bluuebunny/crossref_metadata_2025 huggingface dataset:
Motor Imagery and Pain Processing in Patients with Entrapment Neuropathies
Authors: Matesanz-García Luis , Fernández-Chamorro Laura , Rubio-Vallejo Alberto , Cecilia-López David , Cuenca-Martínez Ferran , Di-Bonaventura Silvia , Fernández-Carnero Josué
Published: September 2023

Objectives:

1) To assess the ability to generate both kinesthetic and visual motor imagery in participants with carpal tunnel syndrome (CTS), compared with asymptomatic participants. 2) To assess the influence of psychophysiological and functional variables in the motor imagery (MI) process.

Methods:

20 patients with unilateral CTS and 18 healthy subjects were recruited. an observational case-control study with a non-probability sample was conducted to assess visual and kinesthetic movement imagery ability and psychophysiological variables in patients with CTS compared to asymptomatic participants in a control group (CG). The trial was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

Results:

CTS patients have more difficulties in generating visual motor images compared to asymptomatic subjects (t=−2.099; P<.05; d=0,70). They need more time to complete the mental tasks (visual, t=−2.424; P<.05 and kinesthetic t=−2.200; P<.05). A negative correlation was found between the ability to imagine and functional deficits (r=−0.569; P=0.021), for the kinesthetic subscale and temporal summation (r=−0.515; P=<0.5). A positive correlation was found between pain pressure threshold homolateral (PPT-homolateral) and time to generate the visual mental imagens (r=0.537; P<.05).

Discussion:

CTS patients have greater difficulty generating motor images. Patients also spend more time during mental tasks. CTS patients present a relationship between temporal summation and the capacity to generated kinesthetic images. In addition, the CST patients presented a correlation between chronometry mental tasking and the mechanical hyperalgesia.
Reverse Obliquity Intertrochanteric Femur Fractures: Technical Tips to Avoid Failure
Authors: Sekimura Troy , Son Sung Jun , Lee Christopher
Published: September 2023

Reverse obliquity intertrochanteric femur fractures represent a substantial proportion of all trochanteric hip fractures. These challenging fracture patterns are unique, with their primary fracture plane from distal-lateral to proximal-medial. The use of modern cephalomedullary fixation has yielded successful results, although technical factors including avoiding malreduction and preventing collapse remain challenging. The use of adjunctive techniques including cerclage wires, colinear clamps, and mini-fragment plates can facilitate reduction efforts. The purpose of this article was to review technical tips and common pitfalls in the operative treatment of reverse obliquity intertrochanteric femur fractures.
Can we change automatic processes: the influence of social priming on alcohol attentional bias
Authors: Cantarutti Stephen A. , Pothos Emmanuel M. , Ziori Eleni , Tapper Katy
Published: September 2023

The Stroop Effect has been linked to social concept priming, suggesting that the latter may trigger automatic behaviour aligned with the primed concept. This study examined the effects of social priming on alcohol attentional bias, with a sample of mostly light drinkers; it used a social priming task and an alcohol-Stroop test to measure participants’ response times (RTs) before and after they had been socially primed. Participants were separated into one of three social priming conditions: Neutral, Alcohol Addiction, and Alcohol Preoccupation. A mixed ANOVA was run to determine whether participants’ RTs to alcohol-related stimuli, “rather than to neutral sitmuli,” slowed significantly after the alcohol interference tasks, relative to the neutral interference task, suggesting an alcohol attentional bias had been induced by the social priming exercise. Key interaction terms did not reveal such an interaction, but rather a general slowing down (for both neutral and alcohol stimuli), in the Alcohol conditions, relative to the Neutral one. As a result, we can conclude that while we did not induce an alcohol-specific bias in participants, we did discover a generalised interference effect, following alcohol-related social priming tasks.
High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL
Authors: Hengeveld Paul J. , Kolijn P. Martijn , Demmers Jeroen A.A. , Doff Wouter , Dubois Julie M.N. , Rijken Melissa , Assmann Jorn L.J.C. , van der Straten Lina , Boiten Henk Jan , Gussinklo Kirsten J. , Valk Peter J.M. , Faber Laura M. , Westerweel Peter E. , Kater Arnon P. , Levin Mark-David , Langerak Anton W.
Published: September 2023

It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.
Factors Predicting Loss of Best-Corrected Visual Acuity After Hyperopic Laser-Assisted In Situ Keratomileusis
Authors: Mimouni Michael , Kaiserman Igor , Gutkovitch Elena , Ben-Shaul Or , Lavy Itay , Sela Tzahi , Munzer Gur , Sorkin Nir
Published: September 2023

Purpose:

The aim of this study was to identify risk factors for the loss of corrected distance visual acuity (CDVA) after uncomplicated hyperopic laser-assisted in situ keratomileusis (LASIK).

Methods:

A retrospective study including hyperopic patients who underwent microkeratome-assisted LASIK between January 2000 and December 2019 at Care-Vision Laser Centers, Tel-Aviv, Israel. Loss of CDVA was defined as ≥ 2 lines (0.20 logarithm of the minimum angle of resolution [logMAR] increase). Excluded were patients who had loss of CDVA because of intraoperative or postoperative complications or developed cataract at their final visit.

