bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome
Authors: Matsuda Kazuki M , Kotani Hirohito , Yamaguchi Kei , Ono Chihiro , Okumura Taishi , Ogawa Koji , Miya Ayako , Sato Ayaka , Uchino Rikako , Yumi Murakami , Matsunaka Hiroshi , Kono Masanori , Norimatsu Yuta , Hisamoto Teruyoshi , Kawanabe Ruriko , Kuzumi Ai , Fukasawa Takemichi , Yoshizaki-Ogawa Asako , Okamura Tomohisa , Shoda Hirofumi , Fujio Keishi , Matsushita Takashi , Goshima Naoki , Sato Shinichi , Yoshizaki Ayumi
Published: January 2024

Objectives

To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance.

Methods

We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electronic medical records.

Results

PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs.

Conclusion

Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement.
Tradeoff between Gender and Class Equality: An Analysis of Tax Policy in Japan
Authors: Toyofuku Miki
Published: January 2024

Although conservative parties in developed countries are becoming more positive about women’s labor force participation, serious economic gender gaps persist in some conservative welfare regimes. By focusing on Japan as a most-likely case, this article reexamines the view that emphasizes conservative parties’ preference for traditional gender roles as a key factor contributing to policies that negatively affect gender equality. Analyses using text data from parliamentary statements reveal that parties’ preference for class equality, held by both conservative and leftist parties, contributes to a tax policy that suppresses women’s labor force participation. The findings illuminate a tradeoff between class and gender equality and provide implications for how conservative welfare regimes can achieve higher levels of economic gender equality.
Spatial analysis of renal acetaminophen metabolism and its modulation by 4-methylpyrazole with DESI mass spectrometry imaging
Authors: Akakpo Jephte Yao , Olivos Hernando , Shrestha Bindesh , Midey Anthony , Jaeschke Hartmut , Ramachandran Anup
Published: January 2024

Acute kidney injury (AKI) is a common complication in acetaminophen (APAP) overdose patients and can negatively impact prognosis. Unfortunately, N-acetylcysteine, which is the standard of care for the treatment of APAP hepatotoxicity does not prevent APAP-induced AKI. We have previously demonstrated the renal metabolism of APAP and identified fomepizole (4-methylpyrazole, 4MP) as a therapeutic option to prevent APAP-induced nephrotoxicity. However, the kidney has several functionally distinct regions, and the dose-dependent effects of APAP on renal response and regional specificity of APAP metabolism are unknown. These aspects were examined in this study using C57BL/6J mice treated with 300–1200 mg/kg APAP and mass spectrometry imaging (MSI) to provide spatial cues relevant to APAP metabolism and the effects of 4MP. We find that renal APAP metabolism and generation of the nonoxidative (APAP-GLUC and APAP-SULF) and oxidative metabolites (APAP-GSH, APAP-CYS, and APAP-NAC) were dose-dependently increased in the kidney. This was recapitulated on MSI which revealed that APAP overdose causes an accumulation of APAP and APAP GLUC in the inner medulla and APAP-CYS in the outer medulla of the kidney. APAP-GSH, APAP-NAC, and APAP-SULF were localized mainly to the outer medulla and the cortex where CYP2E1 expression was evident. Interestingly, APAP also induced a redistribution of reduced GSH, with an increase in oxidized GSH within the kidney cortex. 4MP ameliorated these region-specific variations in the formation of APAP metabolites in renal tissue sections. In conclusion, APAP metabolism has a distinct regional distribution within the kidney, the understanding of which provides insight into downstream mechanisms of APAP-induced nephrotoxicity.
Temporal dynamics of stomatal regulation and carbon- and water-related traits for a native tree species in low subtropical China
Authors: Zhu Li-Wei , Li Yan-Qiong , Lu Long-Wei , Wang Jing-Yi , Du Jie , Zhao Ping
Published: January 2024

Stomata are pivotal in modulating water and carbon processes within plants. However, our understanding of the temporal dynamics of water- and carbon-related traits, as influenced by stomatal behavior, remains limited. Here, we explore how stomatal regulation behavior and water- and carbon-related traits vary with changing environments by examining the seasonal variations in these traits of the native tree species Schima superba Gardn. et Champ. in low subtropical China. In February, April and July of 2022, a series of water- and carbon-related traits were measured in the leaves and stems. The results showed that S. superba exhibited isohydric behavior in February when the soil dried out and vapor pressure deficit (VPD) was lower but anisohydric behavior in April and July when the soil was wetter and VPD was higher. In February, nonstructural carbohydrates (NSC) and their components increased, and a relatively large contribution of soluble sugars to the change in NSC was observed. In the branches and phloem, NSC and their components displayed a relatively high monthly variability, suggesting their role in maintaining carbon balance within the trees. Conversely, the NSC in the leaves demonstrated minimal monthly variability. The specific leaf area, as well as the concentration of nitrogen (N) and phosphorus (P) per unit mass in leaves and the cumulative stem water release, exhibited a decrease with a reduction in soil water potential. Interestingly, the hydraulic conductivity remained consistent throughout this process. Furthermore, the relatively low monthly growth rate observed in February could suggest a carbon sink limitation. In conclusion, the increased NSC and decreased water status of S. superba under relatively stressed soil conditions indicated a trade-off between water and carbon storage. Our findings enhance our comprehension of the dynamics and regulation of water and carbon status in forests, thereby advancing the development of plant carbon and water process models under climate change scenarios.
Water storage capacity is inversely associated with xylem embolism resistance in tropical karst tree species
Authors: Liu Yan-Yan , Chao Lin , Li Zhong-Guo , Ma Lin , Hu Bao-Qing , Zhu Shi-Dan , Cao Kun-Fang
Published: January 2024

