bluuebunny/crossref_metadata_2025 huggingface dataset:
“I Came up Short on the Academic Ladder”
Authors: Isak Ergest , Hegde Yash D. , Barrett Meredith , Mazer Laura M. , Dimick Justin B. , Sandhu Gurjit
Published: April 2023

Objective:

This study aims to explore the definition of career success in academic surgery.

Background:

Career success in academic surgery is frequently defined as the achievement of a specific title, from full professor to department chair. This type of definition is convenient and established but potentially incomplete. The business literature has a more nuanced view of the relationship between titles and success, but this relationship has not been studied in medicine.

Methods:

Semi-structured interviews were conducted from May to November 2020. Data were analyzed in an iterative fashion using grounded theory methodology to develop a conceptual model.

Results:

We conducted 26 semi-structured interviews with practicing surgeons differing in years of experience; 12 (46%) participants were female, mean age of 48. Participants included 5 chairs of surgery, 6 division chiefs, and 7 past or current presidents of national societies. Four themes emerged on the importance of titles: Some study participants reported that (1) titles are a barometer of success; others argued that (2) titles are not a sufficient metric to define success; (3) titles are a means to an end; and (4) there is a desire to achieve the title of a respected mentor.

Conclusions:

As the definition of career success in academic surgery changes to encompass a broader range of interests and ambitions, the traditional markers of success must come into review. Academic surgeons see the value of titles as a marker of success and as a means to achieving other goals, but overwhelmingly our interviewees felt that titles were a double-edged sword and that a more inclusive definition of academic success was needed.
Chimerism-based Tolerance Induction in Clinical Transplantation: Its Foundations and Mechanisms
Authors: Mengrelis Konstantinos , Muckenhuber Moritz , Wekerle Thomas
Published: April 2023

Hematopoietic chimerism remains the most promising strategy to bring transplantation tolerance into clinical routine. The concept of chimerism-based tolerance aims to extend the recipient’s mechanisms of self-tolerance (ie, clonal deletion, anergy, and regulation) to include the tolerization of donor antigens that are introduced through the cotransplantation of donor hematopoietic cells. For this to be successful, donor hematopoietic cells need to engraft in the recipient at least temporarily. Three pioneering clinical trials inducing chimerism-based tolerance in kidney transplantation have been published to date. Within this review, we discuss the mechanisms of tolerance that are associated with the specific therapeutic protocols of each trial. Recent data highlight the importance of regulation as a mechanism that maintains tolerance. Insufficient regulatory mechanisms are also a likely explanation for situations of tolerance failure despite persisting donor chimerism. After decades of preclinical development of chimerism protocols, mechanistic data from clinical trials have recently become increasingly important. Better understanding of the required mechanisms for tolerance to be induced in humans will be a key to design more reliable and less invasive chimerism protocols in the future.
Genome sequencing and multifaceted taxonomic analysis of novel strains of violacein-producing bacteria and non-violacein-producing close relatives
Authors: De León Marina Estella , Wilson Harriet S. , Jospin Guillaume , Eisen Jonathan A.
Published: April 2023

Violacein is a water-insoluble violet pigment produced by various Gram-negative bacteria. The compound and the bacteria that produce it have been gaining attention due to the antimicrobial and proposed antitumour properties of violacein and the possibility that strains producing it may have broad industrial uses. Bacteria that produce violacein have been isolated from diverse environments including fresh and ocean waters, glaciers, tropical soils, trees, fish and the skin of amphibians. We report here the isolation and characterization of six violacein-producing bacterial strains and three non-violacein-producing close relatives, each isolated from either an aquatic environment or moist food materials in northern California, USA. For each isolate, we characterized traditional phenotypes, generated and analysed draft genome sequences, and carried out multiple types of taxonomic, phylogenetic and phylogenomic analyses. Based on these analyses we assign putative identifications to the nine isolates, which include representatives of the genera

Chromobacterium

,

Aquitalea

,

Iodobacter

,

Duganella

,

Massilia

and

Janthinobacterium

. In addition, we discuss the utility of various metrics for taxonomic assignment in these groups including average nucleotide identity, whole genome phylogenetic analysis and extent of recent homologous recombination using the software program PopCOGenT.
Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis
Authors: Saber Morteza M. , Donner Jannik , Levade Inès , Acosta Nicole , Parkins Michael D. , Boyle Brian , Levesque Roger C. , Nguyen Dao , Shapiro B. Jesse
Published: April 2023

The severity and progression of lung disease are highly variable across individuals with cystic fibrosis (CF) and are imperfectly predicted by mutations in the human gene CFTR, lung microbiome variation or other clinical factors. The opportunistic pathogen