Results:

Overall, 1998 eyes of 1998 patients were included in the study, of which 35 eyes (1.75%) had CDVA loss at final follow-up (mean 387 days). The vision-loss group had a significantly greater spherical treatment (3.4 vs. 2.8 D, P = 0.02), ablation depth (69.4 vs. 53.8 μm, P = 0.01), a higher proportion of treatments with a smaller optic zone (6.0 mm) (31.4% vs. 13.4%, P = 0.002), treatment with the EX200 (Alcon) excimer rather than the EX500 (Alcon) (74.3% vs. 39.0%, P < 0.001), and treatment with the Moria M2-90 microkeratome rather than the Moria Sub-Bowman’s keratomileusis (SBK) microkeratome (65.7% vs. 29.6%, P < 0.001). In multivariate binary logistic regression, factors that remained significant predictors of CDVA loss were a greater spherical treatment (per 1 D treatment, odds ratio = 1.42, 95% CI, 1.11–1.81, P = 0.004) and the use of the Moria M2-90 microkeratome (odds ratio = 4.66, 95% CI, 2.30–9.45, P < 0.001).

Conclusions:

In patients undergoing uncomplicated hyperopic LASIK, a greater spherical hyperopic treatment is associated with a higher risk for vision loss. Transition to a newer microkeratome model significantly reduced vision loss rate.
Corneal Epithelial Cell Density Is Reduced in Young Adults With Conjunctival Ultraviolet Autofluorescence
Authors: Bhattacharya Pradipta , Edwards Katie , Harkin Damien , Schmid Katrina L.
Published: September 2023

Purpose:

The aim of this study was to investigate the effects of chronic ultraviolet (UV) radiation exposure on the corneal microstructure using conjunctival UV autofluorescence (CUVAF) as a marker of exposure.

Methods:

Young healthy adults aged 18 to 35 years were recruited. Participant's demographics and sun exposure behavior were recorded using questionnaires. Images of the bulbar conjunctiva from the right eye were captured and analyzed for the CUVAF area. Corneal microstructure was assessed by in vivo confocal microscopy and anterior segment optical coherence tomography. The presence of palisades of Vogt in all 4 limbal quadrants was recorded.

Results:

CUVAF was observed in 31 of 52 eyes (60%), with a mean (±SD) nasal, temporal, and total CUVAF area of 5.39 ± 4.16 mm2, 4.29 ± 4.27 mm2, and 9.67 ± 7.01 mm2, respectively. Individuals with CUVAF were significantly more likely to report undertaking moderate-intensity to high-intensity outdoor exercise (P = 0.021). Individuals with CUVAF were less likely to have visible nasal and temporal palisades of Vogt (P = 0.011). Corneal basal cell densities anterior to the nerve whorl (P < 0.001) and nasally (P = 0.005) were lower in individuals with CUVAF. Wing cell density anterior to the nerve whorl was lower in individuals with CUVAF (P = 0.011). No significant changes in the central and limbal corneal epithelial thickness were observed.

Conclusions:

Significant reductions in corneal epithelial cell density were observed in individuals with CUVAF, a biomarker of chronic UV exposure. This observation suggests that chronic UV exposure is damaging to the corneal microstructure.
Mitapivat: A Quinolone Sulfonamide to Manage Hemolytic Anemia in Adults With Pyruvate Kinase Deficiency
Authors: Wills Josef , Horenstein Melissa , Kim Alicia , Silva Matthew A. , Dima Lorena
Published: September 2023

Background:

Pyruvate kinase (PK) deficiency is a rare enzyme-linked glycolytic defect resulting in mild-to-severe chronic persistent erythrocyte hemolysis. The disease is an autosomal recessive trait caused by mutations in the PK liver and red blood cell gene characterized by insufficient erythrocyte PK activity. PK deficiency is most diagnosed in persons of northern European descent and managed with packed red blood cell transfusions, chelation, and splenectomy with cholecystectomy. Mitapivat is the first approved therapy indicated for hemolytic anemia in adults with PK deficiency with the potential for delaying splenectomy in mild–moderate disease.

Mechanism of Action, Pharmacodynamics, and Pharmacokinetics:

Mitapivat is a PK activator that acts by allosterically binding to the PK tetramer and increases PK activity. The red blood cell form of PK is mutated in PK deficiency, which leads to reduced adenosine triphosphate, shortened red blood cell lifespan, and chronic hemolysis. The half-life of elimination is 3–5 hours, with 73% bioavailability, 98% plasma protein binding, and a median duration of response of 7 months.

Clinical Trials:

Mitapivat has been investigated through various clinical trials for different therapeutic indications. Pivotal trials that serve the primary focus throughout this article are ACTIVATE, ACTIVATE-T, and RISE. ACTIVATE is a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of mitapivat in adult patients who were not receiving regular blood transfusions. Contrarily, ACTIVATE-T explored the safety and efficacy of mitapivat in adults with PK deficiency who received regular blood transfusions. Both trials demonstrated favorable use of mitapivat in PK deficiency. Focusing on another indication, the ongoing RISE trial investigates the optimal dosage of mitapivat in sickle cell disease.

