bluuebunny/crossref_metadata_2025 huggingface dataset:
The Evolution of C4 Photosynthesis in Flaveria (Asteraceae): Insights from the Flaveria linearis Complex
Authors: Adachi Shunsuke , Stata Matt , Martin Duncan G , Cheng Shifeng , Liu Hongbing , Zhu Xin-Guang , Sage Rowan F
Published: October 2022

Flaveria is a leading model for C4 plant evolution due to the presence of a dozen C3-C4 intermediate species, many of which are associated with a phylogenetic complex centered around Flaveria linearis. To investigate C4 evolution in Flaveria, we updated the Flaveria phylogeny and evaluated gas exchange, starch δ13C, and activity of C4 cycle enzymes in 19 Flaveria species and 28 populations within the F. linearis complex. A principal component analysis identified six functional clusters: (1) C3, (2) sub-C2, (3) full C2, (4) enriched C2, (5) sub-C4, and (6) fully C4 species. The sub-C2 species lacked a functional C4 cycle, while a gradient was present in the C2 clusters from little to modest C4 cycle activity as indicated by δ13C and enzyme activities. Three Yucatan populations of F. linearis had photosynthetic CO2 compensation points equivalent to C4 plants but showed little evidence for an enhanced C4 cycle, indicating they have an optimized C2 pathway that recaptures all photorespired CO2 in the bundle sheath (BS) tissue. All C2 species had enhanced aspartate aminotransferase activity relative to C3 species and most had enhanced alanine aminotransferase activity. These aminotransferases form aspartate and alanine from glutamate and in doing so could help return photorespiratory nitrogen (N) from BS to mesophyll cells, preventing glutamate feedback onto photorespiratory N assimilation. Their use requires upregulation of parts of the C4 metabolic cycle to generate carbon skeletons to sustain N return to the mesophyll, and thus could facilitate the evolution of the full C4 photosynthetic pathway.
Fear Avoidance Beliefs in Upper-Extremity Musculoskeletal Pain Conditions: Secondary Analysis of a Prospective Clinical Study on Digital Care Programs
Authors: Janela Dora , Costa Fabíola , Molinos Maria , Moulder Robert G , Lains Jorge , Scheer Justin K , Bento Virgílio , Yanamadala Vijay , Cohen Steven P , Correia Fernando Dias
Published: October 2022

Background

Fear-avoidance beliefs (FAB) have been associated with poorer prognosis and decreased adherence to exercise-based treatments in musculoskeletal (MSK) pain. However, the impact of high FAB on adherence and outcomes in upper extremity MSK (UEMSK) pain is poorly explored, particularly through exercise-based digital care programs (DCP).

Objective

Assess the adherence levels, clinical outcomes and satisfaction in patients with UEMSK pain and elevated FAB after a fully remote multimodal DCP. Associations between FABQ-PA and clinical outcomes were conducted.

Methods

Secondary analysis of an ongoing clinical trial. Participants with UEMSK pain (shoulder, elbow, and wrist/hand) and elevated FAB-physical activity (FABQ-PA ≥ 15) were included. Adherence (completion rate, sessions/week, total exercise time) and mean change in clinical outcomes—disability (QuickDASH), numerical pain score, FABQ-PA, anxiety (GAD-7), and depression (PHQ-9)—between baseline and end-of-program were assessed. Associations between FABQ-PA and clinical outcomes were conducted.

Results

520 participants were included, with mean baseline FABQ-PA of 18.02 (SD 2.77). Patients performed on average 29.3 exercise sessions (2.8 sessions/week), totalizing 338.2 exercise minutes. Mean satisfaction was 8.5/10 (SD 1.7). Significant improvements were observed in all clinical outcomes. Higher baseline FAB were associated with higher baseline disability (P < .001), and smaller improvements in disability (P < .001) and pain (P = .001). Higher engagement was associated with greater improvements in FABQ-PA (P = .043) and pain (P = 0.009).

Conclusions

This study provides evidence of the potential benefits of a structured and multimodal home-based DCP in the management of UEMSK pain conditions in patients with elevated FAB in a real-world context.
Does Directed Innovation Mitigate Climate Damage? Evidence from U.S. Agriculture
Authors: Moscona Jacob , Sastry Karthik A
Published: October 2022

This article studies how innovation reacts to climate change and shapes its economic impacts, focusing on U.S. agriculture. We show in a model that directed innovation can either mitigate or exacerbate climate change’s potential economic damage depending on the substitutability between new technology and favorable climatic conditions. To empirically investigate the technological response to climate change, we measure crop-specific exposure to damaging extreme temperatures and crop-specific innovation embodied in new variety releases and patents. We find that innovation has redirected since the mid-twentieth century toward crops with increasing exposure to extreme temperatures. Moreover, this effect is driven by types of agricultural technology most related to environmental adaptation. We next show that U.S. counties’ exposure to induced innovation significantly dampens the local economic damage from extreme temperatures. Combining these estimates with the model, we find that directed innovation has offset 20% of potential losses in U.S. agricultural land value due to damaging climate trends since 1960 and that innovation could offset 13% of projected damage by 2100. These findings highlight the vital importance, but incomplete effectiveness, of endogenous technological change as a source of adaptation to climate change.
Capital Structure and the Yield Curve
Authors: Duarte Diogo , Öztekin Özde , Saporito Yuri F
Published: October 2022

