bluuebunny/crossref_metadata_2025 huggingface dataset:
Real and Financial Integration in Asia – Recent Evidence and Policy Perspective
Authors: Beckmann Joscha , Schmerer Hans-Jörg
Published: July 2023

The papers in this Special Issue focus on real and financial integration in Asia. The papers were presented at a workshop organized by the FernUniversität Hagen. We discuss core results and discuss potential policy implications related to monetary policy in China and the integration of Asia in the world economy.
Two Unnarrated Stories in Horace's Roman Odes (Carm.3.2.1–12 and 3.6.21–32): Echoes of Vergil's UnfinishedAeneidand a Lowlife Epigram
Authors: Werner Shirley
Published: July 2023

Within the rhetorical frameworks of exhortation and illustrative exemplum, Horace's second and sixth Roman Odes offer compressed, contrasting images of a young person's education and transformation, presenting these as stories about apuerand avirgo, respectively, in a lyric mode that does not narrate. In the first of these stories (Carm. 3.2.1–12), Horace slyly usurps characters from Vergil's unfinishedAeneid, alluding to some of its distinctive narrative techniques, but also draws on the similes and plot structure of its Iliadic model. The second of Horace's stories (Carm. 3.6.21–32) plays off his first, as he converts theadulta virgowho figures inCarm. 3.2 into her antitype. This story has as its intertext an obscene Hellenistic epigram by Automedon. Horace makes both intertextual and metatextual use of his models, while his indirect references, through Homer, to Vergil's intended design for his emergingAeneidmay be considered under the new heading of extratextual.
Prototyping an additive co-fabrication workflow for architecture: utilizing cyanobacterial MICP in robotic deposition
Authors: Armaly Perla , Iliassafov Lubov , Kirzner Shay , Kashi Yechezkel , Barath Shany
Published: July 2023

With the increasing need for architectural sustainability, biodesign offers a new approach to incorporating living organisms in building materials. Bacteria hold a range of biological activities that impact their environment, and which could enable the solidification of inorganic materials; this has already been seen with microbially-induced carbonate precipitation that strengthens bonds between sand particles. This paper describes the novel development of an additive co-fabrication manufacturing process, demonstrating an interdisciplinary approach of architecture and microbiology. Specifically, the activity of a biological deposition (i.e., cyanobacterial calcium carbonate precipitation) and its integration with that of a robotic deposition (i.e., a sand-based biomixture) within an architectural biofabrication workflow. Two bacterial strains were successfully grown in potential sand-based construction materials. Microbiological protocols, such as optical density and fluorescence measurements, were then applied to identify parameters, for harvesting light through photosynthesis and harnessing it to the sedimentation of calcium carbonate. Assessments of the proposed mechanical delivery system and printing properties enabled the outlining of a suitable robotic deposition system for sand-based mixtures. Through examinations of these microbiological and mechanical protocols, this paper outlines design strategies and tradeoffs for an integrated workflow, that corresponds with both the biological (micro) and architectural (macro) scales.
The impact of L2 English on choice perception, interpretation, and preference for L1 Arabic speakers
Authors: AboHamed Lama , Mashaqba Bassil , Al-Khawaldeh Nisreen
Published: July 2023

This article compares risk tolerance of native Arabic speakers under two language contexts: their first language (L1 Arabic) and their foreign language (L2 English). We aim to evaluate whether thinking in a foreign language actually reduces the negative effects of cognitive biases, such as loss aversion and mental accounting, on financial decision-making. Toward this aim, we conducted two experiments in which the risk tolerance levels of 144 participants were evaluated across four different types of decision-making problems: the Asian disease problem, the financial crisis problem, the discount problem, and the ticket/money lost problem. In study 1, we adopted Keysar et al.’s (2012,Psychological Science,23, 661–668) experiment to test the effect of L2 on framing effects associated with loss aversion, and in Study 2, we adopted Costa et al.’s (2014,Cognition,130, 236–254) experiment to test the effect of L2 on framing effects associated with mental accounting biases. We found that individuals were risk-averse for gains and risk-seeking for losses when presented with choices in their L1, but were almost unaffected by framing manipulation under the L2 condition. When it came to mental accounting, however, framing effects were nearly absent in both L1 and L2 conditions. In our investigation, we examined various potential factors that could explain the foreign language effect on decision-making. The primary factor that appears to account for this linguistic phenomenon is the heightened cognitive and emotional distance experienced when using an L2.
How Partisan Is Local Election Administration?
Authors: FERRER JOSHUA , GEYN IGOR , THOMPSON DANIEL M.
Published: July 2023