Therapeutic Advance:

Mitapivat is an appropriate treatment for adults with PK deficiency requiring transfusions and may be considered for patients with symptomatic anemia who do not require transfusions and/or PK deficiency with compensated hemolysis without overt anemia.
Hospital Performance Under Alternative Readmission Measures Incorporating Observation Stays
Authors: Sabbatini Amber K. , Parrish Canada , Liao Joshua M. , Wright Brad , Basu Anirban , Kreuter William , Joynt-Maddox Karen E.
Published: September 2023

Objective:

To determine the extent to which counting observation stays changes hospital performance on 30-day readmission measures.

Methods:

This was a retrospective study of inpatient admissions and observation stays among fee-for-service Medicare enrollees in 2017. We generated 3 specifications of 30-day risk-standardized readmissions measures: the hospital-wide readmission (HWR) measure utilized by the Centers for Medicare and Medicaid Services, which captures inpatient readmissions within 30 days of inpatient discharge; an expanded HWR measure, which captures any unplanned hospitalization (inpatient admission or observation stay) within 30 days of inpatient discharge; an all-hospitalization readmission (AHR) measure, which captures any unplanned hospitalization following any hospital discharge (observation stays are included in both the numerator and denominator of the measure). Estimated excess readmissions for hospitals were compared across the 3 measures. High performers were defined as those with a lower-than-expected number of readmissions whereas low performers had higher-than-expected or excess readmissions. Multivariable logistic regression identified hospital characteristics associated with worse performance under the measures that included observation stays.

Results:

Our sample had 2586 hospitals with 5,749,779 hospitalizations. Observation stays ranged from 0% to 41.7% of total hospitalizations. Mean (SD) readmission rates were 16.6% (5.4) for the HWR, 18.5% (5.7) for the expanded HWR, and 17.9% (5.7) in the all-hospitalization readmission measure. Approximately 1 in 7 hospitals (14.9%) would switch from being classified as a high performer to a low performer or vice-versa if observation stays were fully included in the calculation of readmission rates. Safety-net hospitals and those with a higher propensity to use observation would perform significantly worse.

Conclusions:

Fully incorporating observation stays in readmission measures would substantially change performance in value-based programs for safety-net hospitals and hospitals with high rates of observation stays.
Associations Between Pro/Anti-Tobacco Media and Messaging Exposure and Knowledge and Support of Smoke-Free Policy Among Adults in Armenia and Georgia
Authors: LoParco Cassidy R. , Sargsyan Zhanna , Topuridze Marina , Sturua Lela , Kegler Michelle C. , Petrosyan Varduhi , Torosyan Arevik , Grigoryan Lilit , Bazarchyan Alexander , Berg Carla J.
Published: September 2023

Context:

Despite high smoking rates, Armenia and Georgia recently adopted smoke-free policies (2022 and 2018).

Objective:

We examined associations between exposure to pro-tobacco media (news opposing smoke-free policies; cigarette, e-cigarette, heated tobacco product [HTP] advertisements) and anti-tobacco media (media, community-based action) and (1) knowledge that the policies applied to alternative tobacco products (ATPs), and (2) support for the policies applying to ATPs and various settings.

Design:

We analyzed 2022 survey data.

Setting:

Data were from 28 communities in Armenia and Georgia.

Participants:

The sample comprised 1468 adults (31.6% past-month smokers).

Methods:

We conducted multivariable regressions, controlling for country and sociodemographics.

Results:

Participants were knowledgeable that the policy applied to ATPs (79.2%) and supportive of them applying to ATPs and various settings (means = 3.43 and 3.00; 1-4 = strongly support). Greater exposure to anti-tobacco media/community-based action correlated with more likely knowing that the policies applied to ATPs and greater support of the policies applying to various settings; HTP advertisement exposure correlated with less support of the policies applying to various settings. Less exposure to news opposing smoke-free policies and greater exposure to media supporting such policies correlated with greater support of the policies applying to ATPs.

Conclusions:

Media and community-based action may promote smoke-free policy knowledge and support. HTP advertisements may uniquely undermine smoke-free policies.
scEGOT: Single-cell trajectory inference framework based on entropic Gaussian mixture optimal transport
Authors: Yachimura Toshiaki , Wang Hanbo , Imoto Yusuke , Yoshida Momoko , Tasaki Sohei , Kojima Yoji , Yabuta Yukihiro , Saitou Mitinori , Hiraoka Yasuaki
Published: September 2023