Tropical karst habitats are characterized by limited and patchy soil, large rocky outcrops and porous substrates, resulting in high habitat heterogeneity and soil moisture fluctuations. Xylem hydraulic efficiency and safety can determine the drought adaptation and spatial distribution of woody plants growing in karst environments. In this study, we measured sapwood-specific hydraulic conductivity (Ks), vulnerability to embolism, wood density, saturated water content, and vessel and pit anatomical characteristics in the branch stems of 12 evergreen tree species in a tropical karst seasonal rainforest in southwestern China. We aimed to characterize the effects of structural characteristics on hydraulic efficiency and safety. Our results showed that there was no significant correlation between Ks and hydraulic safety across the tropical karst woody species. Ks was correlated with hydraulic vessel diameter (r = 0.80, P < 0.05) and vessel density (r = −0.60, P < 0.05), while the stem water potential at 50 and 88% loss of hydraulic conductivity (P50 and P88) were both significantly correlated with wood density (P < 0.05) and saturated water content (P = 0.052 and P < 0.05, respectively). High stem water storage capacity was associated with low cavitation resistance possibly because of its buffering the moisture fluctuations in karst environments. However, both Ks and P50/P88 were decoupled from the anatomical traits of pit and pit membranes. This may explain the lack of tradeoff between hydraulic safety and efficiency in tropical karst evergreen tree species. Our results suggest that diverse hydraulic trait combination may facilitate species coexistence in karst environments with high spatial heterogeneity.
Bi-objective simulation optimization for online feedback control of variable speed limits considering uncertain traffic demands and compliance behaviours
Authors: Wei Xiang , Zheng Liang , Liu Pengjie , Zhang Shuaichao , Tang Hewei
Published: January 2024

Variable speed limits (VSL) stands out as a well-established and effective strategy to alleviate traffic congestion and enhance traffic safety on motorways. It allows variable message signs (VMSs) to dynamically determine the speed limits according to real-time traffic states. This paper introduces an innovative online feedback control approach designed to regulate speed limit values on VMSs, addressing multiple bottlenecks while considering their spatiotemporal constraints. Moreover, we offline optimize the gain coefficients of this feedback control approach in the simulation-based optimization (SBO) framework. Specifically, with average and variance of space-mean speeds as bi-objectives, a stochastic SBO model considering uncertain traffic demands and compliance behaviours is established and solved by a bi-objective surrogate-based promising area search (BOSPAS) algorithm. Real-field experiments conducted in Edmonton, Canada, demonstrate the well-performing bi-objectives of the proposed approach, especially in handling uncertain compliance behaviours and traffic demands. Compared with the uncontrolled scenario, the feedback control schemes with the offline optimized gain coefficients improve the average and variance of space-mean speeds by up to 16.2% and 20.8%, respectively. Meanwhile, by the comparison of detailed performances, it is found that the optimized control schemes perform better than the uncontrolled scheme from the overall and local aspects. In conclusion, this study puts forward a general framework that applies an online feedback control approach with gain coefficients optimized offline by an SBO method to deal with real-time decision-making problems under uncertainties.
Biorational Fungicides to Manage Cucurbit Powdery Mildew on Winter Squash in New York
Authors: Indermaur Elizabeth J. , Day Charles T. C. , Dunn-Silver Amara R. , Smart Christine D.
Published: January 2024