Pseudomonas aeruginosa

(Pa) dominates airway infections in most CF adults. Here we hypothesized that within–host genetic variation of Pa populations would be associated with lung disease severity. To quantify Pa genetic variation within CF sputum samples, we used deep amplicon sequencing (AmpliSeq) of 209 Pa genes previously associated with pathogenesis or adaptation to the CF lung. We trained machine learning models using Pa single nucleotide variants (SNVs), microbiome diversity data and clinical factors to classify lung disease severity at the time of sputum sampling, and to predict lung function decline after 5 years in a cohort of 54 adult CF patients with chronic Pa infection. Models using Pa SNVs alone classified lung disease severity with good sensitivity and specificity (area under the receiver operating characteristic curve: AUROC=0.87). Models were less predictive of lung function decline after 5 years (AUROC=0.74) but still significantly better than random. The addition of clinical data, but not sputum microbiome diversity data, yielded only modest improvements in classifying baseline lung function (AUROC=0.92) and predicting lung function decline (AUROC=0.79), suggesting that Pa AmpliSeq data account for most of the predictive value. Our work provides a proof of principle that Pa genetic variation in sputum tracks lung disease severity, moderately predicts lung function decline and could serve as a disease biomarker among CF patients with chronic Pa infections.
The Prevalence of the Female Athlete Triad in Female Service Members
Authors: Mattison Cameron S. , Wiese John
Published: April 2023

Osteoporosis, amenorrhea, and low energy with or without disordered eating (the female athlete triad) are frequent clinical outcomes associated with female athletes in constant low energy availability (LEA). The rigorous training demands of the Army and the strict weight limits suggest that female service members may be susceptible to states of LEA, where energy expenditure exceeds dietary energy intake.

To understand the prevalence of the female athlete triad among female service members and how restrictive weight requirements influence these symptoms, we compared survey responses measuring symptoms of the female athlete triad between female active-duty service members and female veterans.

The results indicated that female veterans had significantly higher female athlete triad and disordered eating scores. Therefore, female veterans are more likely to demonstrate female athlete triad symptoms than active-duty service members. Specifically, female veterans are more likely to demonstrate symptoms of low energy with or without disordered eating.

Female veterans’ unique stressors of no longer being in the military (reintegration into society and losing support system within the military) could be why they are more likely to present with female athlete triad symptoms than active-duty female service members.
Reduced male fertility of an Antarctic mite following extreme heat stress could prompt localized population declines
Authors: Benoit Joshua B. , Finch Geoffrey , Ankrum Andrea L. , Niemantsverdriet Jennifer , Paul Bidisha , Kelley Melissa , Gantz J. D. , Matter Stephen F. , Lee Richard E. , Denlinger David L.
Published: April 2023

Climate change is leading to substantial global thermal changes, which are particularly pronounced in polar regions. Few studies have examined the impact of heat stress on reproduction in Antarctic terrestrial arthropods, specifically how brief, extreme events may alter survival. We observed that sublethal heat stress reduces male fecundity in an Antarctic mite, yielding females that produced fewer viable eggs. Females and males collected from microhabitats with high temperatures showed a similar reduction in fertility. This impact is temporary, as indicated by recovery of male fecundity following return to cooler, stable conditions. The diminished fecundity is likely due to a drastic reduction in the expression of male-associated factors that occur in tandem with a substantial increase in the expression of heat shock proteins. Cross mating between mites from different sites confirmed that heat-exposed populations have impaired male fertility. However, the impact on fertility declines with time when the mites are allowed to recover under less stressful conditions, suggesting that the negative effects are transient. Modeling indicated that heat stress is likely to reduce population growth and that short bouts of non-lethal heat stress could have substantial effects on local populations of Antarctic arthropods.
MGAT5 (GnTase-V) products are overexpressed in primary osteoblastic osteogenic sarcoma
Authors: McClure John , McClure Sheena F
Published: April 2023

It is well documented that MGAT5 (Glycosyltransferase V) products are over expressed in carcinomas and likely accelerate metastasis by promoting neoangiogenesis. We now report a similar over expression in primary osteoblastic osteogenic sarcoma and demonstrate new intratumoural blood vessels. Expansion of the tumours is by osteoclastic resorption of both trabecular and cortical bone with the latter by cutting channels similar to physiological cutting cones. Osteoclasts, adjacent capillaries, and related mast cells also overexpress MGAT5 products and we speculate that this facilitates neoangiogenesis.
The Impact of Stability Considerations on Genetic Fine-Mapping
Authors: Aw Alan , Jin Lionel Chentian , Ioannidis Nilah , Song Yun S.
Published: April 2023