Time-series scRNA-seq data have opened a door to elucidate cell differentiation, and in this context, the optimal transport theory has been attracting much attention. However, there remain critical issues in interpretability and computational cost. We present scEGOT, a comprehensive framework for single-cell trajectory inference, as a generative model with high interpretability and low computational cost. Applied to the human primordial germ cell-like cell (PGCLC) induction system, scEGOT identified the PGCLC progenitor population and bifurcation time of segregation. Our analysis showsTFAP2Ais insufficient for identifying PGCLC progenitors, requiringNKX1-2. Additionally,MESP1andGATA6are also crucial for PGCLC/somatic cell segregation. These findings shed light on the mechanism that segregates PGCLC from somatic lineages. Notably, not limited to scRNA-seq, scEGOT’s versatility can extend to general single-cell data like scATAC-seq, and hence has the potential to revolutionize our understanding of such datasets and, thereby also, developmental biology.
Differential Expression Analysis of miRNAs and mRNAs in Epilepsy Uncovers Potential Biomarkers
Authors: El Abed Fatma , Baraket Ghada , Nyamari Marion N. , Naitore Careen , Awe Olaitan I.
Published: September 2023

Epilepsy is a neurological disease defined by episodes of synchronous convulsions. Recently, miRNAs have been proven as promising biomarkers for multiple ailments like tumors and neurodegenerative disorders; their role in epilepsy is still unclear. This study aimed to understand the involvement of miRNAs in the disease and to detect the potential biomarkers for the treatment of epilepsy.

RNA transcripts, and miRNA from brain tissue and plasma small extracellular vesicle samples of epileptogenic patients from 6 different studies downloaded from the NCBI sequence read archive (SRA) were analyzed with particular interest in genes that might be involved in epilepsy. Alignment of transcripts to hg38 was done using HISAT2 and the raw counts were generated using HTseq-count. miRNA genes were identified using miRDeep2. EdgeR and GEO2 were used to identify DEGs for both mRNA and miRNA datasets. Finally, TargetScan web tool was used to predict potentially significantly expressed mRNA target genes using the identified miRNA genes.

Analysis of these datasets revealed target genes in epilepsy and their associated miRNAs. SIX4 and KCTD7 were under-expressed in epileptogenic zones of the brain compared to the irritative zone. CABP1, SLC20A1 and SLC35G1 were under-expressed in brain tissues. Hsa-miR-27a-3p was identified as a regulator of CABP1 expression, hsa-let-7b-5p regulates SLC20A1 while hsa-miR-15a-5p and hsa-miR-195-5p are regulators for SLC35G1. These observations highlight the importance of miRNAs as novel biomarkers of epilepsy.

Understanding and controlling these regulatory interactions may help to define potential therapies for epilepsy. This would also help to better understand miRNA-mediated gene regulation in epilepsy.
A metabolic perspective on polyploid invasion and the emergence of life histories: insights from a mechanistic model
Authors: Milosavljevic Silvija , Kauai Felipe , Mortier Frederik , Van de Peer Yves , Bonte Dries
Published: September 2023

Whole genome duplication (WGD, polyploidization), the fusion of unreduced gametes, has been identified as a driver of genetic and phenotypic novelty. Unreduced gamete formation is common in a wide range of species, but surprisingly, few polyploidization events have shown to be ecologically successful. Positive density dependence, by minority cytotype exclusion, and niche shifts are currently considered the most important drivers behind ecological failure or success. Genome doubling also results in increased cell sizes and metabolic expenses which, on their own may be sufficient to drive polyploid establishment in stable environments where their simple ancestors thrive.

We developed a mechanistic model, motivated by data from natural plant polyploid species, to test whether realistic changes in size and metabolic efficiency allow polyploids to coexist with, or even invade, their original diploid population. Central to the model is metabolic efficiency, a functional trait that determines how energy gained from size-dependent photosynthetic metabolism is allocated to basal metabolism, somatic growth and reproductive growth.

Polyploid invasion was observed across a wide range of metabolic efficiency differences between polyploids and their ancestors. Higher metabolic efficiency facilitates polyploid invasion, but even with minor deficits, establishment was facilitated by recurrent formation in these settings of high competition for nutrients. Interestingly, a long-term coexistence with the diploid ancestor was found to be possible only within a narrow range of this parameter space. Perenniality of the plants did not qualitatively affect these insights. Feedbacks between size-dependent metabolism and allocation of gained energy generated eventually size and age differences, resulting in intra- and intercytotype competition for nutrients as the major force for population dynamics. We thus demonstrate that changes in metabolic efficiency on their own are sufficient to impose establishment, but these advantages do not need to be substantial.
Algebraic Invariants for Inferring 4-leaf Semi-directed Phylogenetic networks
Authors: Martin Samuel , Moulton Vincent , Leggett Richard M.
Published: September 2023

A core goal of phylogenomics is to determine the evolutionary history of a set of species from biological sequence data. Phylogenetic networks are able to describe more complex evolutionary phenomena than phylogenetic trees but are more difficult to accurately reconstruct. Recently, there has been growing interest in developing methods to infer semi-directed phylogenetic networks. As computing such networks can be computationally intensive, one approach to building such networks is to puzzle together smaller networks. Thus, it is essential to have robust methods for inferring semi-directed phylogenetic networks on small numbers of taxa. In this paper, we investigate an algebraic method for performing phylogenetic network inference from nucleotide sequence data on 4-leaved semi-directed phylogenetic networks by analysing the distribution of leaf-pattern probabilities. On simulated data, we found that we can correctly identify with high accuracy semi-directed networks as sequences approach 10Mbp in length, and that we are able to use our approach to identify tree-like evolution and determine the underlying tree. We also applied our approach to published transcriptome data from swordtail fish to compare its performance with a pseudolikelihood method for inferring semi-directed networks.
A Unified Framework to Analyze Transposable Element Insertion Polymorphisms using Graph Genomes
Authors: Groza Cristian , Chen Xun , Wheeler Travis J. , Bourque Guillaume , Goubert Clément
Published: September 2023

