: The prevalence of abnormal RTP test results potentially representing COVID-19-associated cardiac injury, and results and outcomes of additional testing generated by the initial screening process., Results: The study included 789 professional athletes (mean [SD] age, 25 [3] years; 777 men [98.5%]). A total of 460 athletes (58.3%) had prior symptomatic COVID-19 illness, and 329 (41.7%) were asymptomatic or paucisymptomatic (minimally symptomatic). Testing was performed a mean (SD) of 19 (17) days (range, 3-156 days) after a positive test result. Abnormal screening results were identified in 30 athletes (3.8%; troponin, 6 athletes [0.8%]; ECG, 10 athletes [1.3%]; echocardiography, 20 athletes [2.5%]), necessitating additional testing; 5 athletes (0.6%) ultimately had cardiac magnetic resonance imaging findings suggesting inflammatory heart disease (myocarditis, 3; pericarditis, 2) that resulted in restriction from play. No adverse cardiac events occurred in athletes who underwent cardiac screening and resumed professional sport participation., Conclusions and Relevance: This study provides large-scale data assessing the prevalence of relevant COVID-19-associated cardiac pathology with implementation of current RTP screening recommendations. While long-term follow-up is ongoing, few cases of inflammatory heart disease have been detected, and a safe return to professional sports activity has thus far been achieved.

Bio-based plastics that can supplant petroleum-derived materials are necessary to meet the future demands of sustainability in the life cycle of plastic materials. While there are significant efforts to develop protein-based plastic materials for commercial use, their application is limited by poor processability and limitations in mechanical performance. Here, we present a bovine serum albumin (BSA)-based resin for stereolithographic apparatus (SLA) 3D printing that affords bioplastic objects with shape-memory behavior. We demonstrate that the native conformation of these globular proteins is largely retained in the 3D-printed constructs and that each protein molecule possesses a "stored length" that could be revealed during mechanical deformation (extension or compression) of the 3D bioplastic objects. While the plastically deformed objects could retain this state for an indefinite period of time, heating the object or submerging in water allowed it to return to its original 3D-printed shape.

Objectives: Cases of sporadic vestibular schwannoma (sVS) have a low rate of association with germline pathogenic variants. However, some individuals with sVS can represent undetected cases of neurofibromatosis type 2 (NF2) or schwannomatosis. Earlier identification of patients with these syndromes can facilitate more accurate familial risk prediction and prognosis., Methods: Cases of sVS were ascertained from a local register at the Manchester Centre for Genomic Medicine. Genetic analysis was conducted in NF2 on blood samples for all patients, and tumour DNA samples when available. LZTR1 and SMARCB1 screening was also performed in patient subgroups., Results: Age at genetic testing for vestibular schwannoma (VS) presentation was younger in comparison with previous literature, a bias resulting from updated genetic testing recommendations. Mosaic or constitutional germline NF2 variants were confirmed in 2% of patients. Pathogenic germline variants in LZTR1 were found in 3% of all tested patients, with a higher rate of 5% in patients <30 years. No pathogenic SMARCB1 variants were identified within the cohort. Considering all individuals who received tumour DNA analysis, 69% of patients were found to possess two somatic pathogenic NF2 variants, including those with germline LZTR1 pathogenic variants., Conclusions: Undiagnosed schwannoma predisposition may account for a significant minority of apparently sVS cases, especially at lower presentation ages. Loss of NF2 function is a common event in VS tumours and may represent a targetable common pathway in VS tumourigenesis. These data also support the multi-hit mechanism of LZTR1 -associated VS tumourigenesis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Premise: The xylem tissue of plants performs three principal functions: transport of water, support of the plant body, and nutrient storage. Tradeoffs may arise because different structural requirements are associated with different functions or because suites of traits are under selection that relate to resource acquisition, use, and turnover. The structural and functional basis of xylem storage is not well established. We hypothesized that greater starch storage would be associated with greater sapwood parenchyma and reduced fibers, which would compromise resistance to xylem tensions during dehydration., Methods: We measured cavitation resistance, minimum water potential, starch content, and sapwood parenchyma and fiber area in 30 species of southern California chaparral shrubs (evergreen and deciduous)., Results: We found that species storing greater starch within their xylem tended to avoid dehydration and were less cavitation resistant, and this was supported by phylogenetic independent contrasts. Greater sapwood starch was associated with greater parenchyma area and reduced fiber area. For species without living fibers, the associations with parenchyma were stronger, suggesting that living fibers may expand starch storage capacity while also contributing to the support function of the vascular tissue. Drought-deciduous species were associated with greater dehydration avoidance than evergreens., Conclusions: Evolutionary forces have led to an association between starch storage and dehydration resistance as part of an adaptive suite of traits. We found evidence for a tradeoff between tissue mechanical traits and starch storage; moreover, the evolution of novel strategies, such as starch-storing living fibers, may mitigate the strength of this tradeoff., (© 2020 Botanical Society of America.)