Fine-mapping methods, which aim to identify genetic variants responsible for complex traits following genetic association studies, typically assume that sufficient adjustments for confounding within the association study cohort have been made, e.g., through regressing out the top principal components (i.e., residualization). Despite its widespread use, however, residualization may not completely remove all sources of confounding. Here, we propose a complementary stability-guided approach that does not rely on residualization, which identifies consistently fine-mapped variants across different genetic backgrounds or environments. We demonstrate the utility of this approach by applying it to fine-map eQTLs in the GEUVADIS data. Using 378 different functional annotations of the human genome, including recent deep learning-based annotations (e.g., Enformer), we compare enrichments of these annotations among variants for which the stability and traditional residualization-based fine-mapping approaches agree against those for which they disagree, and find that the stability approach enhances the power of traditional fine-mapping methods in identifying variants with functional impact. Finally, in cases where the two approaches report distinct variants, our approach identifies variants comparably enriched for functional annotations. Our findings suggest that the stability principle, as a conceptually simple device, complements existing approaches to fine-mapping, reinforcing recent advocacy of evaluating cross-population and cross-environment portability of biological findings. To support visualization and interpretation of our results, we provide a Shiny app, available at:https://alan-aw.shinyapps.io/stability_v0/.
Emergence of catalytic function in prebiotic information-coding polymers
Authors: Tkachenko Alexei V. , Maslov Sergei
Published: April 2023

Life as we know it relies on the interplay between catalytic activity and information processing carried out by biological polymers. Here we present a plausible pathway by which a pool of prebiotic information-coding oligomers could acquire an early catalytic function, namely sequence- specific cleavage activity. Starting with a system capable of non-enzymatic templated replication, we demonstrate that even non-catalyzed spontaneous cleavage would promote proliferation by generating short fragments that act as primers. Furthermore, we show that catalytic cleavage function can naturally emerge and proliferate in this system. Specifically, a cooperative catalytic network with four subpopulations of oligomers is selected by the evolution in competition with chains lacking catalytic activity. The cooperative system emerges through the functional differentiation of oligomers into catalysts and their substrates. The model is inspired by the structure of the hammerhead RNA enzyme as well as other DNA- and RNA-based enzymes with cleavage activity that readily emerge through natural or artificial selection. We identify the conditions necessary for the emergence of the cooperative catalytic network. In particular, we show that it requires the catalytic rate enhancement over the spontaneous cleavage rate to be at least 102− 103, a factor consistent with the existing experiments. The evolutionary pressure leads to a further increase in catalytic efficiency. The presented mechanism provides an escape route from a relatively simple pairwise replication of oligomers towards a more complex behavior involving catalytic function. This provides a bridge between the information-first origin of life scenarios and the paradigm of autocatalytic sets and hypercycles, albeit based on cleavage rather than synthesis of reactants.
Comprehensive Characterization of Endogenous Phospholamban Proteoforms Enabled by Photocleavable Surfactant and Top-down Proteomics
Authors: Rogers Holden T. , Roberts David S. , Larson Eli J. , Melby Jake A. , Rossler Kalina J. , Carr Austin V. , Brown Kyle A. , Ge Ying
Published: April 2023

Top-down mass spectrometry (MS)-based proteomics has become a powerful tool for analyzing intact proteins and their associated post-translational modification (PTMs). In particular, membrane proteins play critical roles in cellular functions and represent the largest class of drug targets. However, the top-down MS characterization of endogenous membrane proteins remains challenging, mainly due to their intrinsic hydrophobicity and low abundance. Phospholamban (PLN) is a regulatory membrane protein located in the sarcoplasmic reticulum and is essential for regulating cardiac muscle contraction. PLN has diverse combinatorial PTMs and their dynamic regulation has significant influence on cardiac contractility and disease. Herein, we have developed a rapid and robust top-down proteomics method enabled by a photocleavable anionic surfactant, Azo, for the extraction and comprehensive characterization of endogenous PLN from cardiac tissue. We employed a two-pronged top-down MS approach using an online reversed-phase liquid chromatography tandem MS (LC-MS/MS) method on a quadrupole time-of-flight (Q-TOF) MS and a direct infusion method via an ultrahigh-resolution Fourier-transform ion cyclotron resonance (FTICR) MS. We have comprehensively characterized the sequence and combinatorial PTMs of endogenous human cardiac PLN. We have shown the site-specific localization of phosphorylation to Ser16 and Thr17 by MS/MS for the first time and the localization of S-palmitoylation to Cys36. Taken together, we have developed a streamlined top-down targeted proteomics method for comprehensive characterization of combinatorial PTMs in PLN toward better understanding the role of PLN in cardiac contractility.
Barcode-free multiplex plasmid sequencing using Bayesian analysis and nanopore sequencing
Authors: Uematsu Masaaki , Baskin Jeremy M.
Published: April 2023