Transposable Elements are ubiquitous mobile DNA sequences evolving among their hosts’ genomes, generating insertion polymorphisms that contribute to genomic diversity. We present GraffiTE, a flexible pipeline to analyze polymorphic mobile elements. By integrating state-of-the-art structural variant detection algorithms and graph genomes, GraffiTE identifies polymorphic mobile elements from genomic assemblies and/or long-read sequencing data, and genotypes these variants using short or long read sets. Benchmarking on simulated and real datasets reports high precision and recall rates. GraffiTE is designed to allow non-expert users to perform comprehensive analyses, including in models with limited transposable element knowledge and is compatible with various sequencing technologies. GraffiTE is freely available athttps://github.com/cgroza/GraffiTE. Here, we demonstrate the versatility of GraffiTE by analyzing human,Drosophila melanogaster,maize, andCannabis sativapangenome data. These analyses reveal the landscapes of polymorphic mobile elements and their frequency variations across individuals, strains, and cultivars.
HiTaxon: A hierarchical ensemble framework for taxonomic classification of short reads
Authors: Verma Bhavish , Parkinson John
Published: September 2023

Whole microbiome DNA and RNA sequencing (metagenomics and metatranscriptomics) are pivotal to determining functional roles within microbial communities. A key challenge in analysing these complex datasets, typically composed of tens of millions of short reads, is accurately classifying reads to their taxon of origin. Traditional reference-based short-read classification tools are compromised by reference database biases, leading to interest in classifiers leveraging machine learning (ML) algorithms. While ML classifiers have shown promise, they still lag reference-based tools in species-level classification. To address this performance gap, attention has turned to approaches that incorporate the hierarchical structure of taxonomic classifications, albeit with limited results. Here we introduce HiTaxon, a hierarchical framework for creating ensembles of reference-dependent and ML classifiers. HiTaxon facilitates data collection and processing, reference database construction and model training to streamline ensemble creation. We show that databases created by HiTaxon improve the species-level performance of reference-dependent classifiers, while reducing their computational overhead. Additionally, through exploring hierarchical methods for HiTaxon, we highlight that our custom hierarchical ML approach improves species-level classification relative to traditional strategies. Finally, we demonstrate the improved performance of our hierarchical ensemble over current state-of-the-art classifiers in species classification using datasets comprised of either simulated or experimentally-derived reads.
TGF-β3 increases the severity of radiation-induced oral mucositis and salivary gland fibrosis in a mouse model
Authors: Hanson Ingunn , Juvkam Inga Solgård , Zlygosteva Olga , Søland Tine Merete , Galtung Hilde Kanli , Malinen Eirik , Jeppesen Edin Nina Frederike
Published: September 2023

Purpose

Toxicities from head and neck (H&N) radiotherapy (RT) may affect patient quality of life and can be dose-limiting. Proteins from the transforming growth factor beta (TGF-β) family are key players in the fibrotic response. While TGF-β1 is known to be pro-fibrotic, TGF-β3 has mainly been considered anti-fibrotic. Moreover, TGF-β3 has been shown to act protective against acute toxicities after radio- and chemotherapy. In the present study, we investigated the effect of TGF-β3 treatment during fractionated H&N RT in a mouse model.

Materials and methods

30 C57BL/6J mice were assigned to three treatment groups. The RT + TGF-β3 group received local fractionated H&N RT with 66 Gy over five days, combined with TGF-β3-injections at 24-hour intervals. Animals in the RT reference group received identical RT without TGF-β3 treatment. The non-irradiated control group was sham-irradiated according to the same RT schedule. In the follow-up period, body weight and symptoms of oral mucositis and lip dermatitis were monitored. Saliva was sampled at five time points. The experiment was terminated 105 days after the first RT fraction. Submandibular and sublingual glands were preserved, sectioned, and stained with Masson’s trichrome to visualize collagen.

Results

A subset of mice in the RT + TGF-β3 group displayed increased severity of oral mucositis and increased weight loss, resulting in a significant increase in mortality. Collagen content was significantly increased in the submandibular and sublingual glands for the surviving RT + TGF-β3 mice, compared with non-irradiated controls. In the RT reference group, collagen content was significantly increased in the submandibular gland only. Both RT groups displayed lower saliva production after treatment compared to controls. TGF-β3 treatment did not impact saliva production.