Cucurbit powdery mildew (CPM) is one of the most common foliar diseases of winter squash grown in New York. Conventional fungicides remain the primary method for managing CPM. However, increasing consumer demand for organic produce and concerns about both environmental safety and fungicide resistance development have driven research to identify alternative management strategies. Biorational fungicides, including biologicals, botanicals, and minerals, are increasingly available for certified organic production but are generally considered less effective at managing CPM than conventional products. Copper-containing pesticides approved for use in organic production are effective, but concerns about nontarget effects are driving exploration of alternative biorational solutions for CPM. Further research is warranted to validate and expand management strategies for organic cucurbit production. In this study, we evaluated 9 and 10 biorational fungicides to reduce CPM on winter squash in field trials in 2021 and 2022, respectively. The treatment that consistently and most effectively reduced disease severity was Kocide 3000-O (copper hydroxide) followed by Theia ( Bacillus subtilis) and Regalia plus Stargus ( Reynoutria sachalinensis plus B. amyloliquefaciens). The developmental product Curezin (copper zinc) and the adjuvant Dyne-Amic (alkylphenol ethoxylate) also significantly reduced disease compared with the untreated control in 2022. No differences in yield were observed in either year. We conclude that copper-based biorational fungicides most effectively managed CPM compared with other biological and botanical products evaluated, followed by Theia and Regalia plus Stargus. Knowledge gained from this study can inform current CPM management practices and the development of future tools for IPM strategies.
Characterization of Quantitative Trait Loci for Leaf Rust Resistance in the Uzbekistani Wheat Landrace Teremai Bugdai
Authors: Xu Xiangyang , Li Genqiao , Bai Guihua , Bian Ruolin , Bernardo Amy , Kolmer Jim , Carver Brett F. , Wolabu Tezera W. , Wu Yanqi
Published: January 2024

Leaf rust, caused by Puccinia triticina, is a major cause of wheat yield losses globally, and novel leaf rust resistance genes are needed to enhance wheat leaf rust resistance. Teremai Bugdai is a landrace from Uzebekistan that is highly resistant to many races of P. triticina in the United States. To unravel leaf rust resistance loci in Teremai Bugdai, a recombinant inbred line (RIL) population of Teremai Bugdai × TAM 110 was evaluated for response to P. triticina race Pt54-1 (TNBGJ) and genotyped using single nucleotide polymorphism (SNP) markers generated by genotyping-by-sequencing (GBS). Quantitative trait loci (QTL) analysis using 5,130 high-quality GBS-SNPs revealed three QTLs, QLr-Stars-2DS, QLr-Stars-6BL, and QLr.Stars-7BL, for leaf rust resistance in two experiments. QLr-Stars-2DS, which is either a new Lr2 allele or a new resistance locus, was delimited to an ∼19.47-Mb interval between 46.4 and 65.9 Mb on 2DS and explained 31.3 and 33.2% of the phenotypic variance in the two experiments. QLr-Stars-6BL was mapped in an ∼84.0-kb interval between 719.48 and 719.56 Mb on 6BL, accounting for 33 to 36.8% of the phenotypic variance in two experiments. QLr.Stars-7BL was placed in a 350-kb interval between 762.41 and 762.76 Mb on 7BL and explained 4.4 to 5.3% of the phenotypic variance. Nine GBS-SNPs flanking these QTLs were converted to kompetitive allele specific PCR (KASP) markers, and these markers can be used to facilitate their introgression into locally adapted wheat lines.
Complications and outcomes after fixation of Lisfranc injuries at an urban level 1 trauma center
Authors: Sinkler Margaret A. , Benedick Alex , Kavanagh Michael , Alfonso Nicholas , Vallier Heather A.
Published: January 2024

OBJECTIVES:

To evaluate patients with tarsometatarsal fractures and dislocations and describe complications and secondary operations

METHODS:

Design: Retrospective cohort study

Setting:

Level 1 trauma center

Patient Selection Criteria:

Consecutive adults treated acutely for Lisfranc injuries with reduction and fixation using standard techniques of rigid medial fixation and flexible lateral fixation

Outcome Measures and Comparisons: Complications: infections, wound healing problems, nonunion, malunion, and post-traumatic arthrosis (PTA) and secondary unplanned procedures after minimum two-year radiographic follow-up.

RESULTS:

Mean age of the included 118 patients was 40 years (range, 18-73) and 96 (74%) were male. Comorbidities included obesity (n=32: 40%), diabetes mellitus (n=12: 9%), and tobacco use (n=67: 52%). Thirty (23%) were open injuries, and concomitant forefoot injuries were present in 47% and hindfoot injuries in 12%. Unplanned secondary procedures, including implant removals, were performed on 39 patients (33%), most often for removal of painful implants (26%) or infectious debridement (9%). 67 complications occurred, with PTA most frequent (37%). Deep infections occurred in 8%. On multivariate analysis, open injury (p=0.028, CI=1.22 – 30.63, OR=6.12) and concomitant forefoot injury (p=0.03, CI=1.12 – 9.76, OR=3.31 were independent risk factors for complication.

CONCLUSIONS:

Open Lisfranc injuries were associated with complications with deep infections occurring in 9%. Secondary procedures were most often performed for pain relief; the most common late complication was PTA, warranting counseling of patients about potential long-term sequelae of injury.