Plasmid construction is central to life science research, and sequence verification is arguably its costliest step. Long-read sequencing has emerged as a competitor to Sanger sequencing, with the principal benefit that whole plasmids can be sequenced in a single run. Nevertheless, the current cost of nanopore sequencing is still prohibitive for routine sequencing during plasmid construction. We develop a computational approach termed Simple Algorithm for Very Efficient Multiplexing of Oxford Nanopore Experiments for You (SAVEMONEY) that guides researchers to mix multiple plasmids and subsequently computationally de-mixes the resultant sequences. SAVEMONEY defines optimal mixtures in a pre-survey step, and following sequencing, executes a post-analysis workflow involving sequence classification, alignment, and consensus determination. By using Bayesian analysis with prior probability of expected plasmid construction error rate, high-confidence sequences can be obtained for each plasmid in the mixture. Plasmids differing by as little as two bases can be mixed for submission as a single sample for nanopore sequencing, and routine multiplexing of even six plasmids per 180 reads can still maintain high accuracy of consensus sequencing. SAVEMONEY should further democratize whole-plasmid sequencing by nanopore and related technologies, driving down the effective cost of whole-plasmid sequencing to lower than that of a single Sanger sequencing run.
Rbm8a deficiency causes hematopoietic defects by modulating Wnt/PCP signaling
Authors: Kocere Agnese , Chiavacci Elena , Soneson Charlotte , Wells Harrison H. , Méndez-Acevedo Kevin Manuel , MacGowan Jacalyn S. , Jacobson Seth T. , Hiltabidle Max S. , Raghunath Azhwar , Shavit Jordan A. , Panáková Daniela , Williams Margot L. K. , Robinson Mark D. , Mosimann Christian , Burger Alexa
Published: April 2023

Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function forRBM8A/Y14that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafishrbm8aperturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphicrbm8azebrafish, we observe a significant reduction ofcd41-positive thrombocytes.rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish thatrbm8a-mutant embryos show convergent extension defects and that reducedrbm8afunction interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b,wnt11f2,fzd7a, andvangl2. Using live-imaging, we found reducedrbm8afunction impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants forrbm8aand for the PCP genevangl2feature impaired expression of early hematopoietic/endothelial genes includingrunx1and the megakaryocyte regulatorgfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reducedrbm8afunction. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism.

HIGHLIGHTS

Zebrafish mutants for the TAR Syndrome generbm8ashow thrombocyte reduction

Attenuated Rbm8a function results in retained introns in mRNAs encoding PCP components

Early PCP defects result in lateral plate mesoderm anomalies and hematopoietic defects

PCP anomalies selectively impact cell fate patterning
Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore module
Authors: Schott Katharina , Usher Samuel George , Serra Oscar , Carnevale Vincenzo , Pless Stephan Alexander , Chua Han Chow
Published: April 2023

The sodium (Na+) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (NaVs and CaVs, respectively). Unlike NaVs and CaVs, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145 and Y1436) that block these openings. Structural data suggest that oc-cluded lateral fenestrations underlie the pharmacological resistance of NALCN to lipophilic compounds, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned resi-dues with alanine (AAAA) and compared the effects of NaV, CaVand NALCN block-ers on both wild-type (WT) and AAAA channels. Most compounds behaved in a simi-lar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cav-ity through distinct fenestrations, implying structural specificity to their modes of ac-cess. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug bind-ing site(s) within the pore region. Intrigued by the activity of 2-APB and its ana-logues, we tested additional compounds containing the diphenylmethane/amine moiety on WT channels. We identified compounds from existing clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the resistance of NALCN to pharmacological targeting, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties.

Significance statement

The sodium leak channel (NALCN) is essential for survival: mutations cause life-threatening developmental disorders in humans. However, no treatment is currently available due to the resistance of NALCN to pharmacological targeting. One likely reason is that the lateral fenestrations, a common route for clinically used drugs to enter and block related ion channels, are occluded in NALCN. Using a combination of computational and functional approaches, we unplugged the fenestrations of NALCN which led us to the first molecularly defined drug binding site within the pore region. Besides that, we also identified additional NALCN modulators from existing clinically used therapeutics, thus expanding the pharmacological toolbox for this leak channel.
Fission yeast obeys a linear size law under nutrient titration
Authors: Bertaux François , Kleijn Istvan T. , Marguerat Samuel , Shahrezaei Vahid
Published: April 2023

Steady-state cell size and geometry depend on growth conditions. Here, we use an experimental setup based on continuous culture and single-cell imaging to study how cell volume, length, width and surface-to-volume ratio vary across a range of growth conditions including nitrogen and carbon titration, the choice of nitrogen source, and translation inhibition. Overall, we find cell geometry is not fully determined by growth rate and depends on the specific mode of growth rate modulation. However, under nitrogen and carbon titrations, we observe that the cell volume and the growth rate follow the same linear scaling.

