bluuebunny/crossref_metadata_2025 huggingface dataset:
Corneal Stromal Densitometry Evolution in a Clinical Model of Cellular Therapy for Advanced Keratoconus
Authors: El Zarif Mona , Alió del Barrio Jorge L. , Mingo David , A Jawad Karim , Alió Jorge L.
Published: October 2022

Purpose:

The aim of this study was to report the corneal densitometry (CD) evolution studied by Scheimpflug tomography, anterior segment optical coherence tomography (AS-OCT), and confocal microscopy changes, in patients with advanced keratoconus included in a clinical experience of advanced cell therapy using autologous humans adipose-derived adult stem cells (ADASCs) and corneal decellularized and ADASCs-recellularized human donor corneal laminas.

Methods:

This study is an interventional prospective, consecutive, randomized, comparative series of cases. Fourteen patients with keratoconus were randomly distributed into 3 groups for 3 types of surgical interventions: group 1 (G-1), autologous ADASC implantation (n = 5); group 2 (G-2), decellularized human corneal stroma (n = 5); and group 3 (G-3), autologous ADASCs + decellularized human corneal stroma (n = 4). Participants were assessed with Scheimpflug-based Oculus Pentacam CD module, AS-OCT (Visante; Carl Zeiss), and confocal microscopy (HRT3 RCM Heidelberg).

Results:

A significant improvement of 1 to 2 logMAR lines in all visual parameters in the 3 groups was obtained. The central and total CD were statistically significantly higher in G-2 compared with G-1 and G-3 compared with G-1 at the studied annular zones centered on the corneal apex (0–2, 2–6, and 6–10 mm). There was statistical significance higher in G-3 compared with G-2 at the central corneal stroma at 0–2 and 2–6 mm. The confocal microscopy findings and the AS-OCT reflected the densitometry changes.

Conclusions:

The intrastromal implantation of ADASCs produced very subtle changes in CD at the level of the central corneal stroma. However, the intrastromal implantation of decellularized corneal laminas increases it slightly, but with lower values than the implantation of recellularized laminas with ADASCs.
Glucose Metabolism in Midlife Is Associated With Preceding 30-Year Employment Trajectories
Authors: Varanka-Ruuska Tuulia , Rautio Nina , Sebert Sylvain , Ala-Mursula Leena
Published: October 2022

Objective

The aim of the study is to evaluate how glucose metabolism in midlife is related to preceding 30-year-long employment trajectories.

Methods

In the Northern Finland Birth Cohort 1966, we compared glucose metabolism at 46 to employment trajectories (previously defined for men and women and named as high-educated, traditional, self-employed, delayed, and floundering;n= 6399).

Results

Compared with individuals in high-educated trajectories, odds ratios for type 2 diabetes (T2D, 95% confidence interval) in traditional and floundering trajectories in men were 1.65 (1.02–2.68) and 2.42 (1.38–4.23) and in women 1.89 (1.04–3.43) and 2.60 (1.46–4.62), respectively. In self-employed trajectory in women, odds ratios for prediabetes and T2D were 1.66 (1.09–2.51) and 2.47 (1.21–5.04).

Conclusions

The highest risks for T2D in midlife were associated after traditional and floundering trajectories in men and women and after self-employment trajectory in women.
18F-MFBG PET/CT Is an Effective Alternative of 68Ga-DOTATATE PET/CT in the Evaluation of Metastatic Pheochromocytoma and Paraganglioma
Authors: Wang Peipei , Li Tuo , Cui Yuying , Zhuang Hongming , Li Fang , Tong Anli , Jing Hongli
Published: October 2022

Purpose

The current guidelines state that the functional imaging choice in the evaluation of metastatic pheochromocytoma and paraganglioma (PPGL) is 68Ga-DOTATATE PET/CT. 18F–meta-fluorobenzylguanidine (18F-MFBG) is a new PET tracer and an analog of meta-iodobenzylguanidine (MIBG). This study aimed to compare 18F-MFBG and 68Ga-DOTATATE PET/CT in patients with metastatic PPGL.

Patients and Methods

Twenty-eight patients with known metastatic PPGL were prospectively recruited for this study. All patients underwent both 18F-MFBG and 68Ga-DOTATATE PET/CT studies within 1 week. Lesion numbers detected were compared between these 2 studies.

Results

18F-MFBG PET/CT was positive for detecting metastases in all patients, whereas positive results of 68Ga-DOTATATE PET/CT were in 27 (96.4%) patients. A total of 686 foci of metastatic lesions were detected by both 18F-MFBG and 68Ga-DOTATATE imaging. In addition, 33 foci of abnormal activity were only detected by 18F-MFBG, whereas 16 foci were only shown on 68Ga-DOTATATE PET/CT.