LEVEL OF EVIDENCE:

Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.
Perinatal Psychopharmacology: Innovative Approaches to Care Delivery
Authors: Nagle-Yang Sarah , Miller Emily S. , Lebin Lindsay G. , Blissett Gabriella , Dossett Emily C.
Published: January 2024

Perinatal mental health conditions are the most common complications of childbirth and have well-established enduring negative effects. Obstetric (Ob) clinicians care for patients with perinatal mental health conditions across a spectrum of acuity, severity, and complexity. Ob and psychiatric clinicians can collaborate to create a cohesive continuum of psychopharmacologic care for perinatal patients. This chapter provides an overall framework for Ob-psychiatric clinician collaboration with examples of innovation in care delivery.
Hyperammonemia in the Pediatric Emergency Department
Authors: Rojas Christina R. , Chapman Jennifer , Regier Debra
Published: January 2024

Hyperammonemia is a serious clinical condition associated with significant morbidity and mortality. In the pediatric population, this is often caused by urea cycle disorders, acute liver failure, or other less common underlying etiologies. Children and teens with hyperammonemia can have a broad range of clinical findings, including vomiting, respiratory distress, and changes in mental status. As ammonia levels worsen, this presentation can progress to respiratory failure, encephalopathy, cerebral edema, seizures, and death. Given the risk of neurologic damage, timely identification and management of hyperammonemia is critical and includes initial resuscitation, early consultation with subspecialists, and initiation of appropriate therapies. It is important for pediatric emergency medicine providers to understand the clinical findings, causes, diagnosis, and management of hyperammonemia because they play a key role in the provision of effective, multidisciplinary care of these patients.
Evaluation of Combined p57KIP2 Immunohistochemistry and Fluorescent in situ Hybridization Analysis for Hydatidiform Moles Compared with Genotyping Diagnosis
Authors: Usui Hirokazu , Hoshimoto Kazufusa , Sato Asuka , Kano Motofumi , Fukusato Toshio , Nakatani Yukio , Shozu Makio
Published: January 2024

Immunostaining with p57KIP2 is a widely used diagnostic technique to differentiate complete hydatidiform moles (CHMs) from partial hydatidiform moles (PHM) and non-molar hydropic abortion. However, distinguishing between PHMs and non-molar hydropic abortions using histopathology alone is often challenging. This study aimed to evaluate the technical validity and additional benefits of using fluorescence in situ hybridization (FISH) in combination with p57KIP2 immunostaining to diagnose molar and non-molar conceptuses. The study involved 80 specimens, which underwent genetic diagnosis using short tandem repeat analysis, including 44 androgenetic CHMs, 20 diandric monogynic PHMs, 14 biparental non-molar hydropic abortions, 1 monoandric digynic triploid abortion, and 1 vaginal specimen of gestational trophoblastic neoplasia. Two pathologists independently diagnosed the cases based on morphology and p57KIP2 immunostaining while the clinical information was masked. FISH analysis was performed using 3 probes (CEP17, CEPX, and CEPY), which revealed that all androgenetic CHM and biparental diploid non-molar hydropic abortion specimens were diploid. Among the 20 diandric monogynic PHM cases examined by analyzing short tandem repeat polymorphisms, 18 were triploid, and the remaining 2 were diploid. These two specimens were possibly androgenetic/biparental mosaics based on FISH analysis, where the three-signal ratios counting 50 cells were clearly within the diploid ranges. Eight of the 20 genetic PHMs and 2 of the 14 genetically confirmed non-molar hydropic abortions that were falsely diagnosed based on morphology and immunohistochemistry by at least 1 pathologist were correctly diagnosed as PHM and non-molar hydropic abortion, respectively, by FISH analysis. However, 1 monoandric digynic villus was classified as triploid by FISH analysis, leading to a false PHM diagnosis. In conclusion, the combination of FISH analysis with p57KIP2 immunostaining helps in diagnosing molar and non-molar conceptuses in numerous cases; nevertheless, exceptional cases should be considered.
Predicting Progestin Therapy Response With PTEN, PAX2, and β-Catenin in Patients With Endometrioid Precancer
Authors: Liu Naijia , Lin Wanrun , Wang Yan , Yao Zhigang , Rivera-Colon Glorimar , Li Yan , Carrick Kelley S. , Chen Hao , Lucas Elena , Zheng Wenxin
Published: January 2024