Abstract Figure

Figure

A. Graphical outline of the growth and imaging assays.B. Illustration of the procedure used to extract cell size and geometry data.C. Average surface-to-volume (S/V) ratio plotted as a function of average cell width across all steady-state cultures. The dark grey circle indicates the base growth medium, EMM2. Cultures limited in their growth by the concentration of ammonium, glucose, and cycloheximide in the medium are indicated with cyan lozenges, green triangles, and orange squares, respectively. Cultures limited by the choice of nitrogen source are indicated with light grey circles; the amino-acid nitrogen source used is labelled with its three-letter abbreviation, using Amm for the equivalent culture grown with ammonium chloride as its sole nitrogen source.D. Average cell volume plotted against the growth rate across all cultures, showing collapse for ammonium- and glucose-limited cultures and differing behaviour for nitrogen-source- and translation-limited cultures. Plotted in dark grey is a linear fit to the ammonium- and glucose-limited data, including the base medium, with 95% confidence interval; a similar fit (without CI) to the cycloheximide-limited cultures is indicated by a dashed orange line.E. Average surface-to-volume (S/V) ratio against growth rate across all cultures, with dashed lines for ammonium-, glucose-, and translation-limited cultures representing linear fits to the respective data, each including the base medium. Under ammonium limitation, the surface-to-volume ratio increases markedly as the growth rate decreases. A moderate increase is observed for glucose limitation and a moderate decrease is observed for protein synthesis inhibition with cycloheximide. There is no consistent trend with the growth rate when the quality of the nitrogen source is varied.F. Average surface area,G. cell length,H. cell width against growth rate, showing that ammonium-limited cells are thinner than glucose-limited cells at equivalent growth rates, consistent with their different surface-to-volume ratios and the relation between surface-to-volume ratio and cell width (see C).
Activation and substrate specificity of the human P4-ATPase ATP8B1
Authors: Dieudonné Thibaud , Kümmerer Felix , Laursen Michelle Juknaviciute , Stock Charlott , Flygaard Rasmus Kock , Khalid Syma , Lenoir Guillaume , Lyons Joseph A. , Lindorff-Larsen Kresten , Nissen Poul
Published: April 2023

Asymmetric distribution of phospholipids in eukaryotic membranes is essential for maintaining cell integrity, signaling pathways, and vesicular trafficking. P4-ATPases, also known as flippases, participate in creating and maintaining this asymmetry through active transport of phospholipids from the exoplasmic to the cytosolic leaflet. In this study, we present a total of nine cryo-electron microscopy structures at a resolution ranging from 2.4 to 3.1 Å, along with functional and computational studies of the human flippase ATP8B1-CDC50A complex, describing the autophosphorylation steps from ATP, substrate recognition and occlusion, as well as its regulation by phosphoinositides. Our findings show that the P4-ATPase transport site is filled with water upon phosphorylation from ATP. Additionally, we identify two different autoinhibited states, a closed and an outward-open conformation. Furthermore, we identified and characterized the PI(3,4,5)P3binding site of ATP8B1 in an electropositive pocket between transmembrane segments 5, 7, 8, and 10. Our study also highlights the structural basis of ATP8B1 broad specificity for lipids and identifies a new transport substrate for P4-ATPases, phosphatidylinositol (PI). We report the critical role of the sn-2 ester bound of glycerophospholipids in substrate recognition by ATP8B1. These findings provide fundamental insights into ATP8B1 regulation, the catalytic cycle, and substrate recognition in P4-ATPases.
Nectophore coordination and kinematics by physonect siphonophores
Authors: Strock Shirah , Costello John H. , Daniels Joost , Katija Kakani , Colin Sean P.
Published: April 2023

Siphonophores are ubiquitous and often highly abundant members of pelagic ecosystems throughout the open ocean. They are unique among animal taxa in that they use multiple jets for propulsion. Little is known about kinematics of the individual jets produced by nectophores or how the jets are coordinated during normal swimming behavior. Using remotely operated vehicles and SCUBA, we video recorded the swimming behavior of several physonect species in their natural environment. The pulsed kinematics of the individual nectophores that comprise the siphonophore nectosome were quantified and, based on these kinematics, we examined the coordination of adjacent nectophores. We found for all species that nectophores sharing the same side of the nectosomal axis were coordinated metachronally. However, this coordination was not shared with nectophores on the opposite side of the nectosomal axis. For most species, the metachronal contraction waves of nectophores were initiated by the apical nectophores and traveled dorsally. However, the metachronal wave ofApolemia rubriversatraveled in the opposite direction. Although nectophore groups on opposite sides of the nectosome were not coordinated, they pulsed with similar frequencies. This enabled siphonophores to maintain relatively linear trajectories during swimming. The timing and characteristics of the metachronal coordination of pulsed jets affects how the jet wakes interact and may provide important insight into how interacting jets may be optimized for efficient propulsion.
Engineering GliaTrap: a biodegradable non-swelling hydrogel with tuned release of CXCL12 to attract migrating glioblastoma cells
Authors: Suita Yusuke , Miriyala Saradha , Merih-Toruner Deniz , Yue Weizhou , Xie Lingxiao , Akobundu Blessing , Pertsch Nathan , Fiser Andras , Fajardo Eduardo , Shen Jie , Tapinos Nikos
Published: April 2023