In the United States, elections are often administered by directly elected local officials who run as members of a political party. Do these officials use their office to give their party an edge in elections? Using a newly collected dataset of nearly 5,900 clerk elections and a close-election regression discontinuity design, we compare counties that narrowly elect a Democratic election administrator to those that narrowly elect a Republican. We find that Democrats and Republicans serving similar counties oversee similar election results, turnout, and policies. We also find that reelection is not the primary moderating force on clerks. Instead, clerks may be more likely to agree on election policies across parties than the general public and selecting different election policies may only modestly affect outcomes. While we cannot rule out small effects that nevertheless tip close elections, our results imply that clerks are not typically and noticeably advantaging their preferred party.
Intergenerational Transmission of BMI and Educational Outcomes in Children and Adolescents
Authors: Alrouh Hekmat , van Bergen Elsje , Dolan Conor , Boomsma Dorret I.
Published: July 2023

Individual differences in educational attainment (EA) and physical health, as indexed by body mass index (BMI), are correlated within individuals and across generations. The aim of our study was to assess the transmission of these traits from parents to their offspring in childhood and adolescence. We analyzed BMI and EA in 13,916 families from the Netherlands. Data were available for 27,577 parents (mean age 33) and 26,855 of their offspring at 4 and 12 years of age. We employed structural equation modeling to simultaneously estimate the phenotypic transmission of BMI and EA from parents to offspring, the spousal correlations, and the residual child BMI-EA associations after accounting for intergenerational transmission and testing for gender differences therein. We found a significant intergenerational transmission of BMI to BMI in childhood (age 4; standardized regression coefficient β = .10) and adolescence (age 12; β = .20), and of EA to academic achievement in adolescence (β = .19). Cross-trait parent-to-offspring transmission was weak. All transmission effects were independent of parent or offspring gender. We observed within-person EA-BMI correlations that were negative in parents (∼−.09), positive in children (∼.05) and negative in adolescents (∼−.06). Residual EA-BMI were positive in children (∼.05) and insignificant in adolescents. Spousal correlations were .46 for EA, .21 for BMI, and ∼−.09 cross-trait. After accounting for spousal correlations, the intergenerational transmission for BMI and EA is mainly predictive within, but not across, traits. The within-person correlation between BMI and EA can change in direction between childhood and adulthood.
Comprehensive evaluation of artifact reduction and tissue recovery effects of metal artifact reduction technique based on full-reference metric
Authors: Jung Yunsub , Song You Seon , Lee In Sook , Rhee Seung Joon
Published: July 2023

For the comprehensive evaluation of metal artifact reduction (MAR) technique, not only the removal of metal artifacts but also the evaluation of the area restored by MAR is required. We propose a method to comprehensively evaluate the effect by MAR in this study. We have conducted the computed tomography scan to acquire both the evaluation image and the reference image for the full-reference based evaluation. The evaluation image and reference image were reconstructed into 24 image sets according to the tube potentials, image reconstruction method, and use of the MAR technique. Images of two different positions were selected according to the distance from metal and material (bone, tissue) distribution, and bone and tissue were automatically segmented in both evaluation and reference images. The values of full width at half the maximum (FWHM) and centroid were extracted after Gaussian modeling of each segmented region. Then, we computed four evaluation metrics (FWHMNM: non-MAR to non-metal ratio of FWHM, FWHMM: MAR to non-metal ratio of FWHM, CENTNM: non-MAR to non-metal ratio of centroid, CENTM: MAR to non-metal ratio of centroid), and the MAR image and non-MAR image were compared. The overlap ratio automatically segmented from the evaluation image and reference image were position 1 (bone: 99.61%, tissue: 99.23%) with 80 kVp, position 1 (bone: 99.32%, tissue: 99.56%) with 120 kVp, position 2 (bone: 99.20%, tissue: 99.73%) with 80 kVp, and position 2 (bone: 99.23%, tissue: 99.67%) with 120 kVp. The FWHMNMshowing the change of image pixel value by metal artifact was calculated as (bone: 1.32–1.46, tissue: 1.08–1.16) at 80 kVp and (bone: 1.19–1.27, tissue: 1.02–1.05) at 120 kVp. More metal artifacts occurred at 80 kVp tube potential. Regardless of the tube potential and image reconstruction method, the MAR showed an overall artifact reduction effect (1 < FWHMM < FWHMNM). However, distortion of pixel values occurred due to the MAR in regions where metal artifacts were high in proximity to metal (1 < FWHMNM < FWHMM). Overall, the average value of the medium was maintained (CENTM: 0.98–1.03) after MAR application, but there was a change of image value in region around the metal (CENTM: 0.97–1.11). In this study, we propose a new method to evaluate the effect of metal artifacts and MAR technique using full-reference based method. Metal artifacts, effect of MAR technique, and side-effect caused by MAR technique were quantitatively analyzed through proposed method. There are some limitations in applying it to clinical imaging since our method is a reference-based evaluation. However, our experimental results were important for understanding the effects of the MAR technique and its functional properties.
Efficient practical method for differential protection of power transformer in the presence of the fault current limiters
Authors: Sahebi Ali , Askarian‐Abyaneh Hossein , Sadeghi Seyed Hossein Hesamedin , Samet Haidar , Malik Om Parkash
Published: July 2023