Biological and heterogeneous catalysts for the electrochemical CO 2 reduction reaction (CO 2 RR) often exhibit a high degree of electronic delocalization that serves to minimize overpotential and maximize selectivity over the hydrogen evolution reaction (HER). Here, we report a molecular iron(II) system that captures this design concept in a homogeneous setting through the use of a redox non-innocent terpyridine-based pentapyridine ligand (tpyPY2Me). As a result of strong metal-ligand exchange coupling between the Fe(II) center and ligand, [Fe(tpyPY2Me)] 2+ exhibits redox behavior at potentials 640 mV more positive than the isostructural [Zn(tpyPY2Me)] 2+ analog containing the redox-inactive Zn(II) ion. This shift in redox potential is attributed to the requirement for both an open-shell metal ion and a redox non-innocent ligand. The metal-ligand cooperativity in [Fe(tpyPY2Me)] 2+ drives the electrochemical reduction of CO 2 to CO at low overpotentials with high selectivity for CO 2 RR (>90%) and turnover frequencies of 100 000 s -1 with no degradation over 20 h. The decrease in the thermodynamic barrier engendered by this coupling also enables homogeneous CO 2 reduction catalysis in water without compromising selectivity or rates. Synthesis of the two-electron reduction product, [Fe(tpyPY2Me)] 0 , and characterization by X-ray crystallography, Mössbauer spectroscopy, X-ray absorption spectroscopy (XAS), variable temperature NMR, and density functional theory (DFT) calculations, support assignment of an open-shell singlet electronic structure that maintains a formal Fe(II) oxidation state with a doubly reduced ligand system. This work provides a starting point for the design of systems that exploit metal-ligand cooperativity for electrocatalysis where the electrochemical potential of redox non-innocent ligands can be tuned through secondary metal-dependent interactions.

The human genome encodes for over 1,500 RNA-binding proteins (RBPs), which coordinate regulatory events on RNA transcripts. Most studies of RBPs have concentrated on their action on host protein-encoding mRNAs, which constitute a minority of the transcriptome. A widely neglected subset of our transcriptome derives from integrated retroviral elements, termed endogenous retroviruses (ERVs), that comprise ∼8% of the human genome. Some ERVs have been shown to be transcribed under physiological and pathological conditions, suggesting that sophisticated regulatory mechanisms to coordinate and prevent their ectopic expression exist. However, it is unknown how broadly RBPs and ERV transcripts directly interact to provide a posttranscriptional layer of regulation. Here, we implemented a computational pipeline to determine the correlation of expression between individual RBPs and ERVs from single-cell or bulk RNA-sequencing data. One of our top candidates for an RBP negatively regulating ERV expression was RNA-binding motif protein 4 (RBM4). We used photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation to demonstrate that RBM4 indeed bound ERV transcripts at CGG consensus elements. Loss of RBM4 resulted in an elevated transcript level of bound ERVs of the HERV-K and -H families, as well as increased expression of HERV-K envelope protein. We pinpointed RBM4 regulation of HERV-K to a CGG-containing element that is conserved in the LTRs of HERV-K-10, -K-11, and -K-20, and validated the functionality of this site using reporter assays. In summary, we systematically identified RBPs that may regulate ERV function and demonstrate a role for RBM4 in controlling ERV expression., Competing Interests: The authors declare no competing interest.

We present a bioinspired strategy for enhancing electrochemical carbon dioxide reduction catalysis by cooperative use of base-metal molecular catalysts with intermolecular second-sphere redox mediators that facilitate both electron and proton transfer. Functional synthetic mimics of the biological redox cofactor NADH, which are electrochemically stable and are capable of mediating both electron and proton transfer, can enhance the activity of an iron porphyrin catalyst for electrochemical reduction of CO 2 to CO, achieving a 13-fold rate improvement without altering the intrinsic high selectivity of this catalyst platform for CO 2 versus proton reduction. Evaluation of a systematic series of NADH analogues and redox-inactive control additives with varying proton and electron reservoir properties reveals that both electron and proton transfer contribute to the observed catalytic enhancements. This work establishes that second-sphere dual control of electron and proton inventories is a viable design strategy for developing more effective electrocatalysts for CO 2 reduction, providing a starting point for broader applications of this approach to other multielectron, multiproton transformations.