Glioblastoma is the most aggressive type of brain cancer with an average overall survival of 15-21 months after first diagnosis. The relapse is mainly caused by migrating glioblastoma cells that diffuse away from the tumor mass into the brain parenchyma and retain cancer stem cell (GSC) properties. Current therapeutic options are ineffective and inevitably result in relapse, indicating a high unmet medical need for innovative therapies in the treatment of invasive glioblastoma. To address this challenge, we propose a new therapeutic modality: GliaTrap, a biodegradable non-swelling, injectable hydrogel with sustained release of a chemoattractant for GSCs that lures and traps the migrating cells back to the tumor resection cavity. We developed a biodegradable and injectable hyaluronan/collagen II-based (HA/Col) hydrogel that does not swell in vivo. The hydrogel is embedded with CXCL12 loaded liposomes and is tuned for sustained release of CXCL12. The safety profile of liposome-embedded HA/Col hydrogel was determined in-vivo after stereotactic implantation in the mouse brain. The efficacy of GliaTrap to attract GSCs was determined ex vivo using a 3D tumor spheroid model and in-vivo using 3D light-sheet microscopy in orthotopic human glioblastoma xenografts. Our findings suggest that GliaTrap could represent a safe and efficacious new therapeutic approach for glioblastoma and potentially serve as a drug delivery platform to locally deliver tumor-killing agents.

One Sentence Summary

GliaTrap is a biodegradable non-swelling hydrogel with tuned release of a chemoattractant to attract invading glioma cells and serve as delivery platform for local therapeutics.
Optimal HLA imputation of admixed population with dimension reduction
Authors: Douillard Venceslas , dos Santos Brito Silva Nayane , Bourguiba-Hachemi Sonia , Naslavsky Michel S. , Scliar Marilia O. , Duarte Yeda A. O. , Zatz Mayana , Passos-Bueno Maria Rita , Limou Sophie , Gourraud Pierre-Antoine , Launay Élise , Castelli Erick C. , Vince Nicolas
Published: April 2023

Human genomics has quickly evolved, powering genome-wide association studies (GWASs). SNP-based GWASs cannot capture the intense polymorphism ofHLAgenes, highly associated with disease susceptibility. There are methods to statistically imputeHLAgenotypes from SNP-genotypes data, but lack of diversity in reference panels hinders their performance. We evaluated the accuracy of the 1,000 Genomes data as a reference panel for imputing HLA from admixed individuals of African and European ancestries, focusing on (a) the full dataset, (b) 10 replications from 6 populations, (c) 19 conditions for the custom reference panels. The full dataset outperformed smaller models, with a good F1-score of 0.66 forHLA-B. However, custom models outperformed the multiethnic or population models of similar size (F1-scores up to 0.53, against up to 0.42). We demonstrated the importance of using genetically specific models for imputing admixed populations, which are currently underrepresented in public datasets, opening the door to HLA imputation for every genetic population.
Impact of repeated short light exposures on sustained pupil responses in an fMRI environment
Authors: Beckers Elise , Campbell Islay , Sharifpour Roya , Paparella Ilenia , Berger Alexandre , Balda Aizpurua Jose Fermin , Koshmanova Ekaterina , Mortazavi Nasrin , Talwar Puneet , Sherif Siya , Jacobs Heidi I.L. , Vandewalle Gilles
Published: April 2023

Light triggers numerous non-image forming (NIF), or non-visual, biological effects. The brain correlates of these NIF effects have been investigated, notably using Magnetic Resonance Imaging (MRI) and short light exposures varying in irradiance and spectral quality. However, it is not clear whether having light in subsequent blocks may induce carry over effects of one light block onto the next, thus biasing the study. We reasoned that pupil light reflex (PLR) was an easy readout of one of the NIF effects of light that could be used to address this issue. We characterized the sustained PLR in 13 to 16 healthy young individuals under short light exposures during three distinct cognitive processes (executive, emotional and attentional). Light conditions pseudo-randomly alternated between monochromatic orange light [0.16 melanopic Equivalent Daylight Illuminance (mel EDI) lux] and polychromatic blue-enriched white light of three different levels [37, 92, 190 mel EDI lux]. As expected, higher melanopic irradiance was associated with larger sustained PLR in each cognitive domain. This result was stable over the light block sequence under higher melanopic irradiance levels as compared to lower ones. Exploratory frequency-domain analyses further revealed that PLR was more variable within a light block under lower melanopic irradiance levels. Importantly, PLR varied across tasks independently of the light condition pointing to a potential impact of the light history and/or cognitive context on PLR. Together, our results emphasize that the distinct contribution and adaptation of the different retinal photoreceptors influence the NIF effects of light and therefore potentially their brain correlates.
Heterotypic interactions in the dilute phase can drive co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex
Authors: Davis Richoo B. , Supakar Anushka , Ranganath Aishwarya Kanchi , Moosa Mahdi Muhammad , Banerjee Priya R.
Published: April 2023