The algorithms of the present generation of practical differential relays are based on two methods. The first method is based on the ratio of the harmonic content of the differential current, and the second one is based on the length of the time interval between the zero‐crossing points of the differential current, called the gap‐detection method. However, these methods suffer from the installation of the fault current limiters (FCLs) in the power system and current transformer (CT) saturation phenomenon. This paper deals with a simple practical method for differential relays to secure their performance. In the suggested method, a classifying algorithm is used to categorize the input signal of the relay and then the best method of the present generation of differential relays is employed. By this simple decision, the method takes the advantage of harmonic‐based and gap‐detection methods, while avoiding their drawbacks. To prove the robustness of the suggested method, a test bench with a resistive solid‐state fault current limiter (SSFCL) is implemented and examined in different situations. The results validate the consistency and the accuracy of the modified technique not only in the absence and the presence of the FCL but in the case of CT saturation.
Knowledge‐based multiple hypothesis tracking and identification of manoeuvring reentry targets
Authors: Lee Chan‐Seok , Whang Ick‐Ho , Ra Won‐Sang
Published: July 2023

This paper addresses the integrated tracking and identification problem of a manoeuvring reentry target that performs intentional lateral manoeuvres to disrupt ground radars. Unlike previous approaches, prior knowledge of the lift‐induced drag is incorporated into a new manoeuvring model to describe the reentry target dynamics more explicitly. This model can account for the constraint between lift and drag, which is beneficial in ensuring the reliability of target state estimation. Noticing that the lift‐induced drag is an inherent characteristics of a reentry target that distinguishes the target's identity from others belonging to the same class, the integrated target tracking and identification problem is formulated within the framework of the multiple hypothesis testing about a set of manoeuvring models constructed by different prior knowledge. The proposed approach enables the authors to derive the optimal solution to the given problem in a mathematically rigorous manner. To cope with the real‐time implementation issue, a hypothesis merging strategy is also devised in view of maintaining the target identification performance. Simulation results demonstrate that the proposed scheme provides superior performance and reliability both in target tracking and identification compared to the existing method, despite imperfectness of prior knowledge.
Comparison between tubeless mini-percutaneous nephrolithotomy versus flexible ureterorenoscopic lithotripsy for the treatment of upper ureteral calculi larger than 1 cm
Authors: Chou Chu-Min , Wang Chung-Jing , Jou Yeong-Chin , Cheng Ming-Chin , Shen Cheng-Huang , Lin Chang-Te
Published: July 2023

Background

This study aimed to assess the outcome and safety of tubeless mini-percutaneous nephrolithotomy (mPCNL) and flexible ureterorenoscopic lithotripsy (fURSL) in treating upper ureteral stones larger than 1 cm.

Materials and Methods

Between July 2017 and June 2020, 218 patients who underwent tubeless mPCNL and fURSL for upper ureteral calculi larger than 1 cm were enrolled in this study. Patient characteristics and perioperative outcomes and complications were evaluated by retrospective chart review.

Results

Immediate stone-free rates after the procedure were 100% of patients for the tubeless mPCNL and 71.0% of patients for the fURSL group (P = 0.004). The mean ± SD operative time per patient was 79.8 ± 21.8 minutes in the tubeless mPCNL group, and it was 99.7 ± 33.8 minutes in the fURSL groups (P = 0.009). The average hospital stay was 2.7 ± 1.9 days in the tubeless mPCNL group and 1.5 ± 1.2 days in the fURSL group (P < 0.001). The rates of febrile episode for the tubeless mPCNL and fURSL groups were 14.3% and 2.3%, respectively (P = 0.028)

Conclusions

Tubeless mPCNL and fURSL are safe and feasible treatment options for proximal ureteral calculi larger than 1 cm. Tubeless mPCNL offers better outcome of higher stone-free rate and shorter operation time compared with fURSL but with a higher rate of febrile complications and longer hospital stay.
One-year follow-up of a multifocal intraocular lens with optimized elevated phase shift
Authors: Fernández Joaquín , Srinivasan Sathish , Burguera Noemí , Martínez Javier , Rodríguez-Vallejo Manuel
Published: July 2023

Purpose:

To evaluate the standard outcomes of a multifocal intraocular lens (mIOL) with optimized elevated phase shift (EPS).

Setting:

Qvision, Ophthalmology Department, VITHAS Almería, Spain.

Design:

Retrospective observational.

Methods:

41 patients, consecutively operated on cataracts or refractive lens exchange with the implantation of the Liberty 640PM (EPS 2.0) and followed during 12 months, were included in the analysis. Retrieved variables were visual acuities at far, intermediate, and near distances; defocus curves (VADC); and prediction error of 4 formulas optimized for IOLMaster 500 and Pentacam AXL Wave. Patient-reported outcomes were also obtained for assessing spectacle independence, satisfaction, bothersome to dysphotopsia, difficulties in daily life tasks, and decision to be operated with the same mIOL.