Conclusions

When repeatedly administered during fractionated RT at the current dose, TGF-β3 treatment increased acute H&N radiation toxicities and increased mortality. Furthermore, TGF-β3 treatment may increase the severity of radiation-induced salivary gland fibrosis.
Polyimide-Based Flexible Multi-Electrode Arrays: Synthesis, Microfabrication, andin-vivoValidation
Authors: Kumar Kshitij , Deshpande Kaustubh , Kalur Naveen , Chauhan Garima , Chugh Deepti , Ganesh Subramaniam , Ramakrishnan Arjun
Published: September 2023

Thin film neural microelectrodes are popularly being used in brain-computer interfaces and tools for neurosurgical interventions [8]. Among the various thin films used, polyimide stands out as an excellent material for substrate passivation due to its chemical inertness, biocompatibility, mechanical flexibility, and superior dielectric properties. While polyimide is extensively used as a substrate in thin film neural interfaces, the lack of availability of a clinical-grade polyimide limits their use in human clinical applications. This paper presents a comprehensive solution by developing an ISO-10993-11-approved polyamic acid for fabricating thin-film polyimide microelectrodes. Benchtop tests and in-vivo experiments in anesthetized mice demonstrate the potential of this synthesized polyamic acid and microfabrication processes for commercialization in clinical settings, particularly for brain-computer interfaces and invasive neural microelectrodes.
Conserved B cell signaling, activation, and differentiation in porcine jejunal and ileal Peyer's patches despite distinct immune landscapes
Authors: Wiarda Jayne E , Shircliff Adrienne L , Stasko Judith B , Sivasankaran Sathesh K , Ackermann Mark R , Loving Crystal L
Published: September 2023

Peyers patches (PPs) are B cell-rich sites of immune induction in the intestine, yet B cell signaling, activation, and differentiation associated with PPs are poorly defined. Single-cell and spatial transcriptomics were completed to study B cells from porcine jejunum and ileum containing PPs. Intestinal locations had distinct immune landscapes, including more follicular B cells in ileum and increased MHC-II-encoding gene expression in jejunal, non-resting B cells. Despite distinct landscapes, conserved B cell dynamics were detected across intestinal locations. B cell signaling to CD4+ macrophages that are putative phagocytic, cytotoxic, effector cells and deduced routes of B cell activation/differentiation, including resting B cells migrating into follicles to replicate/divide or differentiate into antibody-secreting cells residing in intestinal crypts, were conserved across locations. A six-biomarker panel recapitulated transcriptomics results of B cell phenotypes, frequencies, and spatial locations via ex vivo/in situ staining of gene/protein targets. Findings convey conserved B cell signaling, activation, and differentiation, despite location-specific immune environments in jejunum and ileum containing PPs. Results establish a benchmark of B cell dynamics for understanding intestinal immune induction important to promoting gut and overall health.
Tuning gene expression to music: the compensatory effect of music on age-related cognitive disorders
Authors: Gómez-Carballa Alberto , Navarro Laura , Pardo-Seco Jacobo , Bello Xabier , Pischedda Sara , Viz-Lasheras Sandra , Camino-Mera Alba , Currás María José , Ferreirós Isabel , Mallah Narmeen , Rey-Vázquez Sara , Redondo Lorenzo , Dacosta-Urbieta Ana , Caamaño-Viña Fernando , Rivero-Calle Irene , Rodriguez-Tenreiro Carmen , Martinón-Torres Federico , Salas Antonio
Published: September 2023

Extensive literature has explored the beneficial effects of music in age-related cognitive disorders (ACD), but limited knowledge exists regarding its impact on gene expression. We analyzed transcriptomes of ACD patients and healthy controls, pre-post a music session (n=60), and main genes/pathways were compared to those dysregulated in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) as revealed by a multi-cohort study (n=1269 MCI/AD and controls). Music was associated with 2.3 times more whole-genome gene expression, particularly on neurodegeneration-related genes, in ACD than controls. Co-expressed gene-modules and pathways analysis demonstrated that music impacted autophagy, vesicle and endosome organization, biological processes commonly dysregulated in MCI/AD. Notably, the data indicated a strong negative correlation between musically-modified genes/pathways in ACD and those dysregulated in MCI/AD. These findings highlight the compensatory effect of music on genes/biological processes affected in MCI/AD, providing insights into the molecular mechanisms underlying the benefits of music on these disorders.
Inducer of CBF Expression 1 (ICE1) Promotes Cold-enhanced Immunity by Directly Activating Salicylic Acid Signaling
Authors: Li Shaoqin , He Li , Yang Yongping , Zhang Yixin , Han Xiao , Hu Yanru , Jiang Yanjuan
Published: September 2023

Cold stress affects plant immune responses, and this process may involve the salicylic acid (SA) signaling pathway. However, the underlying mechanism by which low temperature signals coordinate with SA signaling to regulate plant immunity remains not fully understood. Here, we found that low temperatures enhanced the disease resistance of Arabidopsis againstPseudomonas syringaepv.tomato(Pst) DC3000. This process required Inducer of CBF expression 1 (ICE1), the core transcription factor in cold-signal cascades. ICE1 physically interacted with Non-expresser ofPRgenes 1 (NPR1), the master regulator of the SA signaling pathway. Enrichment of ICE1 on thePR1promoter and its ability to transcriptionally activatePR1were enhanced by NPR1. Further analyses revealed that cold stress signals cooperate with SA signals to facilitate plant immunity against pathogen attack in an ICE1-dependent manner. Cold treatment promoted interactions of NPR1 and TGA3 with ICE1, and increased the ability of the ICE1–TGA3 complex to transcriptionally activatePR1. Together, our results characterize a previously unrecognized role of ICE1 as an indispensable regulatory node linking low temperature activated- and SA-regulated immunity. Discovery of a crucial role of ICE1 in coordinating multiple signals associated with immunity broadens our understanding of plant–pathogen interactions.
Seasonal migration alters energetic trade-off optimization and shapes life history
Authors: Pierce Allison K. , Yanco Scott W. , Wunder Michael B.
Published: September 2023