Prion-like domains (PLDs) are low-complexity protein sequences enriched within nucleic acid-binding proteins including those involved in transcription and RNA processing. PLDs of FUS and EWSR1 play key roles in recruiting chromatin remodeler mammalian SWI/SNF complex to oncogenic FET fusion protein condensates. Here, we show that disordered low-complexity domains of multiple SWI/SNF subunits are prion-like with a strong propensity to undergo intracellular phase separation. These PLDs engage in sequence-specific heterotypic interactions with the PLD of FUS in the dilute phase at sub-saturation conditions, leading to the formation of PLD co-condensates. In the dense phase, homotypic and heterotypic PLD interactions are highly cooperative, resulting in the co-mixing of individual PLD phases and forming spatially homogeneous co-condensates. Heterotypic PLD-mediated positive cooperativity in protein-protein interaction networks is likely to play key roles in the co-phase separation of mSWI/SNF complex with transcription factors containing homologous low-complexity domains.
CB1R blockade unmasks TRPV1-mediated contextual fear generalization in female, but not male rats
Authors: Huckleberry Kylie A , Calitri Roberto , Li Anna J. , Mejdell Mackenna , Singh Ashna , Bhutani Vasvi , Laine Mikaela A , Nastase Andrei S. , Morena Maria , Hill Matthew N , Shansky Rebecca M
Published: April 2023

Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, and here we asked specifically whether the endocannabinoid (eCB) system could modulate Pavlovian fear conditioning in a sex-dependent manner. Systemic (i.p.) injection of CB1R antagonist AM251 in adult male and female Sprague Dawley rats prior to auditory cued fear conditioning produced a female-specific increase in freezing that persisted across extinction and extinction retrieval tests but was prevented by co-administration of TRPV1R antagonist Capsazepine. Notably, AM251 also produced robust freezing in a novel context prior to auditory cue presentation the day following drug administration, but not the day of, suggesting that CB1R blockade elicited contextual fear generalization in females. To identify a potential synaptic mechanism for these sex differences, we next used liquid chromatography/tandem mass spectrometry, Western Blot, and confocal-assisted immunofluorescence techniques to quantify anandamide (AEA), TRPV1R, and perisomatic CB1R expression, respectively, focusing on the ventral hippocampus (vHip). Fear conditioning elicited increased vHip AEA levels in females only, and in both sexes, CB1R expression around vHip efferents targeting the basolateral amygdala (BLA) was twice that at neighboring vHip neurons. Finally, quantification of the vHip-BLA projections themselves revealed that females have over twice the number of neurons in this pathway that males do. Together, our data support a model in which sexual dimorphism in vHip-BLA circuitry promotes a female-specific dependence on CB1Rs for context processing that is sensitive to TRPV1-mediated disruption when CB1Rs are blocked.
A GH81-type β-glucan-binding protein facilitates colonization by mutualistic fungi in barley
Authors: Wanke Alan , van Boerdonk Sarah , Mahdi Lisa K. , Wawra Stephan , Neidert Miriam , Chandrasekar Balakumaran , Saake Pia , Saur Isabel M. L. , Derbyshire Paul , Holton Nicholas , Menke Frank L. H. , Brands Mathias , Pauly Markus , Acosta Ivan F. , Zipfel Cyril , Zuccaro Alga
Published: April 2023

Cell walls are important interfaces of plant-fungal interactions. Host cell walls act as robust physical and chemical barriers against fungal invaders, making them an essential line of defense. Upon fungal colonization, plants deposit phenolics and callose at the sites of fungal penetration to reinforce their walls and prevent further fungal progression. Alterations in the composition of plant cell walls significantly impact host susceptibility. Furthermore, plants and fungi secrete glycan hydrolases acting on each other's cell walls. These enzymes release a wide range of sugar oligomers into the apoplast, some of which trigger the activation of host immunity via host surface receptors. Recent characterization of cell walls from plant-colonizing fungi have emphasized the abundance of β-glucans in different cell wall layers, which makes them suitable targets for recognition. To characterize host components involved in immunity against fungi, we performed a protein pull-down with the biotinylated β-glucan laminarin. Thereby, we identified a glycoside hydrolase family 81-type glucan-binding protein (GBP) as the major β-glucan interactor. Mutation of GBP1 and its only paralogue GBP2 in barley led to decreased colonization by the beneficial root endophytes Serendipita indica and S. vermifera, as well as the arbuscular mycorrhizal fungus Rhizophagus irregularis. The reduction of symbiotic colonization was accompanied by enhanced responses at the host cell wall. Moreover, GBP mutation in barley also increased resistance to fungal infections in roots and leaves by the hemibiotrophic pathogen Bipolaris sorokiniana and the obligate biotrophic pathogen Blumeria graminis f. sp. hordei, respectively. These results indicate that GBP1 is involved in the establishment of symbiotic associations with beneficial fungi, a role that has potentially been appropriated by barley-adapted pathogens.
Dissociable roles of the auditory midbrain and cortex in processing the statistical features of natural sound textures
Authors: Peng Fei , Harper Nicol S. , Mishra Ambika Prasad , Auksztulewicz Ryszard , Schnupp Jan W.H.
Published: April 2023