Conclusions

Our data suggest that 18F-MFBG PET/CT is an effective imaging method in the evaluation of metastatic PPGL and could be alternative of 68Ga-DOTATATE PET/CT in this clinical setting.
Warthin-Like Papillary Thyroid Microcarcinoma With Coincidental Ipsilateral Warthin Tumor of the Parotid Gland Detected on 131I-SPECT/US and 18F-PET/US Fusion Imaging
Authors: Werner Anke , Freesmeyer Martin , Bensch Claudia , Eszlinger Markus , Seifert Philipp
Published: October 2022

A 66-year-old woman was referred with an incidental finding of a bilateral papillary thyroid microcarcinoma after thyroidectomy. On the right side, a Warthin-like variant was observed. After radioiodine therapy, whole-body scan revealed an unclear iodine uptake on the right-sided neck. For further clarification, 131I-SPECT/US and 18F-PET/US fusion imaging were performed, unambiguously revealing iodine and glucose uptake within a hypoechoic lesion located in the parenchyma of the right parotid gland. Surgical excision confirmed a Warthin tumor ipsilateral to the Warthin-like variant of the papillary thyroid microcarcinoma. Because the extensive imaging, targeted minimal-invasive surgery was possible.
Management of Orbital Medial Wall Fracture With Endonasal Balloon
Authors: Tedaldi Massimiliano , Vetrano Stefano , Zotos Georgios , Buonaccorsi Sara , Marini Balestra Filippo Maria , Cerulli Giulio , Piccolino Paolo
Published: October 2022

Medial wall fracture of the orbit is a condition that requires surgical correction should the patient presents a series of signs and symptoms such as diplopia and enophthalmos. The classical external approaches for exposure like the transconjunctival or transcutaneous approach have been replaced in specific cases by endoscopic approaches as they are less invasive and they eliminate any risk of potential scarring. Larger defects where the medial wall is comminuted or bony fragments are missing could be reconstructed with permanent autogenous or alloplastic materials. When bony fragments are present, a reduction of the fracture can be performed instead, with only a temporary alloplastic material for support. In this study, the authors discuss our experience regarding the management of orbital medial wall fractures by endoscopic endonasal balloon in 14 patients and describe its indications and contraindications. The authors concluded that the balloon achieves satisfactory mechanical support for the fracture to heal and it can be easily removed on an outpatient basis.
C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes
Authors: Verhoeff Kevin , Marfil-Garza Braulio A. , Dajani Khaled , Bigam David L. , Anderson Blaire , Kin Tatsuya , Lam Anna , O’Gorman Doug , Senior Peter A. , Shapiro A. M. James
Published: October 2022

Background

C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established.

Methods.

We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves.

Results.

We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia (P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2.

Conclusions.

We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.
Comparison of Idiopathic Intracranial Hypertension Patients With and Without Anemia
Authors: Sverdlichenko Irina , Yu Caberry W. , Margolin Edward , Micieli Jonathan A.
Published: October 2022

Background:

Idiopathic intracranial hypertension (IIH) is a condition of elevated intracranial pressure without an identifiable cause. It mostly affects young obese women but has been reported in individuals newly diagnosed with anemia or with chronic anemia. The relationship between anemia and IIH is not well elucidated. This study aims to characterize the course of IIH in anemic patients.

Methods:

Consecutive patients with IIH were recruited from neuro-ophthalmology clinics. Subsequent retrospective chart review obtained information on symptoms, complete blood counts (CBCs), visual acuity, visual fields, and optic disc edema at baseline and follow-up. Anemia was diagnosed by hemoglobin <120 g/L (women) and <130 g/L (men).

Results:

One hundred twenty-three patients with IIH were recruited for this study, and 22.8% (28/123) had anemia. More anemic individuals had mild-to-moderate visual acuity impairment (logarithm of minimum angle of resolution 0.3–1, P = 0.01) and worse automated mean deviation (P = 0.048). The median follow-up time was 47.4 weeks (interquartile range:20.1–91.8). Fifteen of 28 patients with anemia received anemia treatment and showed a trend toward increased hemoglobin. At follow-up, there were no differences in the visual acuity, but patients with anemia had worse automated mean deviation on visual fields (P = 0.045).