Increasing demand for sustainable energy sources continues to motivate the development of new catalytic processes that store intermittent energy in the form of chemical bonds. In this context, photosynthetic organisms harvest light to drive dark reactions reducing carbon dioxide, an abundant and accessible carbon source, to store solar energy in the form of glucose and other biomass feedstocks. Inspired by this biological process, the field of artificial photosynthesis aims to store renewable energy in chemical bonds spanning fuels, foods, medicines, and materials using light, water, and CO 2 as the primary chemical feedstocks, with the added benefit of mitigating the accumulation of CO 2 as a greenhouse gas in the atmosphere. As such, devising new catalyst platforms for transforming CO 2 into value-added chemical products is of importance. Historically, catalyst design for artificial photosynthesis has been approached from the three traditional fields of catalysis: molecular, materials, and biological. In this Account, we show progress from our laboratory in constructing new hybrid catalysts for artificial photosynthesis that draw upon design concepts from all three of these traditional fields of catalysis and blur the boundaries between them. Starting with molecular catalysis, we incorporated biological design elements that are prevalent in enzymes into synthetic systems. Specifically, we demonstrated that proper positioning of intramolecular hydrogen bond donors or addition of intermolecular multipoint hydrogen bond donors with classic iron porphyrin and nickel cyclam platforms can substantially increase rates of CO 2 reduction and break electronic scaling relationships. In parallel, we incorporated a key materials design element, namely, high surface area and porosity for maximizing active site exposure, into molecular systems. A supramolecular porous organic cage molecule was synthesized with iron porphyrin building blocks, and the porosity was observed to facilitate substrate and charge transport through the catalyst film. In turn, molecular design elements can be incorporated into materials catalysts for CO 2 reduction. First, we utilized molecular synthons in a bottom-up reticular approach to drive polymerization/assembly into a bulk framework material. Second, we established an organometallic approach in which molecular ligands, including chelating ones, are adsorbed onto a bulk inorganic solid to create and tune new active sites on surfaces. Finally, we describe two examples in which molecular, materials, and biological design elements are all integrated to catalyze the reduction of CO 2 into CH 4 using a hybrid biological-materials interface with sustainably generated H 2 as the reductant or to reduce CO into value-added C 2 products acetate and ethanol using a hybrid molecular-materials interface to construct a biomimetic, bimetallic active site. Taken together, our program in catalysis for energy and sustainability has revealed that combining more conventional design strategies in synergistic ways can lead to advances in artificial photosynthesis.

We report a supramolecular strategy for promoting the selective reduction of O 2 for direct electrosynthesis of H 2 O 2 . We utilized cobalt tetraphenylporphyrin (Co-TPP), an oxygen reduction reaction (ORR) catalyst with highly variable product selectivity, as a building block to assemble the permanently porous supramolecular cage Co-PB-1(6) bearing six Co-TPP subunits connected through twenty-four imine bonds. Reduction of these imine linkers to amines yields the more flexible cage Co-rPB-1(6). Both Co-PB-1(6) and Co-rPB-1(6) cages produce 90-100 % H 2 O 2 from electrochemical ORR catalysis in neutral pH water, whereas the Co-TPP monomer gives a 50 % mixture of H 2 O 2 and H 2 O. Bimolecular pathways have been implicated in facilitating H 2 O formation, therefore, we attribute this high H 2 O 2 selectivity to site isolation of the discrete molecular units in each supramolecule. The ability to control reaction selectivity in supramolecular structures beyond traditional host-guest interactions offers new opportunities for designing such architectures for a broader range of catalytic applications., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biosourced and biodegradable polymers for additive manufacturing could enable the rapid fabrication of parts for a broad spectrum of applications ranging from healthcare to aerospace. However, a limited number of these materials are suitable for vat photopolymerization processes. Herein, we report a two-step additive manufacturing process to fabricate robust protein-based constructs using a commercially available laser-based stereolithography printer. Methacrylated bovine serum albumin (MA-BSA) was synthesized and formulated into aqueous resins that were used to print complex three-dimensional (3D) objects with a resolution comparable to a commercially available resin. The MA-BSA resins were characterized by rheometry to determine the viscosity and the cure rate, as both parameters can ultimately be used to predict the printability of the resin. In the first step of patterning these materials, the MA-BSA resin was 3D printed, and in the second step, the printed construct was thermally cured to denature the globular protein and increase the intermolecular noncovalent interactions. Thus, the final 3D printed part was comprised of both chemical and physical cross-links. Compression studies of hydrated and dehydrated constructs demonstrated a broad range of compressive strengths and Young's moduli that could be further modulated by adjusting the type and amount of co-monomer. The printed hydrogel constructs demonstrated good cell viability (>95%) after a 21 day culture period. These MA-BSA resins are expected to be compatible with other vat photopolymerization techniques including digital light projection and continuous liquid interface production.