It is well established that sound texture perception takes advantage of a hierarchy of time-averaged statistical features of acoustic stimuli, but much remains unclear about how these statistical features are processed in auditory subcortical and cortical regions. Here, we compared the neural representation of sound textures in the inferior colliculus (IC), and primary and non-primary auditory cortex (AC) of anesthetized rats with texture morph stimuli which gradually add statistical features of increasingly higher order. We generated texture morphs for a representative subset of 13 sound textures, chosen to span the three principal component dimensions of a corpus of 200 natural texture recordings. For each of the 13 texture types, six different exemplar morphs were synthesized using different random seeds. All exemplars of each texture type have the same long term statistics, but they differ in their acoustic waveforms. Meanwhile, different texture types differ in statistical features as well as waveforms. An analysis of transient and ongoing multi-unit responses to our stimulus set showed that the IC units were sensitive to every type of statistical feature, albeit to a varying extent, but only a small proportion of AC units were overtly sensitive to any statistical features. Differences in texture types explained more of the variance of IC neural responses than did differences in exemplars, indicating a degree of “texture-type tuning” in the IC, but this was, perhaps surprisingly, not the case for AC responses. We also evaluated the accuracy of texture type classification from single-trial population activity and found that IC responses became more informative as more summary statistics were included in the texture morphs, while for AC population responses classification performance remained constant, and consistently lower, than for the IC. These results argue against the idea that AC plays an important role in encoding statistical features of natural sound textures.
Dual use insurance for annual forage producers: comparing risk management alternatives
Authors: Graff Natalie A. , Fischer Bart L. , Bryant Henry L. , Anderson David P.
Published: April 2023

Purpose

The purpose of this paper is to evaluate the Dual Use (DU) Option – a crop insurance policy created by the 2018 Farm Bill – relative to other policies available to dual-purpose annual forage producers. The new policy combines existing rainfall-based policies for annual forage crops and multi-peril policies for grain, allowing coverage for multiple crop uses on the same acres during the same growing season.

Design/methodology/approach

The paper uses a simulation model to examine crop insurance choices for a typical Texas dual-purpose wheat farm. The certainty equivalent (CE) of wealth is used to rank choices within and between three insurance plans and to analyze the effects of those choices over a range of producer risk aversion levels and for three cases of yield expectations.

Findings

The DU Option is more preferred as risk aversion increases, but it is not universally preferred. Therefore, while the policy can be a viable risk management tool, certain restrictions may be limiting its effectiveness.

Practical implications

The findings of this paper can help explain farm-level decision making related to dual-purpose annual forage crop insurance program choices.

Originality/value

This paper contributes to the literature by documenting a new crop insurance program made available in the 2018 Farm Bill and provides insights into producers' possible choices by evaluating extensive scenarios.
Dual innovation of the business model: the regulatory role of entrepreneurial orientation in family firms
Authors: Ge Jingguang , Li Leiming
Published: April 2023

Purpose

Family farms are seen as a powerful force for rural development, and they are gaining more and more research attention. This study aims to explore the relationship between the social networks of family farms and the dual innovation of the family farm business model from the perspective of entrepreneurial orientation.

Design/methodology/approach

Using a questionnaire survey of 169 family farms in Qingdao, China, descriptive and inferential statistics were used to analyze the data collected. The study hypothesis was tested using inferential tests (regression analysis).

Findings

The study results show that innovative, efficiency- and novelty-based business models facilitated by social networks have a favorable and significant impact on the performance of family farms. Furthermore, the relationship between social networks and new business model creation is positively influenced by an entrepreneurial orientation.

Originality/value

This study is distinctive in that it examines the mechanisms underlying family farm growth from an entrepreneurial standpoint, classifying family farm social networks for the first time into social, market and governmental categories and looking at their impact on the creation of new business models. In addition, it looks into the relationship between the innovation and social network aspect of the family farm business model from an entrepreneurial perspective, offering fresh insight into this connection. It also examines the family farm business model’s connection to innovation and social networks from an entrepreneurial standpoint, providing new insight into this relationship.