Results:

The median monocular efficacy with best distance correction was 0, 0.1, and 0.1 logMAR at far, intermediate, and near distances, respectively, with patients achieving binocularly a median of 0 logMAR at the 3 distances. VADC showed a depth of field of 3 diopters (D) above 0.2 logMAR with a median increase of 0.07 logMAR from −1.5 to −2.5 D. Complete spectacle independence was achieved at far distance, whereas 97.6% and 85.4% was achieved at intermediate and near distances, respectively. 7.3% of patients were bothered by dysphotopsia, and 92.6% of patients were likely to be operated again.

Conclusions:

EPS 2.0 restored patients' vision in the full range of the depth of field with a nearly monotone decrease of visual performance from far to near, achieving high rates of spectacle independence at all distances and with low positive dysphotopsia rates (ClinicalTrials.gov Identifier: NCT05735990).
Live Imaging of the Dehydration Effect of Isosorbide on the Normal and Hydropic Guinea Pig Cochleae Using Optical Coherence Tomography
Authors: Kakigi Akinobu , Egami Naoya , Fujita Takeshi , Uehara Natsumi , Yokoi Jun , Koda Kento , Nibu Ken-ichi , Yamashita Shinji , Yamasoba Tatsuya
Published: July 2023

Objective

To investigate the isosorbide-induced dehydration effect on the endolymphatic space by intratympanic administration of isosorbide.

Background

Isosorbide, an osmotic diuretic, is used orally as a typical conservative therapy for Menière's disease (MD) in Japan. The dehydration effect occurs 6 hours after isosorbide ingestion. Intratympanic administration of isosorbide resolves endolymphatic hydrops faster than oral ingestion. In addition, the dehydration effect has never been shown directly. Therefore, we investigated the dehydration effect of intratympanic administration of isosorbide on endolymphatic hydrops using optical coherence tomography.

Methods

We used eight Hartley guinea pigs, divided into normal and hydrops groups. In the hydrops group, the animals underwent endolymphatic sac obliteration to create endolymphatic hydrops. We obtained midmodiolar section images of the cochleae using optical coherence tomography. Then, 50 to 70% isosorbide was sequentially administered intratympanically for 5 minutes, and the apical turn of the cochlea was observed. The relative midmodiolar cross-sectional area of the scala media was calculated for quantitative assessment of the endolymphatic space.

Results

In the normal group, 50% isosorbide had a slight but significant dehydration effect on the scala media; at 55 to 70%, Reissner's membrane became flat. In the hydrops group, 50% isosorbide slightly reduced endolymphatic hydrops; 65% flattened Reissner's membrane, and 70% slightly concaved it toward the basilar membrane.

Conclusion

The results suggest that we could select the concentration of isosorbide according to the stage or severity of MD and relief from acute attack. Intratympanic administration of isosorbide may be a promising treatment for patients with MD.
Immediate CPAP Use after Skull Base Reconstruction with Hydroxyapatite Bone Cement
Authors: Cumpston Evan C. , Sualeh Ali H. , Totten Douglas J. , Nelson Rick F.
Published: July 2023

Objective

The timing for resuming continuous positive airway pressure (CPAP) postoperatively after skull base surgery remains controversial because of the risk of pneumocephalus. We determined the safety of immediate CPAP use after middle cranial fossa (MCF) spontaneous cerebrospinal fluid (sCSF) leak repair with bone cement.

Study Design

Prospective cohort study.

Setting

Tertiary academic medical center.

Patients

Thirteen consecutive patients with CPAP-treated obstructive sleep apnea and temporal bone sCSF leaks who underwent skull base repair with hydroxyapatite bone cement between July 2021 and October 2022.

Interventions

CPAP use resumed on postoperative day 1 after the confirmation of skull base reconstruction with temporal bone computed tomography (CT).

Main Outcome Measures

Postoperative skull base defects on CT, pneumocephalus, or intracranial complications.

Results

The average age was 55.5 ± 8.8 years (±standard deviation), and 69.2% were female with a BMI of 45.39 ± 15.1 kg/m2. Multiple tegmen defects were identified intraoperatively in 53.9% of patients with an average of 1.85 ± 0.99 defects and an average defect size on preoperative imaging of 6.57 ± 3.45 mm. All patients had an encephalocele identified intraoperatively. No residual skull base defects were observed on CT imaging on postoperative day 1. No postoperative complications occurred. One patient developed a contralateral sCSF leak 2 months after repair. There were no recurrent sCSF leaks 1 month postoperatively.