Trade-offs between current and future reproduction manifest as a set of co-varying life history and metabolic traits, collectively referred to as “pace of life” (POL). Seasonal migration modulates realized environmental dynamics and putatively affects realized POL, however, the mechanisms by which migratory behavior shapes POL remain unclear. We explored how migratory behavior interacts with environmental and metabolic dynamics to shape POL. Using an individual based model of movement and metabolism we compared fitness-optimized trade-offs among migration strategies. We found annual experienced seasonality and migration distance primarily drove POL differentiation through developmental and migration phenology trade-offs. Similarly, our analysis of empirically-estimated metabolic data from 265 bird species suggested seasonal niche conservatism and migration distance interact to drive POL. We show multiple viable life history strategies are conducive to a migratory lifestyle. Overall, our findings suggest metabolism mediates complex interactions between behavior, environment, and life history.

Authorship statement

AKP and SWY contributed equally to this work. AKP and SWY conceived the project, designed the model, performed analyses, and drafted the manuscript with support from MBW. Simulation and optimization model code written by AKP with input from SWY and MBW. Empirical data analysis and code lead by SWY with input from AKP and MBW. All authors contributed critical input to the manuscript.

Data accessibility statement

All R code for models and analyses are available athttps://doi.org/10.5281/zenodo.10145976andhttps://github.com/allipierce/Pierce_et_al_2023_MigrationPOL. The empirically derived data used in this work are all publicly available. DEB data are available from the Add-My-Pet portal athttps://www.bio.vu.nl/thb/deb/deblab/add_my_pet/. Geographic range data are available from BirdLife International athttp://datazone.birdlife.org/species/requestdis. Niche dissimilarity data came fromhttps://doi.org/10.1111/geb.13722and phylogeny data are available from VertLife athttp://vertlife.org/data/.
Mapping the Single-cell Differentiation Landscape of Osteosarcoma
Authors: Truong Danh D. , Weistuch Corey , Murgas Kevin A. , Deasy Joseph O. , Mikos Antonios G. , Tannenbaum Allen , Ludwig Joseph
Published: September 2023

The genetic and intratumoral heterogeneity observed in human osteosarcomas (OS) poses challenges for drug development and the study of cell fate, plasticity, and differentiation, processes linked to tumor grade, cell metastasis, and survival. To pinpoint errors in OS differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs MSCs toward adipogenic and osteoblastic fates. Incorporating pre-existing chondrocyte data, we applied trajectory analysis and non-negative matrix factorization (NMF) to generate the first human mesenchymal differentiation atlas. This ‘roadmap’ served as a reference to delineate the cellular composition of morphologically complex OS tumors and quantify each cell’s lineage commitment. Projecting these signatures onto a bulk RNA-seq OS dataset unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. Our study takes the critical first step in accurately quantifying OS differentiation and lineage, a prerequisite to better understanding global differentiation bottlenecks that might someday be targeted therapeutically.

Statement of Significance

OS treatment kills proliferating cells without addressing the root cause: dysregulated differentiation. By deconvolving OS tumors by cell type and differentiation archetype, we identified core gene sets linked to cell fate and patient survival. The ability to quantify, and eventually modulate, such archetypes facilitate a novel OS-specific drug-screening strategy.
A Novel Imaging Method (FIM-ID) Reveals that Myofibrillogenesis Plays a Major Role in the Mechanically Induced Growth of Skeletal Muscle
Authors: Jorgenson Kent W. , Hibbert Jamie E. , Sayed Ramy K. A. , Lange Anthony N. , Godwin Joshua S. , Mesquita Paulo H. C. , Ruple Bradley A. , McIntosh Mason C. , Kavazis Andreas N. , Roberts Michael D. , Hornberger Troy A.
Published: September 2023

An increase in mechanical loading, such as that which occurs during resistance exercise, induces radial growth of muscle fibers (i.e., an increase in cross-sectional area). Muscle fibers are largely composed of myofibrils, but whether radial growth is mediated by an increase in the size of the myofibrils (i.e., myofibril hypertrophy) and/or the number of myofibrils (i.e., myofibrillogenesis) is not known. Electron microscopy (EM) can provide images with the level of resolution that is needed to address this question, but the acquisition and subsequent analysis of EM images is a time- and cost-intensive process. To overcome this, we developed a novel method for visualizing myofibrils with a standard fluorescence microscope (FIM-ID). Images from FIM-ID have a high degree of resolution and contrast, and these properties enabled us to develop pipelines for automated measurements of myofibril size and number. After extensively validating the automated measurements, we used both mouse and human models of increased mechanical loading to discover that the radial growth of muscle fibers is largely mediated by myofibrillogenesis. Collectively, the outcomes of this study offer insight into a fundamentally important topic in the field of muscle growth and provide future investigators with a time- and cost-effective means to study it.
Engineering heterothallic strains in fission yeast
Authors: García-Ruano Daniel , Hsu Ian , Leray Baptiste , Billard Bénédicte , Liti Gianni , Coudreuse Damien
Published: September 2023