We develop a dynamic capital structure model in which interest rates are stochastic and driven by three state variables: level, slope, and curvature of the yield curve in an arbitrage-free Nelson-Siegel model. Our analysis suggests that the yield-curve factors are critical determinants of the capital structure of firms and that an increase in any of the three factors is followed by an increase of the firm’s leverage and a shortening of its debt maturity. We perform a two-stage least squares system of equations that accounts for the joint determination of leverage and debt maturity and confirms our model’s predictions. (JEL E43, G12, G32)
The effect of anti-inflammatory treatment on depressive symptoms in spondyloarthritis: does the type of drug matter?
Authors: Webers Casper , Kiltz Uta , Braun Jürgen , van der Heijde Désirée , Boonen Annelies
Published: October 2022

Objective

To investigate the effect of pharmacological treatment of SpA on depressive symptoms and explore whether this effect differs between drug classes.

Methods

Data from the observational Assessment of SpondyloArthritis international Society Health Index Validation Study were used. Patients were assessed at baseline and after initiation of NSAIDs/conventional synthetic DMARDs (csDMARDs)/TNF inhibitors (TNFis). Depressive symptoms were assessed with the Hospital Anxiety and Depression Scale depression subscale [HADS-D; 0–21 (best–worst)]. Covariables included demographics and disease characteristics, including disease activity [Ankylosing Spondylitis Disease Activity Score (ASDAS)/BASDAI]. The change in HADS-D from baseline was compared between treatments (NSAIDs/csDMARDs/TNFis) with analysis of variance and multivariable regression analysis.

Results

A total of 304 patients were included; 102/45/157 initiated NSAIDs/csDMARDs/TNFis and 260 (85%) / 44 (15%) had axial/peripheral SpA. At baseline, the mean HADS-D was 6.9 (s.d. 4.2); 126 (42%) were possibly depressed (HADS-D ≥8) and 66 (22%) were probably depressed (HADS-D ≥11). At follow-up, depressive symptoms significantly improved in all treatment groups. In multivariable regression without disease activity measures, initiating TNFis compared with NSAIDs was associated with greater improvement in depressive symptoms [β = −1.27 (95% CI −2.23, −0.32)] and lower odds of possible depression at follow-up [odds ratio 0.47 (95% CI 0.23, 0.94)]. This association was attenuated after additional adjustment for disease activity (ASDAS/BASDAI) but not CRP. csDMARDs did not differ from NSAIDs regarding their effect on HADS-D. Between-drug class results were confirmed in axial SpA (axSpA), although less clear in peripheral SpA.

Conclusion

Treatment of active SpA also improves depressive symptoms. Especially in axSpA, TNFis have a greater effect than NSAIDs, which is mainly explained by a stronger effect on disease activity. We found no evidence for a direct link between CRP-mediated inflammation and depressive symptoms in SpA.
Comorbidities and extra-articular manifestations in difficult-to-treat rheumatoid arthritis: different sides of the same coin?
Authors: Dey Mrinalini , Nagy György , Nikiphorou Elena
Published: October 2022

Despite the improvement in treatment for people with RA, ∼30% of patients remain symptomatic in the presence of optimized medical therapy, described as having ‘difficult-to-treat’ (D2T) RA. The average patient with RA has 1.6 other clinical conditions, which accumulate over time. Comorbidities are increasingly recognized as key contributors to D2T disease, and are themselves perpetuated by the D2T state. In this review, we discuss the commonest comorbidities in the context of D2T RA. We propose the need for a paradigm shift in the clinical and research agenda for comorbidities—including a need to consider and manage these prior to the development of D2T disease and not as an afterthought.
Targeted Intracellular Demethylation of Methylmercury Enhances Elimination Kinetics and Reduces Developmental Toxicity in TransgenicDrosophila
Authors: Krout Ian N , Scrimale Thomas , Rand Matthew D
Published: October 2022

Methylmercury (MeHg) persists today as a priority public health concern. Mechanisms influencing MeHg metabolism, kinetics, and toxicity outcomes are therefore essential knowledge for informing exposure risks. Evidence points to different toxic potencies of MeHg and inorganic mercury (Hg2+), highlighting the role for biotransformation (demethylation) in regulating MeHg toxicokinetics/dynamics. Whereas microbial MeHg demethylation in the gut is seen to influence elimination kinetics, the potential for systemic demethylation in tissues and target organs to influence MeHg toxicity remains uncertain. To investigate the consequences of systemic MeHg demethylation across development, we engineered transgenic Drosophila to express the bacterial organomercurial lyase enzyme (merB) in a targeted and tissue-specific manner. With all combinations of merB-induced demethylation, ubiquitously (via an actin promoter) or in a tissue-specific manner (ie, gut, muscle, neurons), we observe a rescue of MeHg-induced eclosion failure at the pupal to adult transition. In MeHg-fed larvae with ubiquitous or targeted (gut and muscle) merB expression, we see a significant decrease in MeHg body burden at the pupal stage relative to control flies. We also observe a significant increase in the MeHg elimination rate with merB demethylation induced in adults (control, t1/2 = 7.2 days; merB flies, t1/2 = 3.1 days). With neuronal-specific merB expression, we observe a rescue of MeHg-induced eclosion failure without a decrease in Hg body burden, but a redistribution of Hg away from the brain. These results demonstrate the previously unidentified potential for intracellular MeHg demethylation to promote transport and elimination of Hg, and reduce developmental MeHg toxicity.