Conclusion

Immediate postoperative CPAP use is safe in patients undergoing MCF sCSF leak repair with bone cement because of the robust skull base repair.
Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth
Authors: Frank Daniel , Bergamasco Maria , Mlodzianoski Michael , Kueh Andrew , Tsui Ellen , Hall Cathrine , Kastrappis Georgios , Voss Anne Kathrin , McLean Catriona , Faux Maree , Rogers Kelly , Tran Bang , Vincan Elizabeth , Komander David , Dewson Grant , Tran Hoanh
Published: July 2023

Trabid/ZRANB1missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterised these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organisation and neural development.Trabid/ZRANB1knock-in mice harbouring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalised causing impaired organisation of the cytoskeleton that underlie the neuronal and developmental phenotypes.
High-dimensional spectral cytometry panels for whole blood immune phenotyping
Authors: Dott Tom , Culina Slobodan , Chemali Rene , Mansour Cedric Ait , Dubois Florian , Jagla Bernd , Doisne Jean Marc , Rogge Lars , Huetz François , Jönsson Friederike , Commere Pierre-Henri , Santo James Di , Terrier Benjamin , Quintana-Murci Lluis , Duffy Darragh , Hasan Milena ,   Milieu Intérieur Consortium
Published: July 2023

The need to understand the mechanisms and pathways of immune responses in pathogenic conditions such as cancer and autoimmunity requires awareness of natural immune variability in healthy subjects. To this end, various systems immunology studies have been established. Among them, theMilieu Intérieur(MI) study was established to define the boundaries of a healthy immune response and identify determinants of immune response variation. MI used immunophenotyping of a 1000 healthy donor cohort by flow cytometry as a principal outcome for immune variance at steady state. For the 10-year longitudinal MI study, we have developed two high-dimensional spectral flow cytometry panels that allow deep characterization of innate and adaptive whole blood immune cells (35 and 34 fluorescent markers, respectively) and standardized the protocol for sample handling, staining, acquisition, and data analysis. This permits the reproducible quantification of over 182 immune cell phenotypes through robust immunophenotyping at a single site. This highly standardized protocol was applied to samples from patients with autoimmune/inflammatory diseases. It is currently used for characterization of the impact of age and environmental factors on peripheral blood immune phenotypes of >400 donors from the initial MI cohort.
Benchmarking software tools for trimming adapters and merging next-generation sequencing data for ancient DNA
Authors: Lien Annette , Legori Leonardo Pestana , Kraft Louis , Sackett Peter Wad , Renaud Gabriel
Published: July 2023

Ancient DNA is highly degraded, resulting in very short sequences. Reads generated with modern high-throughput sequencing machines are generally longer than ancient DNA molecules, therefore the reads often contain some portion of the sequencing adaptors. It is crucial to remove those adaptors, as they can interfere with downstream analysis. Furthermore, overlapping portions when DNA has been read forward and backward (paired-end) can be merged to correct sequencing errors and improve read quality. Several tools have been developed for adapter trimming and read merging, however, no one has attempted to evaluate their accuracy and evaluate their potential impact on downstream analyses. Through the simulation of sequencing data, seven commonly used tools were analyzed in their ability to reconstruct ancient DNA sequences through read merging. The analyzed tools exhibit notable differences in their abilities to correct sequence errors and identify the correct read overlap, but the most substantial difference is observed in their ability to calculate quality scores for merged bases. Selecting the most appropriate tool for a given project depends on several factors, although some tools such as fastp have some shortcomings, whereas others like leeHom outperform the other tools in most aspects. While the choice of tool did not result in a measurable difference when analyzing population genetics using principal component analysis, it is important to note that downstream analyses that rely on quality scores can be significantly impacted by the choice of tool.
Gamma responses to colored natural stimuli can be predicted from local low-level stimulus features
Authors: Kanth Sidrat Tasawoor , Ray Supratim
Published: July 2023

The role of gamma rhythm (30-80 Hz) in visual processing is debated; stimuli like gratings and hue patches generate strong gamma, but many natural images do not. Could image gamma responses be predicted by approximating images as gratings or hue patches? Surprisingly, this question remains unanswered, since the joint dependance of gamma on multiple features is poorly understood. We recorded local field potentials and electrocorticogram from two monkeys while presenting natural images and parametric stimuli varying along several feature dimensions. Gamma responses to different grating/hue features were separable, allowing for a multiplicative model based on individual features. By fitting a hue patch to the image around the receptive field, this simple model could predict gamma responses to chromatic images across scales with reasonably high accuracy. Our results provide a simple “baseline” model to predict gamma from local image properties, against which more complex models of natural vision can be tested.
Frequent allopolyploidy with distant progenitors in the moss generaPhyscomitriumandEntosthodon(Funariaceae) identified via subgenome phasing of targeted nuclear genes
Authors: Patel Nikisha , Medina Rafael , Williams Lindsay D. , Lemieux Olivia , Goffinet Bernard , Johnson Matthew G.
Published: July 2023