Pathway Commons (https://www.pathwaycommons.org) is an integrated resource of publicly available information about biological pathways including biochemical reactions, assembly of biomolecular complexes, transport and catalysis events and physical interactions involving proteins, DNA, RNA, and small molecules (e.g. metabolites and drug compounds). Data is collected from multiple providers in standard formats, including the Biological Pathway Exchange (BioPAX) language and the Proteomics Standards Initiative Molecular Interactions format, and then integrated. Pathway Commons provides biologists with (i) tools to search this comprehensive resource, (ii) a download site offering integrated bulk sets of pathway data (e.g. tables of interactions and gene sets), (iii) reusable software libraries for working with pathway information in several programming languages (Java, R, Python and Javascript) and (iv) a web service for programmatically querying the entire dataset. Visualization of pathways is supported using the Systems Biological Graphical Notation (SBGN). Pathway Commons currently contains data from 22 databases with 4794 detailed human biochemical processes (i.e. pathways) and ∼2.3 million interactions. To enhance the usability of this large resource for end-users, we develop and maintain interactive web applications and training materials that enable pathway exploration and advanced analysis., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Purpose: To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2)., Methods: Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing., Results: The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant., Conclusion: This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.

Fetal hematopoietic stem and progenitor cells (HSPCs) hold promise to cure a wide array of hematological diseases, and we previously found a role for the RNA-binding protein (RBP) Lin28b in respecifying adult HSPCs to resemble their fetal counterparts. Here we show by single-cell RNA sequencing that Lin28b alone was insufficient for complete reprogramming of gene expression from the adult toward the fetal pattern. Using proteomics and in situ analyses, we found that Lin28b (and its closely related paralog, Lin28a) directly interacted with Igf2bp3, another RBP, and their enforced co-expression in adult HSPCs reactivated fetal-like B-cell development in vivo more efficiently than either factor alone. In B-cell progenitors, Lin28b and Igf2bp3 jointly stabilized thousands of mRNAs by binding at the same sites, including those of the B-cell regulators Pax5 and Arid3a as well as Igf2bp3 mRNA itself, forming an autoregulatory loop. Our results suggest that Lin28b and Igf2bp3 are at the center of a gene regulatory network that mediates the fetal-adult hematopoietic switch. A method to efficiently generate induced fetal-like hematopoietic stem cells (ifHSCs) will facilitate basic studies of their biology and possibly pave a path toward their clinical application., (Published by Cold Spring Harbor Laboratory Press.)

Engineered tubular constructs made from soft biomaterials are employed in a myriad of applications in biomedical science. Potential uses of these constructs range from vascular grafts to conduits for enabling perfusion of engineered tissues and organs. The fabrication of standalone tubes or complex perfusable constructs from biofunctional materials, including hydrogels, via rapid and readily accessible routes is desirable. Here we report a methodology in which customized coaxial nozzles are 3D printed using commercially available stereolithography (SLA) 3D printers. These nozzles can be used for the fabrication of hydrogel tubes via coextrusion of two shear-thinning hydrogels: an unmodified Pluronic ® F-127 (F127) hydrogel and an F127-bisurethane methacrylate (F127-BUM) hydrogel. We demonstrate that different nozzle geometries can be modeled via computer-aided design and 3D printed in order to generate tubes or coaxial filaments with different cross-sectional geometries. We were able to fabricate tubes with luminal diameters or wall thicknesses as small as ∼150 μm. Finally, we show that these tubes can be functionalized with collagen I to enable cell adhesion, and human umbilical vein endothelial cells can be cultured on the luminal surfaces of these tubes to yield tubular endothelial monolayers. Our approach could enable the rapid fabrication of biofunctional hydrogel conduits which can ultimately be utilized for engineering in vitro models of tubular biological structures.