Impact Statement: These findings demonstrate the potential for MeHg demethylation in situ to contribute significantly to the MeHg elimination and distribution kinetics of whole animals and thereby affords a means of protection against the toxic insult of MeHg. Therefore, this study reveals important insight into processes that can determine an individual’s resistance or susceptibility to MeHg and provides rationale for therapies targeting a novel metabolism-based pathways to alleviate toxicity risk stemming from MeHg exposure.
XThe Seventeenth Century, Part II
Authors: Baker William , Stelzer Emily , Airey Jennifer , Martin Catherine Gimelli , Parry David
Published: October 2022

This chapter has four sections: 1. General and Poetry; 2. Restoration Drama Excluding Dryden; 3. Dryden; 4. Prose. Section 1 is by William Baker, with Emily Stelzer covering Marvell, Herrick, and Crashaw; sections 2 and 3 are by Jennifer Airey; section 4 is by William Baker on Hobbes, William Baker and Catherine Gimelli Martin on Locke, David Parry on Bunyan, and Emily Stelzer on Pepys. There is no ‘Miscellaneous’ section this year.
Mitral valve surgery after failed transcatheter edge-to-edge repair: a review and word of caution
Authors: El-Eshmawi Ahmed , Costa Ana Claudia , Boateng Percy , Pandis Dimosthenis , Israel Yonatan , Adams David H. , Tang Gilbert H.L.
Published: October 2022

Purpose of review

As transcatheter edge-to-edge mitral valve repair (TEER) evolves and indications broaden to include younger and lower surgical risk patients, it is essential to understand TEER failure trends and potential impact on subsequent mitral valve surgery, especially when pertaining to feasibility of durable valve reconstruction as opposed to de-novo repair.

Recent findings

Results of the two largest series analysing mitral valve surgery following TEER have demonstrated remarkably low repairability rates with consequent need for valve replacement. Post TEER surgery was associated with high early and late mortalities, likely as a reflection of patient baseline characteristics and acuity of surgery. Presence and correction of concomitant cardiac pathologies were a frequent finding. Centre and surgeon volumes were important factors in optimizing the likelihood of salvage repair and reducing perioperative risks.

Surgical mitral valve repair in reference centres remain the gold standard and the most durable treatment for degenerative mitral disease with excellent perioperative safety outcomes. Given the high likelihood of needing high-risk mitral valve replacement when TEER fails, consideration for potentially less durable transcatheter alternatives should be taken with caution in younger or lower surgical risk patients.
Speech Recognition Performance Differences Between Precurved and Straight Electrode Arrays From a Single Manufacturer
Authors: Sharma Rahul K. , Smetak Miriam R. , Patro Ankita , Lindquist Nathan R. , Perkins Elizabeth L. , Holder Jourdan T. , Haynes David S. , Tawfik Kareem O.
Published: October 2022

Objective

Precurved cochlear implant (CI) electrode arrays have demonstrated superior audiometric outcomes compared with straight electrodes in a handful of studies. However, previous comparisons have often failed to account for preoperative hearing and age. This study compares hearing outcomes for precurved and straight electrodes by a single manufacturer while controlling for these and other factors in a large cohort.

Study Design

Retrospective cohort study.

Setting

Tertiary academic medical center.

Patients

Two hundred thirty-one adult CI recipients between 2015 and 2021 with cochlear (Sydney, Australia) 522/622 (straight) or 532/632 (precurved) electrode arrays.

Interventions

Postactivation speech recognition and audiometric testing.

Main Outcome Measures

Speech recognition testing (consonant-nucleus-consonant word [CNCw] and AzBio) was collected at 6 and 12 months postactivation. Hearing preservation was characterized by a low-frequency pure-tone average shift, or the change between preoperative and postoperative low-frequency pure-tone average.

Results

Two hundred thirty-one patients (253 ears) with 6-month and/or 12-month CNCw or AzBio testing were included. One hundred forty-nine (59%) and 104 (41%) ears were implanted with straight and precurved electrode arrays, respectively. Average age at implantation was 70 years (interquartile range [IQR], 58–77 y). There was no significant difference in mean age between groups. CNCw scores were significantly different (p = 0.001) between straight (51%; IQR, 36–67%) and precurved arrays (64%; IQR, 48–72%). AzBio scores were not significantly different (p = 0.081) between straight (72%; IQR, 51–87%) and precurved arrays (81%; IQR, 57–90%). Controlling for age, race, sex, preoperative hearing, and follow-up time, precurved electrode arrays performed significantly better on CNCw (b = 10.0; 95% confidence interval, 4.2–16.0; p < 0.001) and AzBio (b = 8.9; 95% confidence interval, 1.8–16.0;, p = 0.014) testing. Hearing preservation was not different between electrodes on adjusted models.

