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By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

BACKGROUNDInformation about the size, airway location, and longitudinal behavior of mucus plugs in asthma is needed to understand their role in mechanisms of airflow obstruction and to rationally design muco-active treatments.METHODSCT lung scans from 57 patients with asthma were analyzed to quantify mucus plug size and airway location, and paired CT scans obtained 3 years apart were analyzed to determine plug behavior over time. Radiologist annotations of mucus plugs were incorporated in an image-processing pipeline to generate size and location information that was related to measures of airflow.RESULTSThe length distribution of 778 annotated mucus plugs was multimodal, and a 12 mm length defined short ("stubby", ≤12 mm) and long ("stringy", >12 mm) plug phenotypes. High mucus plug burden was disproportionately attributable to stringy mucus plugs. Mucus plugs localized predominantly to airway generations 6-9, and 47% of plugs in baseline scans persisted in the same airway for 3 years and fluctuated in length and volume. Mucus plugs in larger proximal generations had greater effects on spirometry measures than plugs in smaller distal generations, and a model of airflow that estimates the increased airway resistance attributable to plugs predicted a greater effect for proximal generations and more numerous mucus plugs.CONCLUSIONPersistent mucus plugs in proximal airway generations occur in asthma and demonstrate a stochastic process of formation and resolution over time. Proximal airway mucus plugs are consequential for airflow and are in locations amenable to treatment by inhaled muco-active drugs or bronchoscopy.TRIAL REGISTRATIONClinicaltrials.gov; NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01716494, and NCT01760915.FUNDINGAstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Sanofi-Genzyme-Regeneron, and TEVA provided financial support for study activities at the Coordinating and Clinical Centers beyond the third year of patient follow-up. These companies had no role in study design or data analysis, and the only restriction on the funds was that they be used to support the SARP initiative.

Abstract In Huntington’s Disease (HD) and related disorders, expansion of CAG trinucleotide repeats produces a toxic gain of function in affected neurons. Expanded huntingtin (expHTT) mRNA forms aggregates that sequester essential RNA binding proteins, dysregulating mRNA processing and translation. The physical basis of RNA aggregation has been difficult to disentangle owing to the heterogeneous structure of the CAG repeats. Here, we probe the folding and unfolding pathways of expHTT mRNA using single-molecule force spectroscopy. Whereas normal HTT mRNAs unfold reversibly and cooperatively, expHTT mRNAs with 20 or 40 CAG repeats slip and unravel non-cooperatively at low tension. Slippage of CAG base pairs is punctuated by concerted rearrangement of adjacent CCG trinucleotides, trapping partially folded structures that readily base pair with another RNA strand. We suggest that the conformational entropy of the CAG repeats, combined with stable CCG base pairs, creates a stick-slip behavior that explains the aggregation propensity of expHTT mRNA.

Individuals from Asian American (AA) and international Asian (IA) backgrounds are often lumped together in mental health research, which may obscure important differences in mental health presentation and need. While previous research has examined differences amongst AA and IA students seeking therapy at a single university counseling center, our study sought to better generalize these findings by utilizing a national data set to examine differences in treatment utilization, presenting concerns, overall distress, and improvement in treatment. Our results showed that IA students utilize therapy at lower rates than AA students. However, both groups attended appointments at roughly the same rate. Distress at intake was significantly higher for IA students across most domains measured. Finally, both groups improved in treatment at similar rates, with some differences observed between IA undergraduate and graduate students. We discuss implications for college counseling professionals and urge further research in this domain.

As the press for services at university counseling centers increases, so does the need to provide optimal therapeutic services. Ethnic glossing in previous research has combined rather disaggregated the mental health treatment experiences of American Latinx (AL) students and International Latinx (IL) students. The purpose of this paper was to examine potential differences in (1) the number of attended sessions, (2) symptom severity, and (3) treatment improvement rates. We used a nationwide dataset including 13,156 AL students and 911 IL students. Results indicated that (1) there was no significant difference in attendance rates, (2) AL students had significantly worse initial symptom severity (d = 0.24), and (3) there were no significant differences in improvement rates. We discuss the importance of understanding the different clinical presentations of AL and IL students, as well as the importance of addressing ethnic glossing in future research and clinical work.