Research has demonstrated that hyperbaric oxygen (HBO 2 ) treatment produced relief of both acute and chronic pain in patients and animal models. However, the mechanism of HBO 2 antinociceptive effect is still elusive. Based on our earlier findings that implicate NO in the acute antinociceptive effect of HBO 2 , the purpose of this study was to ascertain whether HBO 2 -induced antinociception in a chronic neuropathic pain model is likewise dependent on NO. Neuropathic pain was induced in male Sprague Dawley rats by four injections of paclitaxel (1.0 mg/kg, i.p.). Twenty-four hours after the last paclitaxel injection, rats were treated for one day or four consecutive days with 60-min HBO 2 at 3.5 atmospheres absolute (ATA). Two days before HBO 2 treatment, some groups of rats were implanted with Alzet® osmotic minipumps that continuously infused a selective inhibitor of neuronal NO synthase (nNOS) into the lateral cerebral ventricle for 7 days. Mechanical and cold allodynia were assessed every other day, using electronic von Frey and acetone assays, respectively. Rats in the paclitaxel control group exhibited a mechanical or cold allodynia that was significantly reversed by one HBO 2 treatment for mechanical allodynia and four HBO 2 treatments for cold allodynic. In rats treated with the nNOS inhibitor, the effects of HBO 2 were nullified in the mechanical allodynia test but unaffected in the cold allodynia test. In summary, these results demonstrate that the antiallodynic effect of HBO 2 in two different pain tests is dependent on NO in the CNS., (Copyright © 2019. Published by Elsevier B.V.)

Community-based clergy are highly engaged in helping seriously ill patients address spiritual concerns at the end of life (EOL). While they desire EOL training, no data exist in guiding how to conceptualize a clergy-training program. The objective of this study was used to identify best practices in an EOL training program for community clergy. As part of the National Clergy Project on End-of-Life Care, the project conducted key informant interviews and focus groups with active clergy in five US states (California, Illinois, Massachusetts, New York, and Texas). A diverse purposive sample of 35 active clergy representing pre-identified racial, educational, theological, and denominational categories hypothesized to be associated with more intensive utilization of medical care at the EOL. We assessed suggested curriculum structure and content for clergy EOL training through interviews and focus groups for the purpose of qualitative analysis. Thematic analysis identified key themes around curriculum structure, curriculum content, and issues of tension. Curriculum structure included ideas for targeting clergy as well as lay congregational leaders and found that clergy were open to combining resources from both religious and health-based institutions. Curriculum content included clergy desires for educational topics such as increasing their medical literacy and reviewing pastoral counseling approaches. Finally, clergy identified challenging barriers to EOL training needing to be openly discussed, including difficulties in collaborating with medical teams, surrounding issues of trust, the role of miracles, and caution of prognostication. Future EOL training is desired and needed for community-based clergy. In partnering together, religious-medical training programs should consider curricula sensitive toward structure, desired content, and perceived clergy tensions.

Frozen section telepathology interpretation experience has been largely limited to practices with locations significantly distant from one another with sporadic need for frozen section diagnosis. In 2010, we established a real-time nonrobotic telepathology system in a very active cancer center for daily frozen section service. Herein, we evaluate its accuracy compared to direct microscopic interpretation performed in the main hospital by the same faculty and its cost-efficiency over a 1-year period. From 643 (1,416 parts) cases requiring intraoperative consultation, 333 cases (690 parts) were examined by telepathology and 310 cases (726 parts) by direct microscopy. Corresponding discrepancy rates were 2.6% (18 cases: 6 [0.9%] sampling and 12 [1.7%] diagnostic errors) and 3.2% (23 cases: 8 [1.1%] sampling and 15 [2.1%] diagnostic errors), P = .63. The sensitivity and specificity of intraoperative frozen diagnosis were 0.92 and 0.99, respectively, in telepathology and 0.90 and 0.99, respectively, in direct microscopy. There was no correlation of error incidence with postgraduate year level of residents involved in the telepathology service. Cost analysis indicated that the time saved by telepathology was $19,691.00 over 1 year of the study period, whereas the capital cost for establishing the system was $8,924.00. Thus, real-time nonrobotic telepathology is a reliable and easy-to-use tool for frozen section evaluation in busy clinical settings, especially when frozen section service involves more than one hospital, and it is cost-efficient when travel is a component of the service., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A porous organic cage composed of six iron tetraphenylporphyrins was used as a supramolecular catalyst for electrochemical CO 2 -to-CO conversion. This strategy enhances active site exposure and substrate diffusion relative to the monomeric catalyst, resulting in CO generation with near-quantitative Faradaic efficiency in pH 7.3 water, with activities reaching 55 250 turnovers. These results provide a starting point for the design of supramolecular catalysts that can exploit the properties of the surrounding matrix yet retain the tunability of the original molecular unit., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)