This study investigates the predictive value of biomarkers PTEN, PAX2, and β-catenin for therapeutic outcomes in patients with atypical endometrial hyperplasia or endometrioid intraepithelial neoplasia undergoing progestin therapy. In a retrospective study of 128 patients, we analyzed a total of 351 endometrial biopsy samples and categorized outcomes into responders (absence of residual disease) and nonresponders (presence of residual disease). We found aberrant biomarker expression in pretreatment cases: 48% for PTEN, 65% for PAX2, and 36% for β-catenin. Approximately 77.3% of patients responded to progestin treatment, with nonresponders showing significantly higher initial PTEN loss (75.86% vs 39.79%, P < 0.001). Nonresponders also demonstrated significant PTEN loss (53.33% vs 20.55%, P < 0.001), PAX2 loss (57.33% vs 41.22%, P < 0.05), and β-catenin nuclear staining (53.45% vs 27.91%, P < 0.01) in follow-up samples. In addition, nonresponders exhibited lower recovery of intact PTEN and PAX2, along with higher β-catenin aberrancy in cases initially showing normal β-catenin levels. We conclude that persistent aberrant PTEN and PAX2 expression, coupled with emerging aberrant β-catenin in follow-ups, indicates a greater likelihood of treatment failure. Conversely, the absence of these aberrations suggests successful progestin therapy. Our findings highlight the utility of this 3-marker panel in assessing residual disease status and predicting progestin treatment outcomes, thus offering critical insights for patient management.
Fibre crosslinking drives the emergence of order in a three-dimensional dynamical network model
Authors: Chassonnery Pauline , Paupert Jenny , Lorsignol Anne , Séverac Childérick , Ousset Marielle , Degond Pierre , Casteilla Louis , Peurichard Diane
Published: January 2024

The extracellular-matrix (ECM) is a complex interconnected three-dimensional network that provides structural support for the cells and tissues and defines organ architecture as key for their healthy functioning. However, the intimate mechanisms by which ECM acquire their three-dimensional architecture are still largely unknown. In this paper, we study this question by means of a simple three-dimensional individual based model of interacting fibres able to spontaneously crosslink or unlink to each other and align at the crosslinks. We show that such systems are able to spontaneously generate different types of architectures. We provide a thorough analysis of the emerging structures by an exhaustive parametric analysis and the use of appropriate visualization tools and quantifiers in three dimensions. The most striking result is that the emergence of ordered structures can be fully explained by a single emerging variable: the number of links per fibre in the network. If validated on real tissues, this simple variable could become an important putative target to control and predict the structuring of biological tissues, to suggest possible new therapeutic strategies to restore tissue functions after disruption, and to help in the development of collagen-based scaffolds for tissue engineering. Moreover, the model reveals that the emergence of architecture is a spatially homogeneous process following a unique evolutionary path, and highlights the essential role of dynamical crosslinking in tissue structuring.
Estimation of auto-covariance of log hydraulic conductivity from Generalized Sub-Gaussian porosity and particle size random fields
Authors: Harrison M. , Riva M. , Mousavi Nezhad M. , Guadagnini A.
Published: January 2024

We derive analytical formulations relating the spatial covariance (CY) of (log-transformed) hydraulic conductivities to auto- and cross-covariances of porosity (ϕ) and representative soil particle sizes within the framework of the classical Terzaghi model. The latter provides an empirical relationship which is widely used to obtain conductivity estimates. We frame the study within recent stochastic approaches and conceptualize appropriate transformations ofϕand representative soil particle size as Generalized Sub-Gaussian (GSG) spatially cross-correlated random processes. Consistency of the theoretical framework against sample distributions ofϕand particle size is assessed through the analysis of field data. A perturbation-based approach yields workable expressions ofCYupon truncating the otherwise exact analytical solution at given orders of approximations. Our analytical (truncated) log-conductivity covariance is in agreement with its Monte Carlo-based counterpart. A Global Sensitivity Analysis relying on classical Sobol indices quantifies the relative importance of all parameters embedded in the formulation ofCY. We show that parameters driving the GSG nature of the distribution of (transformed) porosity are key to the main features ofCY. We also document the relevance of properly capturing emergences of possible cross-correlations betweenϕand representative particle size to reconstruct conductivity fields.
Toward a further understanding of the loop formation and elimination in twisted filament: experiments and validation
Authors: Hu Jiongjiong , Teng Jiahui , Liu Lei , Liu Dabiao
Published: January 2024

Motivated by observations of loop formation and elimination phenomena in elastic filaments subjected to torsion and axial end displacement, we develop a tension–torsion tester to study the slack–extension responses of filaments with varied initial twists. The experiments are conducted by initially twisting the filament by a specific degree and subsequently adjusting the axial end displacement. By continuously monitoring the correlation between torque and filament configuration, we can accurately determine the critical points associated with buckling, loop formation and loop elimination. The interconversion of link, twist and writhe is also tracked in the experiment. We establish a relation between torque and end displacement of filament that provides an insight into the conditions leading to instabilities. Three buckling criteria are also evaluated in the context of measurement data. Simulations on the slack and extension of the twisted filaments based on the Cosserat rod theory are performed, providing reliable predictions of the configuration evolution. Our results highlight the importance of twist and slack in torsional buckling processes, providing guidance for the control of systems with twisted slender structures.
The Effect of Electrode-Tissue Distance on Unipolar and Bipolar Voltage Electrograms for large-Tip, Ring-, and Mini-Electrodes
Authors: Schlageter Vincent , Luca Adrian , Badertscher Patrick , Krisai Philipp , Küffer Thomas , Spreen David , Katic Josip , Osswald Stefan , Schaer Beat , Sticherling Christian , Kühne Michael , Knecht Sven
Published: January 2024