Allopolyploids represent a new frontier in species discovery among embryophytes. Within mosses, allopolyploid discovery is challenged by low morphological complexity. The rapid expansion of sub-genome sequencing approaches in addition to computational developments to identifying genome merger and whole-genome duplication using variation among nuclear loci representing homeologs has allowed for increased allopolyploid discovery among mosses. We confirm the intergeneric hybrid nature ofEntosthodon hungaricus, and the allopolyploid origin ofP. eurystomumand of one population ofP. collenchymatum. We also reveal that hybridization gave rise toP. immersum, as well as to yet unrecognized lineages sharing the phenotype ofP. pyriforme, andP. sphaericum.Our findings demonstrate the utility of a novel approach to phasing homeologs within loci and phasing loci across subgenomes, or subgenome assignment, called homologizer, when working with polyploid genomes, and its value in identifying progenitor species using target capture data.
The most remarkable migrants – systematic analysis of the Western European insect flyway at a Pyrenean mountain pass
Authors: Hawkes Will L , Doyle Toby , Massy Richard , Weston Scarlett , Davies Kelsey , Cornelius Elliott , Collier Connor , Chapman Jason W. , Reynolds Don R. , Wotton Karl
Published: July 2023

In 1950 David and Elizabeth Lack chanced upon a huge migration of insects and birds flying through the Pyrenean Pass of Bujaruelo, later describing the spectacle as combining both grandeur with novelty. The intervening years have seen many changes to land use and climate, posing the question as to the current status of this migratory phenomenon, while a lack of quantitative data has prevented insights into the ecological impact of this mass insect migration and into the factors affecting it. To address this, we revisited the site in autumn over a 4-year period and systematically monitored diurnal insect species and numbers. We document an annual mean of 17.1 million day-flying insects from 5 orders moving south, with ‘mass migration’ events associated with warmer temperatures, the presence of a headwind, sunlight, low windspeed, and low rainfall. Diptera dominated the migratory assemblage and annual numbers varied by more than fourfold with larger annual migration flows associated with higher autumn temperatures in Northwest Europe. Finally, using observed environmental thresholds for migration, we estimate an annual ‘bioflow’ of at least 14.6 billion day-flying insects migrating south over the whole Pyrenean Mountain range, highlighting the importance of this route for seasonal insect migrants.
Schizophrenia Risk Mapping and Functional Engineering of the 3D Genome in Three Neuronal Subtypes
Authors: Powell Samuel K. , Liao Will , O’Shea Callan , Kammourh Sarah , Ghorbani Sadaf , Rigat Raymond , Elahi Rahat , Deans PJ Michael , Le Derek J. , Agarwal Poonam , Seow Wei Qiang , Wang Kevin C. , Akbarian Schahram , Brennand Kristen J.
Published: July 2023

Common variants associated with schizophrenia are concentrated in non-coding regulatory sequences, but their precise target genes are context-dependent and impacted by cell-type-specific three-dimensional spatial chromatin organization. Here, we map long-range chromosomal conformations in isogenic human dopaminergic, GABAergic, and glutamatergic neurons to track developmentally programmed shifts in the regulatory activity of schizophrenia risk loci. Massive repressive compartmentalization, concomitant with the emergence of hundreds of neuron-specific multi-valent chromatin architectural stripes, occurs during neuronal differentiation, with genes interconnected to genetic risk loci through these long-range chromatin structures differing in their biological roles from genes more proximal to sequences conferring heritable risk. Chemically induced CRISPR-guided chromosomal loop-engineering for the proximal risk geneSNAP91and distal risk geneBHLHE22profoundly alters synaptic development and functional activity. Our findings highlight the large-scale cell-type-specific reorganization of chromosomal conformations at schizophrenia risk loci during neurodevelopment and establish a causal link between risk-associated gene-regulatory loop structures and neuronal function.
Consensus Tree under the Ancestor-Descendant Distance is NP-hard
Authors: Qi Yuanyuan , El-Kebir Mohammed
Published: July 2023

Due to uncertainty in tumor phylogeny inference from sequencing data, many methods infer multiple, equally-plausible phylogenies for the same cancer. To summarize the solution space 𝒯 of tumor phylogenies, consensus tree methods seek a single best representative treeSunder a specified pairwise tree distance function. One such distance function is the ancestor-descendant (AD) distanced(T, T′), which equals the symmetric difference of the transitive closures of the edge setsE(T) andE(T′). Here, we show that finding a consensus treeSfor tumor phylogenies 𝒯 that minimizes the total AD distance ∑T∈𝒯d(S, T) is NP-hard.
Beyond the MEP Pathway: a novel kinase required for prenol utilization by malaria parasites
Authors: Crispim Marcell , Verdaguer Ignasi Bofill , Hernández Agustín , Kronenberger Thales , Fenollar Àngel , Alberione María Pía , Ramirez Miriam , Katzin Alejandro Miguel , Izquierdo Luis
Published: July 2023