Conclusions:

IIH patients with anemia had worse visual function at presentation and worse final visual field parameters. This suggests that CBCs should be obtained for patients with papilledema because it may influence final visual outcome.
Aestuariirhabdus haliotis sp. nov., isolated from abalone viscera and emended description of the genus Aestuariirhabdus
Authors: Zhang Dan-Dan , Xuan Xiao-Qi , Ye Yu-Qi , Wang Ya-Wei , Du Zong-Jun
Published: October 2022

Two novel strains, Z083T and Z084, were isolated from the viscera of abalone, Haliotis discus hannai, sampled in Weihai, PR China. The phenotypic, chemotaxonomic and genomic characteristics of the two strains were studied. The average nucleotide identity (ANI) and digital DNA–DNA hybridization (dDDH) values between the two strains were 99.8 and 98.9 %, respectively, suggesting that the two strains belonged to the same species. The 16S rRNA gene sequence analysis showed 99.8 % similarity between the two strains, while the genome analysis indicated that they were not from one clonal origin. Phylogenetic analysis of 16S rRNA gene sequences showed the two strains belonged to the genus

Aestuariirhabdus

and

Aestuariirhabdus litorea

JCM 32043T was the closest strain (97.5 %). Genomic analysis, including calculations of ANI, dDDH, amino acid identity (AAI) and percentage of conserved proteins (POCP), between Z083T, Z084 and

A. litorea

JCM 32043T clearly separated those two strains from

A. litorea

JCM 32043T as the values were below the thresholds for species delineation. The genome size of strains Z083T and Z084 were approximately 4.16 and 4.23 Mbp, respectively, and the DNA G+C contents of both strains were 51.8 mol%. According to the phenotypic, chemotaxonomic and phylogenetic characterizations and the results of genome analysis, Z083T and Z084 could be identified as belonging to a novel species of the genus

Aestuariirhabdus

, for which the name Aestuariirhabdus haliotis sp. nov., is proposed, with Z083T (=MCCC 1H00501T=KCTC 92006T) as the type strain.
Normative Sex Differences in Cognition and Morphometric Brain Connectivity: Evidence from 30,000+ UK Biobank Participants
Authors: Yang Crystal C. , Totzek Jana F. , Lepage Martin , Lavigne Katie M.
Published: October 2022

There is robust evidence for sex differences in domain-specific cognitive performance in the general population, where females typically show an advantage for verbal memory (VM), while males tend to perform better on tasks of spatial memory (SM). Sex differences in brain structure and connectivity are also well-documented and may provide insight into sex differences in cognition. In this study, we examined sex differences in cognition and morphometric brain connectivity of a large healthy sample (N = 31,180) from the UK Biobank dataset. Using T1-weighted magnetic resonance imaging (MRI) scans and regional cortical thickness values, we applied jackknife bias estimation and graph theory to obtain subject-specific measures of morphometric brain connectivity, hypothesizing that sex-related differences in brain network global efficiency, or overall connectivity, would underlie observed cognitive differences. As predicted, females demonstrated better VM performance and males showed an advantage in SM. Females also demonstrated faster processing speed, with no observed sex difference in executive functioning. Males tended to have higher global efficiency, as well as higher regional connectivity (nodal strengths) in both the left and right hemispheres relative to females.

Furthermore, higher global efficiency in males was found to mediate observed sex differences in cognition, predicting poorer verbal memory performance, better spatial memory, and slower processing speed in males. These findings contribute to an improved understanding of the way biological sex and differences in cognitive performance are related to morphometric brain connectivity as derived from graph-theoretic methods.
Not just with the natives, but phylogenetic relationship between stages of the invasion process determines invasion success of alien plant species
Authors: Banerjee Achyut Kumar , Feng Hui , Liang Xinru , Tan Fengxiao , Wang Jiakai , Lin Yuting , Yin Minghui , Peng Hao , Guo Wuxia , Zhang Nannan , Huang Yelin
Published: October 2022

Darwin proposed two alternate hypotheses on the invasion success of alien plant species based on their close or distant phylogenetic relationship with the natives. Here we tested these hypotheses along the invasion process at large spatio-temporal scale. Using two abundance-based phylogenetic metrics for the native and alien flora of China, our study showed that invasion success of alien plant species is influenced by the phylogenetic relationship with native and alien species of different invasion stages. Phylogenetic similarity with the native species helps the alien ones to introduce and naturalize, but phylogenetic dissimilarity with the natives facilitates invasion success. The co-occurrence of invasive and naturalized aliens also formed more clustered assemblages, showed specialized responses to environmental stress, and provided temporal stability to the phylogenetic measures. The native-alien phylogenetic relationship is dynamic across spatial, environmental, and taxonomic scales. Therefore, assessing Darwin’s naturalization conundrum at different gradients of community assembly process is important.
Computational Speed-Up of Large-Scale, Single-Cell Model Simulations Via a Fully-Integrated SBML-Based Format
Authors: Mutsuddy Arnab , Erdem Cemal , Huggins Jonah R. , Salim Michael , Cook Daniel , Hobbs Nicole , Feltus F. Alex , Birtwistle Marc R.
Published: October 2022

Large-scale and whole-cell modeling has multiple challenges, including scalable model building and module communication bottlenecks (e.g. between metabolism, gene expression, signaling, etc). We previously developed an open-source, scalable format for a large-scale mechanistic model of proliferation and death signaling dynamics, but communication bottlenecks between gene expression and protein biochemistry modules remained. Here, we developed two solutions to communication bottlenecks that speed up simulation by ~4-fold for hybrid stochastic-deterministic simulations and by over 100-fold for fully deterministic simulations.