SUMMARY: Active or man-made seismic sources are often used to delineate subsurface geological structures via seismic imaging techniques. Although conventional controlled seismic sources have provided high-resolution subsurface images, the high cost of data acquisition necessitates improved use of cheaper alternative seismic sources for subsurface imaging, such as traffic noise, quarry blasts and earthquakes. Here, we explore the potential use of quarry blasts as an active seismic source for subsurface imaging. The goal of our study is to demonstrate the utility of quarry blasts as seismic sources for investigating subsurface structure with a field experiment in Mill Creek, southern Oklahoma. We deployed a 7455-m-long receiver line of 72 receivers (105 m spacing) extending away from a quarry, with a recording time of 28 d. We analyse similarities between blasts, wave types, origin time and excitation location of quarry blasts, which is important information for using such signal as an active source. Given a relative homogeneous geological condition in the study area, we could not observe clear reflected waves. However, the use of P- and S-wave velocities led to the delineation of a major basement damage zone in the study area, which further demonstrates the viability of quarry blasts as a useful seismic source for subsurface geological imaging.

Abstract Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.

Abstract Purpose Transdisciplinarity has been described as a fusion of theories, methods, and expertise across disciplinary boundaries to address complex, global problems. This approach has coincided with an increase in US medical schools offering masters degrees along with an MD degree to equip medical students to practice in complex, interconnected health systems. This study focused on medical schools that graduate the most dual degree students per year and explored the alignment of such programs with a transdisciplinary approach. Methods We identified 19 allopathic medical schools that annually graduated an average of 10 or more dual-degree students from 2015–2020. We surveyed these schools and asked participants to describe the reason(s) their institutions offered dual-degree programs. Two authors coded the narrative responses from the survey. Results Responses were received from 17 of the 19 schools. The analysis of participants’ responses regarding their institutions’ purpose for offering dual programs revealed several themes associated with a transdisciplinary approach to training. The most common themes were expand skill sets beyond a medical degree (73%), provide opportunity for interdisciplinary collaboration (67%), expand career interest and goals (60%), develop leaders (53%), enhance residency applications (47%) and further the institution’s vision and mission (45%). Conclusions This study is the first comprehensive evaluation of MD/Masters programs in the United States that includes a summary of the medical schools with the largest dual degree programs and their reasons for offering them. The findings support the hypothesis that allopathic medical schools recognize the need for a transdisciplinary approach to prepare students for the complexities in healthcare. These programs provide students with opportunities for additional areas of expertise, leadership development, enhancement of competitiveness for residency application, and interdisciplinary collaboration. Medical schools without dual-degree programs may consider developing these programs to provide benefits to students and institutions.

Abstract Fish fecundity scales hyperallometrically with body mass, meaning larger females produce disproportionately more eggs than smaller ones. We explore this relationship beyond the species-level to estimate the “reproductive potential” of 1633 coral reef sites distributed globally. We find that, at the site-level, reproductive potential scales hyperallometrically with assemblage biomass, but with a smaller median exponent than at the species-level. Across all families, modelled reproductive potential is greater in fully protected sites versus fished sites. This difference is most pronounced for the important fisheries family, Serranidae. When comparing a scenario where 30% of sites are randomly fully protected to a current protection scenario, we estimate an increase in the reproductive potential of all families, and particularly for Serranidae. Such results point to the possible ecological benefits of the 30 × 30 global conservation target and showcase management options to promote the sustainability of population replenishment.