Conclusion

During the study period, patients undergoing placement of precurved electrode arrays had significantly higher CNC and AzBio scores than patients receiving straight electrodes, even after controlling for age, preoperative hearing, and follow-up time.

Professional Practice Gap and Educational Need

Understanding the difference in audiometric outcomes between precurved and straight electrode arrays will help to guide electrode selection.

Learning Objective

To understand differences in speech recognition scores postoperatively by electrode array type (precurved versus straight).

Desired Result

To demonstrate a difference in hearing performance postoperatively by electrode type.

Level of Evidence

III

Indicate IRB or IACUC

Approved by the Institutional IRB (090155).
Preliminary Validation Study of the French-Quebec Version of the Mild Behavioral Impairment Checklist
Authors: Pépin Émilie , Tanguay Noémie , Roy Marie-Pier , Macoir Joël , Bruneau Marie-Andrée , Ismail Zahinoor , Hudon Carol
Published: October 2022

Background:

Alzheimer disease dementia may be preceded by cognitive stages during which behavioral and psychological changes can occur. More precisely, behavioral symptoms may be observed during the subjective cognitive decline (SCD) or the mild cognitive impairment (MCI) stages; these symptoms can be measured using the Mild Behavioral Impairment Checklist (MBI–C).

Objective:

To validate the French-Quebec version of the MBI–C in individuals ages 60–85 years.

Method:

The sample included 60 participants (20 MCI, 20 SCD, 20 cognitively healthy) and their informants. To assess the discriminant validity of the MBI–C, a Kruskal-Wallis analysis with a multiple comparisons test was performed on the MBI–C Total score. To determine convergent validity, Spearman correlations were calculated between the MBI–C subscales and a set of validation tools. Finally, test–retest reliability was assessed with Spearman correlations of MBI–C scores between two test sessions.

Results:

All of the analyses indicated satisfactory psychometric properties for the French-Quebec version of the MBI–C.

Conclusion:

This validation study reveals that the MBI–C can be used successfully in dementia risk assessments. From now on, the use of a validated MBI–C will be possible in the French-Quebec population.
Knufia obscura sp. nov. and Knufia victoriae sp. nov., two new species from extreme environments
Authors: Isola Daniela , Prigione Valeria Paola , Zucconi Laura , Varese Giovanna Cristina , Poli Anna , Turchetti Benedetta , Canini Fabiana
Published: October 2022

Six strains of black meristematic fungi were isolated from Antarctic soils, gasoline car tanks and from the marine alga Flabellia petiolata. These fungi were characterized by morphological, physiological and phylogenetic analyses. According to the maximum-likelihood analysis reconstructed with ITS and LSU sequences, these strains belonged to the genus Knufia. Knufia obscura sp. nov. (holotype CBS 148926) and Knufia victoriae sp. nov. (holotype CBS 149015) are proposed as two novel species and descriptions of their morphological, physiological and phylogenetic features are presented. Based on the maximum-likelihood analyses, K. obscura was closely related to Knufia hypolithi (99 % bootstrap support), while K. victoriae clustered in the clade of Knufia cryptophialidica and Knufia perfecta (93 % bootstrap support). Knufia victoriae, recorded in Antarctic soil samples, had a psychrophilic behaviour, with optimal growth between 10 and 15 °C and no growth recorded at 20 °C. Knufia obscura, from a gasoline car tank and algae, displayed optimal growth between 20 and 25 °C and was more tolerant to salinity than K. victoriae.
Published Research on the Human Health Implications of Climate Change from 2012-2019: a Cross-Sectional Study
Authors: Bartlett Victoria L. , Gupta Ravi , Wallach Joshua , Nyhan Kate , Chen Kai , Ross Joseph S.
Published: October 2022

Importance

Climate change is one of the most pressing global public health issues and is increasingly gaining attention from governments and researchers as a critical policy and research focus. While research on the effects of climate change on human health has grown significantly over the past few decades, there remain known gaps in research on non-physical health topics, like mental health, and in research on low-income countries.

Objective

To better understand the current state of research on the human health effects of climate change, including exposures, health conditions, populations, areas of the world studied, funding sources, and publication characteristics, with a focus on topics that are relevant for vulnerable populations.

Evidence Review

We searched the National Institute of Environmental Health Sciences (NIEHS) Climate Change and Human Health Literature Portal, a curated bibliographic database of global peer-reviewed research and gray literature on the science of climate impact on human health, to identify peer-reviewed original research investigating the health effects of climate change published from 2012 to 2019. The database combines searches of multiple search engines including PubMed, Web of Science, and Google Scholar and includes added-value expert tagging of climate change exposures and health impacts. We filtered our search by year published, limited to original research articles published in English. After identifying all original research articles, we selected a 5% random sample to manually perform a detailed characterization of research topics and publication information.

Findings

There were 7082 original research articles published between 2012 and 2019, and the number of articles increased by 23% annually. In our random sample of 348 articles, we found that there were several gaps in research topics that are particularly relevant to vulnerable populations, such as those in the Global South (159; 45.7%) and the elderly (55; 15.8%). Additionally, fewer first authors were from the Global South (110; 31.6%), which may in part explain why there is disproportionally less research focusing on these countries.