Background

The characteristics of intracardiac unipolar and bipolar voltage electrograms (EGM) acquired by electrophysiological catheters depend on the electrode design and configuration.The aim of the study was to assess the impact of electrode design and distance from the myocardial electric source on the unipolar and bipolar intracardiac electrograms recorded with a multi-electrode ablation catheter do deduce a cut-off for far-field versus near-field discrimination.

Methods

We retrospectively analyzed left atrial electroanatomical maps of 25 patients performed using an ablation catheter with a 4.5 mm tip-, mini- and 2 mm ring electrodes. The unipolar and bipolar EGMs were characterized based on peak-to-peak amplitude, signal duration (width), maximal slope, and relative power of the high frequency spectrum (HF_rel). Distances of the electrode from the tissue were calculated from the electroanatomic reconstruction.

Results

We analyzed EGMs of 5183 catheter positions. The unipolar EGM of ring electrodes showed an increased amplitude (140%), slope (150%) and HF_rel (16% vs 11%) compared to the tip- and mini-electrodes. In contrast, for bipolar EGM, the tip-ring pair showed the largest amplitude, width, and slope. The median amplitude, slope, and HF_rel for the ring electrodes followed a power-law decay function with distance. A cut-off of 4 mm was determined for far-field versus near-field discrimination.

Conclusions

We showed a higher unipolar amplitude for small ring-electrodes compared to larger tip electrodes. Furthermore, a rapid decay of the amplitude, slope, and HF_rel with distance could be observed. The decay functions are suggestive for a near-field cut-off distance below 4mm from the tissue.
The Impact of Anesthesia on Ultrasonic Glymphatic Perturbation Protocol: Alertness, and Glymphatic Influx
Authors: Xiao Haijun , Shrestha Binita , Cruz Alexander Aviles , Iliff Jeffrey J , Porter Tyrone , Aryal Muna
Published: January 2024

We have recently discovered that transcranial low-intensity focused ultrasound can enhance glymphatic transport, which facilitates the removal of waste metabolites from the brain in a preclinical rat model [1]. The central hypothesis was that ultrasound, functioning as a pressure wave, has the potential to influence the convective forces generated by arterial pulsations, which are also pressure waves, serving as the primary mechanism for glymphatic transport. Importantly, our data revealed that (i) the ultrasound protocol (650 kHz at 0.2MPa for 10 minutes to the entire brain) is safe, as histological evaluations showed no parenchymal damage and no difference in levels of neuronal degeneration or astrocytic activation 72 hours after the intervention, and (ii) the required pressure is significantly low, 10 times below FDA-approved limits for diagnostic ultrasound, and can be achieved using existing FDA-approved clinical transcranial focused ultrasound systems, suggesting its ease of translation into clinical applications. However, the study was conducted under specific physiological states with approximately 2.5% isoflurane-induced anesthesia. There is a limitation in fully understanding the potential bioeffects of ultrasound within the glymphatic space across various physiological conditions, primarily because the glymphatic transport’s efficiency fluctuates with anesthetically induced physiological states. Hence, establishing standardized protocols of ultrasonic glymphatic transport at optimal physiological state is crucial for ensuring consistent, reliable results across research laboratories during the preclinical development of this technique. The primary objective of this study is to evaluate how ultrasonically manipulated glymphatic transport is influenced by different levels of isoflurane-induced anesthetic conditions, including 3% (just above 2.5%), 2% (slightly below 2.5%), and 1.5% (quasi-awake state, resembling the existing clinical practice of ultrasound treatment). Results show that the impact of ultrasound during glymphatic transport depends on the level of anesthesia. It increases alertness in lightly anesthetized animals and improves glymphatic transport, while it induces drowsiness in heavily anesthetized animals, leading to reduced glymphatic transport. The results suggest that lighter anesthesia is beneficial for efficient ultrasonic glymphatic transport, making it more in line with the awake state in current clinical ultrasound treatments, thus advancing the technology closer to clinical translation.
Comprehensive single-cell atlas of the mouse retina
Authors: Li Jin , Choi Jongsu , Cheng Xuesen , Ma Justin , Pema Shahil , Sanes Joshua R. , Mardon Graeme , Frankfort Benjamin J. , Tran Nicholas M. , Li Yumei , Chen Rui
Published: January 2024

Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular heterogeneity at the single-cell resolution by classifying and characterizing cell types in multiple tissues and species. While several mouse retinal scRNA-seq reference datasets have been published, each dataset either has a relatively small number of cells or is focused on specific cell classes, and thus is suboptimal for assessing gene expression patterns across all retina types at the same time. To establish a unified and comprehensive reference for the mouse retina, we first generated the largest retinal scRNA-seq dataset to date, comprising approximately 190,000 single cells from C57BL/6J mouse whole retinas. This dataset was generated through the targeted enrichment of rare population cells via antibody-based magnetic cell sorting. By integrating this new dataset with public datasets, we conducted an integrated analysis to construct the Mouse Retina Cell Atlas (MRCA) for wild-type mice, which encompasses over 330,000 single cells. The MRCA characterizes 12 major classes and 138 cell types. It captured consensus cell type characterization from public datasets and identified additional new cell types. To facilitate the public use of the MRCA, we have deposited it in CELLxGENE, UCSC Cell Browser, and the Broad Single Cell Portal for visualization and gene expression exploration. The comprehensive MRCA serves as an easy-to-use, one-stop data resource for the mouse retina communities.
Systematic mapping of antibiotic cross-resistance and collateral sensitivity with chemical genetics
Authors: Sakenova Nazgul , Cacace Elisabetta , Orakov Askarbek , Huber Florian , Varik Vallo , Kritikos George , Michiels Jan , Bork Peer , Cossart Pascale , Goemans Camille , Typas Athanasios
Published: January 2024

By acquiring or evolving resistance to one antibiotic, bacteria can become resistant to a second one, due to shared underlying mechanisms. This is called cross-resistance (XR) and further limits therapeutic choices. The opposite scenario, in which initial resistance leads to sensitivity to a second antibiotic, is termed collateral sensitivity (CS) and can inform cycling or combinatorial treatments. Despite their clinical relevance, our current knowledge of such interactions is limited, mostly due to experimental constraints in their assessment and lack of understanding of the underlying mechanisms. To fill this gap, we used published chemical genetic data on the impact of allEscherichia colinon-essential genes on resistance/sensitivity to 40 antibiotics, and devised a metric that robustly discriminates between known XR and CS antibiotic interactions. This metric, based on chemical genetic profile (dis)similarity between two drugs, allowed us to infer 404 XR and 267 CS interactions, thereby expanding the number of known interactions by more than 3-fold – including reclassifying 116 previously reported interactions. We benchmarked our results by validating 55 out of 59 inferred interactions via experimental evolution. By identifying mutants driving XR and CS interactions in chemical genetics, we recapitulated known and uncovered previously unknown mechanisms, and demonstrated that a given drug pair can exhibit both interactions depending on the resistance mechanism. Finally, we applied CS drug pairs in combination to reduce antibiotic resistance development in vitro. Altogether, our approach provides a systematic framework to map XR/CS interactions and their mechanisms, paving the way for the development of rationally-designed antibiotic combination treatments.
Unification of cell-scale metabolic activity with biofilm behavior by integration of advanced flow and reactive-transport modeling and microfluidic experiments
Authors: Zhao Jiao , Zarabadi Mir Pouyan , Hall Derek M. , Dahal Sanjeev , Greener Jesse , Yang Laurence
Published: January 2024

The bacteriaGeobacter sulfurreducens(GS) is a promising candidate for broad applications involving bioelectrochemical systems (BES), such as environmental bioremediation and energy production. To date, most GS studies have reported biofilm-scale metrics, which fail to capture the interactions between cells and their local environments via the complex metabolism at the cellular level. Moreover, the dominance of studies considering diffusion-only molecular mass transport models within the biofilm has ignored the role of internal advection though the biofilm in flow BES. Among other things, this incomplete picture of anode-adhered GS biofilms has led to missed opportunities in optimizing the operational parameters for BES. To address these gaps, we have modernized a GS genome-scale metabolic model (GEM) and complemented it with local flow and reactive-transport models (FRTM). We tuned certain interactions within the model that were critical to reproducing the experimental results from a pure-culture GS biofilm in a microfluidic bioelectrochemical cell under precisely controlled conditions. The model provided insights into the role of mass transport in determining the spatial availability of nutrient molecules within the biofilm. Thus, we verified that fluid advection within biofilms was significantly more important and complex than previously thought. Coupling these new transport mechanisms to GEM revealed adjustments in intracellular metabolisms based on cellular position within the biofilm. Three findings require immediate dissemination to the BES community: (i) Michaelis-Menten kinetics overestimate acetate conversion in biofilm positions where acetate concentration is high, whereas Coulombic efficiencies should be nearly 10% lower than is assumed by most authors; (ii) unification of the empirically observed flow sensitivity of biofilm-scale kinetic parameters and cell-scale values are finally achieved; and (iii) accounting for advection leads to estimations of diffusion coefficients which are much lower than proposed elsewhere in the literature. In conclusion, in-depth spatiotemporal understanding of mechanisms within GS biofilm across relevant size scales opens the door to new avenues for BES optimization, from fine-scale processes to large-scale applications, including improved techno-economic analyses.
Partial rejuvenation of the spermatogonial stem cell niche after gender-affirming hormone therapy in trans women
Authors: Delgouffe Emily , Silva Samuel Madureira , Chalmel Frédéric , Cools Wilfried , Raets Camille , Tilleman Kelly , T’Sjoen Guy , Baert Yoni , Goossens Ellen
Published: January 2024

Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.
Patient derived model ofUBA5-associated encephalopathy identifies defects in neurodevelopment and highlights potential therapies
Authors: Chen Helen , Wang Yong-Dong , Blan Aidan W. , Almanza-Fuerte Edith P. , Bonkowski Emily S. , Bajpai Richa , Pruett-Miller Shondra M. , Mefford Heather C.
Published: January 2024

UBA5encodes for the E1 enzyme of the UFMylation cascade, which plays an essential role in ER homeostasis. The clinical phenotypes of UBA5-associated encephalopathy include developmental delays, epilepsy and intellectual disability. To date, there is no humanized neuronal model to study the cellular and molecular consequences ofUBA5pathogenic variants. We developed and characterized patient-derived cortical organoid cultures and identified defects in GABAergic interneuron development. We demonstrated aberrant neuronal firing and microcephaly phenotypes in patient-derived organoids. Mechanistically, we show that ER homeostasis is perturbed along with exacerbated unfolded protein response pathway in cells and organoids expressingUBA5pathogenic variants. We also assessed two gene expression modalities that augmentedUBA5expression to rescue aberrant molecular and cellular phenotypes. Our study provides a novel humanized model that allows further investigations ofUBA5variants in the brain and highlights novel systemic approaches to alleviate cellular aberrations for this rare, developmental disorder.

One-sentence summary

Patient derived model of UBA5-assoicated DEE recapitulated disease phenotype, revealed defects in neurodevelopment, and highlighted potential therapies.
Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization
Authors: Goldblatt Dena , Rosti Başak , Hamling Kyla R. , Leary Paige , Panchal Harsh , Li Marlyn , Gelnaw Hannah , Huang Stephanie , Quainoo Cheryl , Schoppik David
Published: January 2024

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in premotor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of general principles of neural development.
Phosphate overplus response inChlamydomonas reinhardtii: polyphosphate dynamics to monitor phosphate uptake and turnover
Authors: Zúñiga-Burgos Tatiana , Saiardi Adolfo , Camargo-Valero Miller Alonso , Baker Alison
Published: January 2024

Many micro-organisms store inorganic phosphate (Pi) in the form of polyphosphate (polyP) and exhibit in-cell polyP accumulation, a phenomenon known as ‘phosphate overplus response’, when resupplied with Pi after a period of deprivation. Quantitative and qualitative methods were used to follow the dynamics of polyP synthesis and turnover in four strains ofChlamydomonas reinhardtiiduring Pi deprivation followed by nutrient resupply. The lowest level of in-cell polyP during Pi deprivation, which also correlates with the cessation of growth, is the key parameter for the timing of Pi resupply to maximise the Pi overplus response Additional nutrients do not affect the size of the overplus response, but they are important for continued growth and maximal Pi removal from the media. Tracking polyP allows the correct time for nutrient resupply to be determined and therefore a reproducible Pi overplus response to be achieved. Depending on whether maximum cellular phosphorus (P) content or maximum Pi removal is desired different strategies may be required – e,g., Pi deprivation until growth cessation then resupplying complete nutrients gives the best trade-off between high in-cell P accumulation, high Pi uptake and algal biomass growth. Although polyP levels are maintained after Pi resupply, the polymer is dynamically remodelled. IP6increases during this time. This increase does not precede polyP synthesis as predicted by a model where inositol phosphates switch on polyP synthesis. One strain tested, CC-5325, shows enhanced Pi uptake and levels of polyP and total in-cell P, suggesting that strain selection is also important.

Importance

There is strong interest in using microalgae to sustainably control and recover nutrients, especially P, from wastewater. This would help to meet environmental discharge consents and recycle nutrients into agriculture or other applications. Like bacteria and yeasts, microalgae exhibit a Pi overplus phenomenon when Pi-deprived cells are resupplied with P, but microalgae do not require an additional carbon source and can simultaneously uptake nitrogen as well. Use of microalgae in wastewater treatment is limited by the unpredictability of their response and sensitivity to environmental factors, but engineered systems can greatly benefit from better understanding Pi dynamics and polyP accumulation. In the literature there is a lack of consensus regarding protocols to maximise the Pi overplus. In this work we provide robust measurements of quantitative physiological parameters, which should allow reproducibility in laboratory studies and provide design parameters for algal-based nutrient recovery systems from waste waters.