A promising treatment for malaria is a combination of fosmidomycin and clindamycin. Both compounds inhibit the methylerythritol 4-phosphate (MEP) pathway, the parasitic source of farnesyl and geranylgeranyl pyrophosphate (FPP and GGPP, respectively). Both FPP and GGPP are crucial for the biosynthesis of several essential metabolites such as ubiquinone and dolichol, as well as for protein prenylation. Dietary prenols, such as farnesol (FOH) and geranylgeraniol (GGOH), can rescue parasites from MEP inhibitors, suggesting the existence of a missing pathway for prenol salvage via phosphorylation, by competition. In this study, we identified a gene in the genome ofP. falciparum, encoding a transmembrane prenol kinase (PolK) involved in the salvage of FOH and GGOH. The enzyme was expressed inSaccharomyces cerevisiae, and its FOH/GGOH kinase activities were experimentally validated. Furthermore, conditional gene knockouts were created to investigate the biological importance of the FOH/GGOH salvage pathway. The knockout parasites were viable but more susceptible to fosmidomycin, and their sensitivity to MEP inhibitors could not be rescued by the addition of prenols. Moreover, the knockout parasites lost their ability to use prenols for protein prenylation. These results demonstrate that FOH/GGOH salvage is an additional source of isoprenoids by malaria parasites whende novobiosynthesis is inhibited. This study also identifies a novel kind of enzyme whose inhibition may potentiate the antimalarial efficacy of drugs that affect isoprenoid metabolism.
Development of potent dual BET/HDAC inhibitorsviapharmacophore merging and structure-guided optimization
Authors: Bauer Nicolas , Balourdas Dimitrios-Ilias , Schneider Joel R. , Zhang Xin , Berger Lena M. , Berger Benedict-Tilman , Klopp Nick A. , Siveke Jens T. , Knapp Stefan , Joerger Andreas C.
Published: July 2023

Bromodomain and extra-terminal motif (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors such as pancreatic cancer. Here, we have developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC50values in the 100-nanomolar range in cellular NanoBRET target engagement assays. Importantly, this on-target activity also translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressorHEXIM1and proapoptoticp57, both markers of BET inhibition. In addition, they have the potential to downregulate oncogenic drivers of NUT midline carcinoma, as demonstrated forMYCandTP63mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.
Spatial Dynamic Subspaces Encode Sex-Specific Schizophrenia Disruptions in Transient Network Overlap and its Links to Genetic Risk
Authors: Iraji A. , Chen J. , Lewis N. , Faghiri A. , Fu Z. , Agcaoglu O. , Kochunov P. , Adhikari B. M. , Mathalon D.H. , Pearlson G.D. , Macciardi F. , Preda A. , van Erp T.G.M. , Bustillo J. R. , Díaz-Caneja C. M. , Andrés-Camazón P. , Dhamala M. , Adali T. , Calhoun V.D.
Published: July 2023

Background

Recent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects.

Methods

We adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data.

Results

Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks.

Conclusions

Our method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.
FAIMS-enabled N-terminomics analysis reveals novel legumain substrates in murine spleen
Authors: Ziegler Alexander R. , Dufour Antoine , Scott Nichollas E. , Edgington-Mitchell Laura E.
Published: July 2023

Aberrant levels of the asparaginyl endopeptidase legumain have been linked to inflammation, neurodegeneration and cancer, yet our understanding of this protease is incomplete. Systematic attempts to identify legumain substrates have previously been confined toin vitrostudies, which fail to mirror physiological conditions and obscure biologically relevant cleavage events. Using high-field asymmetric waveform ion mobility spectrometry (FAIMS), we developed a sensitive and streamlined approach for proteome and N-terminome analyses in a single analytical method without the need for N-termini enrichment. Compared to unfractionated proteomic analysis, we demonstrate FAIMS fractionation improves neo-N- termini identification by >2.5 fold, resulting in identification of >2,882 unique neo-N-termini from limited sample amounts. Within murine spleens, this approach identifies 6,366 proteins and 2,528 unique neo-N-termini, with 235 cleavage events enriched in wild-type compared to legumain-deficient spleens. Among these, 119 neo-N-termini arose from asparaginyl endopeptidase activities, representing novel putative physiological legumain substrates. The direct cleavage of selected substrates by legumain was confirmed usingin vitroassays, providing support for the existence of physiologically relevant extra-lysosomal legumain activity. Combined, these data shed critical light on the functions of legumain and demonstrates the utility of FAIMS as an accessible method to improve depth and quality of N- terminomics studies.
Strategy of selection and optimization of single domain antibodies targeting the PHF6 linear peptide within the Tau intrinsically disordered protein
Authors: Mortelecque Justine , Zejneli Orgeta , Bégard Séverine , Marine Nguyen , Cantrelle François-Xavier , Hanoulle Xavier , Rain Jean-Christophe , Colin Morvane , Buée Luc , Landrieu Isabelle , Danis Clément , Dupré Elian
Published: July 2023