Conclusions and Relevance

Our results help elucidate gaps in research that, once addressed, may help us better understand and mitigate some of the most devastating effects of climate change on human health.
Using Trends and Outliers in Managing Delayed Transfusions
Authors: Bahar Burak , Gehrie Eric A. , Mo Yunchuan D. , Jacquot Cyril , Delaney Meghan
Published: October 2022

Delayed transfusions may result in patient morbidity and mortality, but no standards for timely transfusion have been developed. Information technology tools could be implemented to identify gaps in provision of blood and to recognize areas of improvement. Herein, we propose that the time to initiate a blood transfusion after an informative laboratory test could feasibly be used by the transfusion medicine service as a metric to monitor for transfusion delays. Trends and outlier events could be further investigated and used to make decisions and implement protocols to improve patient care.
Real-world evidence: telemedicine for complicated cases of urinary tract infection
Authors: Daumeyer Natalie M. , Kreitzberg Daniel , Gavin Kathleen M. , Bauer Timothy A.
Published: October 2022

Background

Telemedicine programs for the treatment of urinary tract infections (UTIs) offer an opportunity to reduce burdens on patients and providers. However, these programs are typically restricted to patients with uncomplicated UTIs. This real-world analysis evaluated treatment and resolution rates in a large-scale, national UTI telemedicine program inclusive of patients with uncomplicated and complicated UTIs.

Methods and findings

We conducted a retrospective analysis of data obtained from a commercially available telemedicine program for the treatment of UTIs among adult women in the US between 2017 and 2021 (n=51,474). The primary outcomes were the number of women who presented with symptoms of uncomplicated UTI, complicated UTI, and vaginal infection; prescription use and antibiotic type; symptom resolution within 7 days after appointment; and treatment failure or relapse. Most patients reported frequent urination (94.4%), urgency (94.5%), and dysuria (97.6%). Those with uncomplicated UTI symptoms represented the majority of patients (61.6%); however, a substantial number of patients (36.5%) also reported at least 1 symptom associated with a complicated UTI. One-fifth of patients (19.2%) reported at least 1 co-occurring symptom of vaginal infection or sexually transmitted infection. Across all treated patients, 94.0% received recommended antibiotics according to the clinical protocol. Of the treated patients who provided follow-up data (n=3,521), 89.7% reported 7-day symptom resolution. Symptom resolution rates were similar between patients with uncomplicated UTI symptoms (90.8%) and complicated UTI symptoms (87.9%), and symptom resolution among all treated patients (89.7%) was similar to reports for in-person standard of care.

Conclusions

These findings suggest that large-scale telemedicine programs for the treatment of UTIs can be effective in the treatment of complicated UTIs.
Development and Validation of ‘Patient Optimizer’ (POP) Algorithms for Predicting Surgical Risk with Machine Learning
Authors: Kowadlo Gideon , Mittelberg Yoel , Ghomlaghi Milad , Stiglitz Daniel , Kishore Kartik , Guha Ranjan , Nazareth Justin , Weinberg Laurence
Published: October 2022

Background

Pre-operative risk assessment can help clinicians prepare patients for surgery, reducing the risk of perioperative complications, length of hospital stay, readmission and mortality. Further, it can facilitate collaborative decision-making and operational planning.

Objective

To develop effective pre-operative risk assessment algorithms (referred to as Patient Optimizer or POP) using Machine Learning (ML) that predicts the development of post-operative complications and provides pilot data to inform the design of a larger prospective study.

Methods

After institutional ethics approval, we developed a baseline model that encapsulates the standard manual approach of combining patient-risk and procedure-risk. In an automated process, additional variables were included and tested with 10-fold cross-validation, and the best performing features were selected. The models were evaluated and confidence intervals calculated using bootstrapping. Clinical expertise was used to restrict the cardinality of categorical variables (e.g. pathology results) by including the most clinically relevant values. The models were created with extreme gradient-boosted trees using XGBoost [1]. We evaluated performance using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Data was obtained from a metropolitan university teaching hospital from January 2015 to July 2020. Data collection was restricted to adult patients undergoing elective surgery.

Results

A total of 11,475 adult admissions were included. For predicting the risk of any postoperative complication, kidney failure and length-of-stay (LOS), POP achieved an AUROC (95%CI) of 0.755 (0.744, 0.767), 0.869 (0.846, 0.891) and 0.841 (0.833, 0.847) respectively and AUPRC of 0.651 (0.632, 0.669), 0.326 (0.293, 0.359) and 0.741 (0.729, 0.753) respectively. For 30-day readmission and in-patient mortality, POP achieved an AUROC (95%CI) of 0.61 (0.587, 0.635) and 0.866 (0.777, 0.943) respectively and AUPRC of 0.116 (0.104, 0.132) and 0.031 (0.015, 0.072) respectively.