Introduction: Hypertension (HTN) is a major cardiovascular disease that can cause and be worsened by renal damage and inflammation. We previously reported that renal lymphatic endothelial cells (LECs) increase in response to HTN and that augmenting lymphangiogenesis in the kidneys reduces blood pressure and renal pro-inflammatory immune cells in mice with various forms of HTN. Our aim was to evaluate the specific changes that renal LECs undergo in HTN. Methods: We performed single-cell RNA sequencing. Using the angiotensin II-induced and salt-sensitive mouse models of HTN, we isolated renal CD31+ and podoplanin+ cells. Results: Sequencing of these cells revealed three distinct cell types with unique expression profiles, including LECs. The number and transcriptional diversity of LECs increased in samples from mice with HTN, as demonstrated by 597 differentially expressed genes (p < 0.01), 274 significantly enriched pathways (p < 0.01), and 331 regulons with specific enrichment in HTN LECs. These changes demonstrate a profound inflammatory response in renal LECs in HTN, leading to an increase in genes and pathways associated with inflammation-driven growth and immune checkpoint activity in LECs. Conclusion: These results reinforce and help to further explain the benefits of renal LECs and lymphangiogenesis in HTN.

The evolution of psychotherapeutic treatments from Freud to digitally administered evidence-based treatments reflects a history of progressive advance. This history is characterized by identification of problems with the current state of the art, followed by solutions inspired and supported by advances in basic science and technology leading to subsequent recognition of other limitations revealed by the new advance. The common thread running through this process is (a) increasing specificity of the psychotherapeutic interventions, (b) increasing evidence of efficacy and safety, (c) increasing integrity and reliability in the delivery of the intervention, (d) increased equality of access, and (e) recognition of the need for regulation to provide protection for the public from unsafe or ineffective products. This evolution of psychotherapeutic treatments, not surprisingly, has been foreshadowed by the precursor history of the evolution of pharmacologic treatment. Although intellectual history is lumpy and does not sort itself into discrete and coherent epochs, such sorting is a useful heuristic for describing the advance of medicine and the therapeutic enterprise. This paper will discuss six successive epochs of psychotherapy. For each it will discuss the problem of the preceding era it sought to solve, the advance it brought to the field, the emerging science and technology that supported that advance, and the precursor development in pharmacological treatments that foreshadowed that epoch of psychotherapy. Finally, it will conclude with some observations about the proximate future.

Background: Two-stage exchange arthroplasty remains the gold standard for treating chronic hip periprosthetic joint infections. However, controversy remains regarding the optimal spacer type, particularly among patients with increased dislocation risk. This study reports on the outcomes of articulating hip spacers utilizing a single constrained-liner design. Methods: All patients who underwent treatment for hip periprosthetic joint infection at a single institution were screened. Patients were included if they received an articulating spacer utilizing a constrained liner of a single manufacturer design. Indications for constrained liner, demographic variables, and surgical variables were recorded. Patients were assessed for dislocation and component loosening prior to the second stage or at the final follow-up if the second stage was not undertaken. Comparative analysis was performed. Results: Overall, 26 constrained liners were utilized in 25 patients. Indications for constrained liner included history of dislocation (n = 14), massive proximal femoral bone loss (n = 14), greater trochanteric deficiency (n = 12), and absent abductors (n = 7). Many patients had more than one indication. In total, 9 hips (34.6%) underwent a second stage at an average of 7.4 months, while 17 hips never underwent a second stage with an average follow-up of 27.6 months. One patient experienced failure of their constrained liner prior to the second stage due to pelvic discontinuity and massive acetabular bone loss. Conclusions: Utilization of a constrained liner as an articulating spacer is a viable option for patients at high risk of instability. Meticulous cement technique, appropriate component position, and implant selection are crucial in achieving successful outcomes.

IntroductionCardiac rehabilitation (CR) adherence and functional outcomes were measured after COVID-19 regulations reduced group sizes to one-on-one, modeling a natural experiment.MethodsA retrospective analysis using a natural experiment model measured participants in 12 weeks of CR during the 17 months before and after a COVID-19-related closure was conducted. The age, sex, race, ethnicity, and referral diagnoses of the pre-COVID-19 closure and post-COVID-19 closure groups were analyzed using a student's unpaired T-test. Adherence (completion rate of CR) and functional outcomes [change in six-minute walk test (6MWT)] were assessed between the two groups using unpaired two-tailed student T tests in GraphPad Prism and confidence intervals were calculated with the Baptista-Pike method.ResultsThere were 204 patients in the pre-COVID-19 group and 51 patients in the post-COVID-19 group, due to the smaller group sizes in the post-COVID-19 group, with no significant differences in baseline characteristics between the groups. The pre-COVID-19 group had a higher patient-to-provider ratio [2.8 patients/provider (SD 0.74)] relative to the post-COVID-19 group [0.4 patients/provider (SD 0.12); p