In poor nitrogen conditions, fission yeast cells mate, undergo meiosis and form spores that are resistant to deleterious environments. Natural isolates ofSchizosaccharomyces pombeare homothallic. This allows them to naturally switch between the twoh-andh+mating types with a high frequency, thereby ensuring the presence of both mating partners in a population of cells. However, alteration of the mating type locus can abolish mating type switching or reduce it to a very low frequency. Such heterothallic strains have been isolated and are common in research laboratories due to the simplicity of their use for Mendelian genetics. In addition to the standard laboratory strains, a large collection of naturalS. pombeisolates is now available, representing a powerful resource for investigating the genetic diversity and biology of fission yeast. However, most of these strains are homothallic, and only tedious or mutagenic strategies have been described to obtain heterothallic cells from a homothallic parent. Here, we describe a simple approach to generate heterothallic strains. It takes advantage of an alteration of the mating type locus that was previously identified in a mating type switching-deficient strain and the CRISPR-Cas9 editing tool, allowing for a one-step engineering of heterothallic cells with high efficiency.

Take away points

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Conventional methods for obtaining heterothallic fission yeast strains are inefficient

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We implemented a streamlined genetic editing approach to engineer heterothallism

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All fission yeast isolates reported in Jeffares et al. 2015 can be engineered

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This method enhances the exploration of genetic diversity in wild fission yeast
Attenuated incubation of ethanol-induced conditioned taste aversion in a model of dependence
Authors: Ramirez Lindsey A , Przybysz Kathryn R , Pitock Joseph R , Starr E Margaret , Yang Hyerim , Glover Elizabeth J
Published: September 2023

Rationale

Preclinical studies report attenuated ethanol-induced conditioned taste aversion (CTA) following chronic ethanol exposure, suggesting that tolerance develops to the aversive properties of ethanol. However, these studies are confounded by pre-exposure to the unconditioned stimulus (US; ethanol), which is well known to hinder conditioning.

Objectives

This study was designed to determine whether chronic ethanol exposure produces tolerance to the aversive properties of ethanol in the absence of a US pre-exposure confound.

Methods

CTA was performed in adult male and female Long-Evans rats by pairing 0.1% ingested saccharin with an intraperitoneal injection of ethanol (1.5 or 2.0 g/kg) or saline. Rats were then rendered ethanol dependent using chronic intermittent ethanol (CIE) vapor exposure. Controls were exposed to room air (AIR). The effect of chronic ethanol on CTA expression and reconditioning were examined following vapor exposure.

Results

Prior to vapor exposure, both sexes developed CTA to a comparable degree with 2.0 g/kg producing greater CTA than 1.5 g/kg ethanol. Following vapor exposure, AIR controls exhibited an increase in CTA magnitude compared to pre-vapor levels. This effect was absent in CIE-exposed rats. These group differences were eliminated upon re-conditioning after vapor exposure.

Conclusions

These data suggest that chronic ethanol does not facilitate tolerance to the aversive properties of ethanol but rather, attenuates incubation of ethanol-induced CTA. Loss of CTA incubation suggests that CIE exposure disrupts circuits encoding aversion.
After the Infection: A Survey of Pathogens and Non-communicable Human Disease
Authors: Lape Michael , Schnell Daniel , Parameswaran Sreeja , Ernst Kevin , O’Connor Shannon , Salomonis Nathan , Martin Lisa J. , Harnett Brett M. , Kottyan Leah C. , Weirauch Matthew T.
Published: September 2023

There are many well-established relationships between pathogens and human disease, but far fewer when focusing on non-communicable diseases (NCDs). We leverage data from The UK Biobank and TriNetX to perform a systematic survey across 20 pathogens and 426 diseases, primarily NCDs. To this end, we assess the association between disease status and infection history proxies. We identify 206 pathogen-disease pairs that replicate in both cohorts. We replicate many established relationships, includingHelicobacter pyloriwith several gastroenterological diseases and connections between Epstein-Barr virus with multiple sclerosis and lupus. Overall, our approach identified evidence of association for 15 pathogens and 96 distinct diseases, including a currently controversial link between human cytomegalovirus (CMV) and ulcerative colitis (UC).

We validate this connection through two orthogonal analyses, revealing increased CMV gene expression in UC patients and enrichment for UC genetic risk signal near human genes that have altered expression upon CMV infection. Collectively, these results form a foundation for future investigations into mechanistic roles played by pathogens in NCDs. All results are easily accessible on our website,https://tf.cchmc.org/pathogen-disease.