Conclusion

The POP algorithms effectively predicted any post-operative complications, kidney failure and LOS in the sample population. A larger study is justified to improve the algorithm to better predict complications and length of hospital stay. A larger dataset may also improve the prediction of additional specific complications, readmissions and mortality.
Ultrasonic measures of prestin (SLC26a5) charge movements in membrane patches
Authors: Santos-Sacchi Joseph , Bai Jun-Ping , Navaratnam Dhasakumar
Published: October 2022

Charged moieties in the outer hair cell (OHC) molecular motor protein, prestin, are driven by transmembrane voltage to ultimately provide for cochlear amplification. The speed of voltage-dependent conformational switching underlies its ability to influence micromechanics of the cell and the organ of Corti. Corresponding voltage-sensor charge movements in prestin, classically assessed as a voltage-dependent, nonlinear membrane capacitance (NLC), have been used to gauge its frequency response. Using megahertz sampling of prestin charge movements, we extend interrogations of prestin performance into the ultrasonic range (up to 120 kHz) and find response magnitude larger than previously reported. We also confirm kinetic model predictions of prestin by directly observing its cut-off frequency under voltage-clamp as the intersection frequency (Fis) of the real and imaginary components of complex NLC (cNLC), showing values near 19 kHz. At higher frequencies, the imaginary component roll-off exactly tracks that of Abs(cNLC). The frequency response of prestin displacement current noise determined from the Nyquist relation aligns with this cut-off. On the other hand, previous measures of stationary thermal-driven noise of prestin indicated that the cut-off was several fold greater than that of NLC, in violation of the fluctuation-dissipation theorem. We have attempted to confirm this apparent paradox, but find that low frequency (<10kHz), voltage-dependent 1/f noise, likely due to intrinsic prestin conductance, can limit the accessible bandwidth for stationary noise analysis. Nevertheless, within those bandwidths, frequency response comparisons of stationary measures and Nyquist relation measures are consistent. We conclude that voltage stimulation accurately assesses the spectral limits of prestin activity.

Significance

Using megahertz sampling, we extend measures of prestin charge movement into the ultrasonic range and find that the frequency roll-off is less than previously reported. Nevertheless, analysis of complex nonlinear capacitance confirms low-pass behavior, with a characteristic cut-off frequency near 19 kHz. The frequency response of prestin noise garnered by the admittance-based Nyquist relation confirms this cut-off frequency. In conflict with previous results, however, we find a similar low-pass frequency response using direct measures of prestin noise in the absence of voltage stimulation. Our data indicate that voltage perturbation provides an accurate assessment of prestin performance.
Myosin-Binding Protein C Stabilizes, But Is Not the Sole Determinant of SRX Myosin in Cardiac Muscle
Authors: Nelson Shane , Previs Samantha Beck , Sadayappan Sakthivel , Tong Carl , Warshaw David M.
Published: October 2022

The myosin Super Relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with Myosin-Binding Protein C (MyBP-C) in the C-zone, proximal to the sarcomere center. To define how MyBP-C and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic MyBP-C null mice and those expressing MyBP-C with a 271 residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and sub-sarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin was highest in the C-zone (71±6%) and lower in the D-zone (45±10%) which lies farther from the sarcomere center and lacks MyBP-C, suggesting a possible role for MyBP-C in stabilizing the SRX state within the C-zone. However, myofibrils from MyBP-C null mice demonstrated an ~40% SRX reduction, not only within the now MyBP-C-free C-zone (49±9% SRX), but also within the D-zone (22±5% SRX). These data suggest that the influence of MyBP-C on the SRX state is not limited to the C-zone, but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated MyBP-C had an SRX content and spatial gradient similar to the MyBP-C null, indicating that the N terminus of cardiac MyBP-C is necessary for MyBP-C’s role in establishing SRX along the entire thick filament. Given that SRX myosin are enriched in the C-zone, even in the absence of MyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state. One candidate may be a differential in the super repeats of titin that interact with MyBP-C and myosin and which template the thick filament.
Dynamic trade-offs between biomass accumulation and division determine bacterial cell size and proteome in fluctuating nutrient environments
Authors: Kratz Josiah C. , Banerjee Shiladitya
Published: October 2022

Bacteria dynamically regulate cell size and growth rate to thrive in changing environments. While much work has been done to characterize bacterial growth physiology and cell size control during steady-state exponential growth, a quantitative understanding of how bacteria dynamically regulate cell size and growth in time-varying nutrient environments is lacking. Here we develop a dynamic coarse-grained proteome sector model which connects growth rate and division control to proteome allocation in time-varying environments in both exponential and stationary phase. In such environments, growth rate and size control is governed by trade-offs between prioritization of biomass accumulation or division, and results in the uncoupling of single-cell growth rate from population growth rate out of steady-state. Specifically, our model predicts that cells transiently prioritize ribosome production, and thus biomass accumulation, over production of division machinery during nutrient upshift, explaining experimentally-observed size control behaviors. Strikingly, our model predicts the opposite behavior during downshift, namely that bacteria temporarily prioritize division over growth, despite needing to upregulate costly division machinery and increasing population size when nutrients are scarce. Importantly, when bacteria are subjected to pulsatile nutrient concentration, we find that cells exhibit a transient memory of the previous metabolic state due to the slow dynamics of proteome reallocation. This phenotypic memory allows for faster adaptation back to previously-seen environments when nutrient fluctuations are short-lived.
Integration of primary contact physiotherapists in the emergency department for individuals presenting with minor musculoskeletal disorders: Protocol for an economic evaluation
Authors: Gagnon Rose , Hébert Luc J. , Guertin Jason R. , Berthelot Simon , Desmeules François , Perreault Kadija
Published: October 2022

Objectives

1) To compare the average cost of an emergency department (ED) visit for various minor musculoskeletal disorders between two models of care (physiotherapist and ED physician or ED physician alone); 2) To evaluate the incremental cost-effectiveness ratio (ICER) of these two models of care over a 3-month period post-initial visit; and 3) To estimate the ICER of three ED models of care (physiotherapist and ED physician, ED physician alone, physiotherapist alone) over a two-year period.