Abstract By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

Electroluminescence efficiencies and stabilities of quasi-two-dimensional halide perovskites are restricted by the formation of multiple-quantum-well structures with broad and uncontrollable phase distributions. Here, we report a ligand design strategy to substantially suppress diffusion-limited phase disproportionation, thereby enabling better phase control. We demonstrate that extending the π-conjugation length and increasing the cross-sectional area of the ligand enables perovskite thin films with dramatically suppressed ion transport, narrowed phase distributions, reduced defect densities, and enhanced radiative recombination efficiencies. Consequently, we achieved efficient and stable deep-red light-emitting diodes with a peak external quantum efficiency of 26.3% (average 22.9% among 70 devices and cross-checked) and a half-life of ~220 and 2.8 h under a constant current density of 0.1 and 12 mA/cm2, respectively. Our devices also exhibit wide wavelength tunability and improved spectral and phase stability compared with existing perovskite light-emitting diodes. These discoveries provide critical insights into the molecular design and crystallization kinetics of low-dimensional perovskite semiconductors for light-emitting devices.

Abstract Pigments provide a simple means to rapidly visually ascertain the quantities or presence of specific microbes in a complex community. The selection of pigment‐producing colonies that are simple to differentiate from common colony phenotypes provides a high degree of certainty for the identity of pigment‐tagged strains. Successful employment of pigment production is dependent on various intrinsic factors related to proper levels of gene expression and pigment production that are not always easy to predict and vary within each microbe. We have constructed a simple transposon system that incorporates the genes for the production of deoxyviolacein, a pigment produced from intracellular reserves of the amino acid tryptophan, to randomly insert these genes throughout the genome. This tool allows the user to select from many thousands of potential sites throughout a bacterial genome for an ideal location to generate the desired amount of pigment. We have applied this system to a small selection of endophytes and other model bacteria to differentiate these strains from complex communities and confirm their presence after several weeks in natural environments. We provide two examples of applications using the pigments to trace strains following introduction into plant tissues or to produce a reporter strain for extracellular nitrogen compound sensing. We recognize that this tool could have far broader utility in other applications and microbes, and describe the methodology for use by the greater scientific community.

Abstract The capture and reduction of atmospheric dinitrogen gas to ammonium can be accomplished through the enzyme nitrogenase in a process known as biological nitrogen fixation (BNF), by a class of microbes known as diazotrophs. The diazotroph Azotobacter vinelandii is a model organism for the study of aerobic nitrogen fixation, and in recent years has been promoted as a potential producer of biofertilizers. Prior reports have demonstrated the potential to partially deregulate BNF in A. vinelandii, resulting in accumulation and extracellular release of ammonium. In many cases, deregulation requires the introduction of transgenic genes or elements to yield the desired phenotype, and the long‐term stability of these strains has been reported to be somewhat problematic. In this work, we constructed two strains of A. vinelandii where regulation can be precisely controlled without the addition of any foreign genes or genetic markers. Regulation is maintained through native promoters found in A. vinelandii that can be induced through the addition of extraneous galactose. These strains result in varied degrees of regulation of BNF, and as a result, the release of extracellular ammonium is controlled in a precise, and galactose concentration‐dependent manner. In addition, these strains yield high biomass levels, similar to the wild‐type A. vinelandii strain and are further able to produce high percentages of the bioplastic polyhydroxybutyrate.

Summary: Background: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Methods: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Findings: Insomnia was associated with higher risk of endometrioid EOC (OR = 1.60, 95% CI 1.05–2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR = 0.79 and 0.48, 95% CI 0.63–1.00 and 0.27–0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR = 1.45, 95% CI 1.13–1.87) and HGSOC (OR = 1.4, 95% CI 1.04–1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR = 2.48, 95% CI 1.13–5.42), but was attenuated after adjustment for clinical factors. Interpretation: This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. Funding: National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.