The use of VHHs (Variable domain of the Heavy-chain of the Heavy-chain-only antibodies) as disease-modifying biomolecules in neurodegenerative disorders holds promises including to target aggregation-sensitive proteins. Exploitation of their clinical values dependents however on the capacity to deliver VHHs with optimal physico-chemical properties for their specific context of use. We described previously a VHH with high therapeutic potential in a family of neurodegenerative diseases called tauopathies. The activity of this promising parent VHH named Z70 relies on its binding within the central region of the Tau protein. Accordingly, we carried out random mutagenesis followed by yeast two-hybrid screening to obtain optimized variants. The VHHs selected from this initial screen targeted the same epitope as VHH Z70 as shown using nuclear magnetic resonance spectroscopy and had indeed improved binding affinities according to dissociation constant values obtained by surface plasmon resonance spectroscopy. The improved affinities can be partially rationalized based on three-dimensional structures of three complexes consisting of an optimized VHH and a peptide containing the Tau epitope. Interestingly, the ability of the VHH variants to inhibit Tau aggregation and seeding could not be predicted from their affinity alone. We indeed showed that thein vitroandin celluloVHH stabilities are other limiting key factors to their efficacy. Our results demonstrate that only a complete pipeline of experiments, here described, permits a rational selection of optimized VHH variants, resulting in our capacity to propose two VHH variants derived from the parent Z70 for their next development steps.
Taxonomy ofPseudomonasspp determines interactions withBacillus subtilis
Authors: Lyng Mark , Þórisdóttir Birta , Sveinsdóttir Sigrún H. , Hansen Morten L. , Maróti Gergely , Jelsbak Lars , Kovács Ákos T.
Published: July 2023

Bacilli and pseudomonads are among the most well-studied microorganisms commonly found in soil, and frequently co-isolated. Despite this, no systematic approach has been employed to assess the pairwise compatibility of members from these genera. Here, we screened 720 fluorescent soil isolates for their effects onBacillus subtilispellicle formation in two types of media and found a predictor for interaction outcome inPseudomonastaxonomy. Interactions were context-dependent and both medium composition and culture conditions strongly influenced interactions. Negative interactions were associated withPseudomonas capeferrum, Pseudomonas entomophilaandPseudomonas protegens, and 2,4-diacetylphloroglucinol was confirmed as a strong (but not exclusive) inhibitor ofB. subtilis. Non-inhibiting strains were closely related toPseudomonas trivialisandPseudomonas lini, but in this case, cocultures with increasedB. subtilispellicle formation were spatially segregated. Our study is the first to propose an overall negative outcome from pairwise interactions betweenB. subtilisand fluorescent pseudomonads, hence cocultures comprising members from these groups are likely to require additional microorganisms for coexistence.
Increased susceptibility to ischemia causes exacerbated response to microinjuries in the cirrhotic liver
Authors: Leaker Ben D. , Sojoodi Mozhdeh , Tanabe Kenneth K. , Popov Yury V. , Tam Joshua , Anderson R. Rox
Published: July 2023

Background

Fractional laser ablation is a technique developed in dermatology to induce remodeling of skin scars by creating a dense pattern of microinjuries. Despite remarkable clinical results, this technique has yet to be tested for scars in other tissues. As a first step towards determining the suitability of this technique, we aimed to (1) characterize the response to microinjuries in the healthy and cirrhotic liver, and (2) determine the underlying cause for any differences in response.

Methods

Healthy and cirrhotic rats were treated with a fractional laser then euthanized from 0hr up to 14d after treatment. Differential expression was assessed using RNAseq with a difference-in-differences model. Spatial maps of tissue oxygenation were acquired with hyperspectral imaging and disruptions in blood supply were assessed with tomato lectin perfusion.

Results

Healthy rats showed little damage beyond the initial microinjury and healed completely by 7d without scarring. In cirrhotic rats, hepatocytes surrounding microinjury sites died 4-6hr after ablation, resulting in enlarged and heterogeneous zones of cell death. Hepatocytes near blood vessels were spared, particularly near the highly vascularized septa. Gene sets related to ischemia and angiogenesis were enriched at 4hr. Laser-treated regions had reduced oxygen saturation and broadly disrupted perfusion of nodule microvasculature, which matched the zones of cell death.

Conclusions

The cirrhotic liver has an exacerbated response to microinjuries and increased susceptibility to ischemia from microvascular damage, likely related to the vascular derangements that occur during cirrhosis development. Modifications to the fractional laser tool, such as using a femtosecond laser or reducing the spot size, may be able to prevent large disruptions of perfusion and enable further development of a laser-induced microinjury treatment for cirrhosis.