Methods

A randomized clinical trial was conducted among individuals (n=78) aged 18 to 80 years presenting with a musculoskeletal disorder at a Quebec City (Canada) hospital in 2018-2019. Two models of care were compared: management by a physiotherapist and an ED physician versus usual management by an ED physician. Participants follow-ups were conducted at 1 and 3 months post-initial ED visit. Obj.1: The health care costs incurred by the two groups during their ED visit will be calculated using the Time-Driven Activity-Based Costing (TDABC) method and compared using generalized linear models. Obj. 2: The cost-utility analysis over a 3-month time horizon will combine economic and clinical variables (estimated through quality-adjusted life years) using a Societal perspective. The results of the cost-utility analysis will be reported using an ICER. Obj. 3: The ICER will be estimated using a hybrid decision tree (0-3 months post-visit) and Markov model (3-24 months post-visit); the analysis will be conducted from a Societal perspective over a two-year time horizon.

Conclusion

This study will help to determine which model of care is most efficient for the management of individuals who come to the ED with minor musculoskeletal disorders. The increased involvement of various health professionals in the management of patients in the ED paves the way for the development of new avenues of practice and more efficient organization of services.
The crystal structure of a simian Foamy Virus receptor binding domain provides clues about entry into host cells
Authors: Fernández Ignacio , Dynesen Lasse Toftdal , Coquin Youna , Pederzoli Riccardo , Brun Delphine , Haouz Ahmed , Gessain Antoine , Rey Felix A. , Buseyne Florence , Backovic Marija
Published: October 2022

The surface envelope glycoprotein (Env) of all retroviruses mediates virus binding to cells and fusion of the viral and cellular membranes. A structure-function relationship for the HIV Env that belongs to the Orthoretrovirus subfamily has been well established. Structural information is however largely missing for the Env of Foamy viruses (FVs), the second retroviral subfamily. FV Envs lack sequence similarity with their HIV counterpart. We present the X-ray structure of the receptor binding domain (RBD) of a simian FV Env at 2.6 Å resolution, revealing two subdomains and an unprecedented fold. We have generated a model for the organization of the RBDs within the trimeric Env which indicates that the upper subdomain is important for stabilization of the full-length Env, and have demonstrated that residues K342, R343, R359 and R369 in the lower subdomain play key roles in the interaction of the RBD and viral particles with heparan sulfate.
SARS-CoV-2 infection alkalinizes the ERGIC and lysosomes through the viroporin activity of the viral envelope protein
Authors: Wang Wen-An , Sureda Amado Carreras , Demaurex Nicolas
Published: October 2022

The coronavirus SARS-CoV-2, the agent of the deadly COVID-19 pandemic, is an enveloped virus propagating within the endocytic and secretory organelles of host mammalian cells. Enveloped viruses modify the ionic homeostasis of organelles to render their intra-luminal milieu permissive for viral entry, replication, and egress. Here, we show that infection of Vero E6 cells with the delta variant of the SARS-CoV-2 alkalinizes the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) as well as lysosomes, mimicking the effect of inhibitors of vacuolar proton ATPases. We further show the envelope protein of SARS-CoV-2 accumulates in the ERGIC when expressed in mammalian cells and selectively dissipates the ERGIC pH. This viroporin effect is not associated with acute cellular toxicity but is prevented by mutations within the channel pore of E. We conclude that the envelope protein acts as a proton channel in the ERGIC to mitigate the acidity of this intermediate compartment. The altered pH homeostasis of the ERGIC likely contributes to the virus fitness and pathogenicity, making the E channel an attractive drug target for the treatment of COVID-19.
Phloem anatomy restricts root system architecture development: theoretical clues from in silico experiments
Authors: Zhou Xiao-Ran , Schnepf Andrea , Vanderborght Jan , Leitner Daniel , Vereecken Harry , Lobet Guillaume
Published: October 2022

Plant growth and development involve the integration of numerous processes, influenced by both endogenous and exogenous factors. At any given time during a plant’s life cycle, the plant architecture is a readout of this continuous integration. However, untangling the individual factors and processes involved in the plant development and quantifying their influence on the plant developmental process is experimentally challenging.

Here we used a combination of computational plant models to help understand experimental findings about how local phloem anatomical features influence the root system architecture. In particular, we simulated the mutual interplay between the root system architecture development and the carbohydrate distribution to provide a plausible mechanistic explanation for several experimental results.

Our in silico study highlighted the strong influence of local phloem hydraulics on the root growth rates, growth duration and final length. The model result showed that a higher phloem resistivity leads to shorter roots due to the reduced flow of carbon within the root system. This effect was due to local properties of individual roots, and not linked to any of the pleiotropic effects at the root system level.

Our results open the door to a better representation of growth processes in plant computational models.
Deep generative modeling of sample-level heterogeneity in single-cell genomics
Authors: Boyeau Pierre , Hong Justin , Gayoso Adam , Kim Martin , McFaline-Figueroa José L. , Jordan Michael I. , Azizi Elham , Ergen Can , Yosef Nir
Published: October 2022

The field of single-cell genomics is now observing a marked increase in the prevalence of cohort-level studies that include hundreds of samples and feature complex designs. These data have tremendous potential for discovering how sample or tissue-level phenotypes relate to cellular and molecular composition. However, current analyses are based on simplified representations of these data by averaging information across cells. We present MrVI, a deep generative model designed to realize the potential of cohort studies at the single-cell level. MrVI tackles two fundamental and intertwined problems: stratifying samples into groups and evaluating the cellular and molecular differences between groups, both without requiringa priorigrouping of cells into types or states. Due to its single-cell perspective, MrVI is able to detect clinically relevant stratifications of patients in COVID-19 and inflammatory bowel disease (IBD) cohorts that are only manifested in certain cellular subsets, thus enabling new discoveries that would otherwise be overlooked. Similarly, we demonstrate that MrVI can de-novo identify groups of small molecules with similar biochemical properties and evaluate their effects on cellular composition and gene expression in large-scale perturbation studies. MrVI is available as open source atscvi-tools.org.
CHRONO participates in multi-modal repression of circadian transcriptional complexes
Authors: Crosby Priya , Goularte Nicolette F. , Sharma Diksha , Chen Eefei , Parico Gian Carlo G. , Philpott Jon M. , Harold Rachel , Gustafson Chelsea L. , Partch Carrie L.
Published: October 2022

The mammalian protein CHRONO is a rhythmically expressed repressor of the circadian transcriptional activator complex CLOCK:BMAL1, and was proposed to be a novel component of the circadian clock. However, lack of specific mechanistic understanding of the activity and function of CHRONO meant that its role within the circadian machinery was opaque. Here we fill this knowledge gap, confirming an evolutionarily conserved minimal repressive domain (MRD) of CHRONO that interacts with specific regions in the BMAL1 C-terminal transactivation domain (TAD) to repress CLOCK:BMAL1 activity. Notably, this binding region overlaps with the binding site for the repressor CRY and coactivators CBP/p300, with CHRONO capable of competing with both of these classical regulators of BMAL1 for TAD binding, highlighting CHRONO as a direct regulator of BMAL1 function.

Additionally, we investigate the interaction between CHRONO and the major circadian repressor, PERIOD2 (PER2). We show that CHRONO reduces PER2 stability through interaction between the CHRONO C-terminus and the Casein Kinase 1 (CK1)-binding domain of PER2. This results in competition between CHRONO and CK1 for binding at this site on PER2, with CHRONO binding inhibiting CK1 phosphorylation of PER2 at the stabilising S662 residue. Taken together, these data show a more substantive and complex role for CHRONO in molecular circadian timekeeping than previously posited, suggesting that CHRONO acts to fine-tune cellular timekeeping by modulating multiple protein-protein interactions that are critical for maintenance of circadian rhythmicity.
Rapid inactivation of vaccinia, a surrogate virus for monkeypox and smallpox, using ultraviolet-C disinfection
Authors: Koutras Carolina , Wade Richard L.
Published: October 2022

Human monkeypox is an emerging health threat that has the potential to cause serious sequelae. Ultraviolet-C (UV-C) disinfection is a physical process that triggers microbial inactivation through irreversible DNA damage. A high-output mobile UV-C unit was evaluated against vaccinia, a monkeypox surrogate, for antimicrobial efficacy. In under 7 minutes, a single UV-C cycle had a virucidal efficacy of ≥ 99.996 % in a 200 sq feet area. UV-C technology is a promising strategy for infection prevention and control in the post-COVID era.
Genetic architecture of cardiac dynamic flow volumes
Authors: Gomes Bruna , Singh Aditya , O’Sullivan Jack W , Amar David , Kostur Mykhailo , Haddad Francois , Salerno Michael , Parikh Victoria N. , Meder Benjamin , Ashley Euan A.
Published: October 2022

Cardiac blood flow is a critical determinant of human health. However, definition of its genetic architecture is limited by the technical challenge of capturing dynamic flow volumes from cardiac imaging at scale. We present DeepFlow, a deep learning system to extract cardiac flow and volumes from phase contrast cardiac magnetic resonance imaging. A mixed linear model applied to 37,967 individuals from the UK Biobank reveals novel genome-wide significant associations across cardiac dynamic flow volumes including aortic forward velocity, total left ventricular stroke volume, forward left ventricular flow and aortic regurgitation fraction. Mendelian randomization using CAUSE reveals a causal role for aortic root size in aortic valve regurgitation. The most significant contributing variants (near ELN, FBN1 and ULK4) are implicated in connective tissue and blood pressure pathways. DeepFlow cardiac flow phenotyping at scale, combined with population-level genotyping data in the UK Biobank, reinforces the contribution of connective tissue genes, blood pressure and root size to aortic valve function in the general population.