Availability and Implementation

Source code is freely available athttps://github.com/birtwistlelab/SPARCED/releases/tag/v1.1.0implemented in python, and supported on Linux, Windows, and MacOS (via Docker).

Contact

Marc Birtwistlembirtwi@clemson.edu

Supplementary information

N/A
The role of non-additive gene action on gene expression variation in plant domestication
Authors: Díaz-Valenzuela Erik , Hernández-Ríos Daniel , Cibrián-Jaramillo Angélica
Published: October 2022

Background

Plant domestication is a remarkable example of rapid phenotypic transformation of polygenic traits such as organ size. Evidence from a handful of study cases suggests this transformation is due to gene regulatory changes that result in non-additive phenotypes. Employing data from published genetic crosses, we estimated the role of non-additive gene action in the modulation of transcriptional landscapes in three domesticated plants: maize, sunflower, and chili pepper. Using A.thaliana, we assessed the correlation between gene regulatory network (GRN) connectivity properties, transcript abundance variation, and gene action. Finally, we investigated the propagation of non-additive gene action in GRNs.

Results

We compared crosses between domesticated plants and their wild relatives to a set of control crosses that included a pair of subspecies evolving under natural selection and a set of inbred lines evolving under domestication. We found abundance differences on a higher portion of transcripts in crosses between domesticated-wild plants relative to the control crosses. These transcripts showed non-additive gene action more often in crosses of domesticated-wild plants than in our control crosses. This pattern was strong for genes associated with cell cycle and cell fate determination, which control organ size. We found weak but significant negative correlations between the number of targets of trans-acting genes (Out-degree) and both the magnitude of transcript abundance differences a well as the absolute degree of dominance. Likewise, we found that the number of regulators that control a gene’s expression (In-degree) is weakly but negatively correlated with the magnitude of transcript abundance differences. We observed that dominant-recessive gene action is highly propagable through GRNs. Finally, we found that transgressive gene action is driven by trans-acting regulators showing additive gene action.

Conclusions

Our study highlights the role of non-additive gene action on modulating domestication-related traits such as organ size via regulatory divergence. We propose that GRNs are shaped by regulatory changes at genes with modest connectivity, which reduces the effects of antagonistic pleiotropy. Finally, we provide empirical evidence of the propagation of non-additive gene action in GRNs, which suggests a transcriptional epistatic model for the control of polygenic traits such as organ size.
Reflective multi-immersion microscope objectives inspired by the Schmidt telescope
Authors: Voigt Fabian F. , Reuss Anna Maria , Naert Thomas , Hildebrand Sven , Schaettin Martina , Hotz Adriana L. , Whitehead Lachlan , Bahl Armin , Neuhauss Stephan C. F. , Roebroeck Alard , Stoeckli Esther T. , Lienkamp Soeren S. , Aguzzi Adriano , Helmchen Fritjof
Published: October 2022

Rapid advances in tissue clearing protocols have begun to outpace the capabilities of existing microscope objectives: High-resolution imaging inside cm-sized cleared samples is often not possible as it requires multi-immersion objectives with high numerical aperture (NA > 0.7), long working distance (WD > 10 mm) and a large field-of-view (FOV > 1 mm). Here, we introduce a novel mirror-based optical design, the “Schmidt objective”, which meets all these criteria despite containing only two optical elements. It consists of a spherical mirror in contact with the immersion medium and an aspherical correction plate. We showcase a multi-photon variant of a Schmidt objective that reaches NA 1.08 at an refractive index of 1.56 and demonstrate its versatility by imaging fixed samples in a wide range of immersion media ranging from air and water to BABB, DBE, and ECI. In addition, we demonstrate in vivo imaging by recording neuronal activity in larval zebrafish.
Identification of potent anti-fibrinolytic compounds against plasminogen and tissue-type plasminogen activator using computational approaches
Authors: Banerjee Suparna , M Yeshwanth , Prabhu Dhamodharan , Sekar Kanagaraj , Sen Prosenjit
Published: October 2022

The zymogen protease Plasminogen (Plg) and its active form plasmin (Plm) carry out important functions in the blood clot disintegration (breakdown of fibrin fibres) process. Inhibition of plasmin effectively reduces fibrinolysis to circumvent heavy bleeding. Currently, available Plm inhibitor tranexamic acid (TXA) that is used to treat severe hemorrhages is associated with an increased incidence of seizures which in turn were traced to gamma-aminobutyric acid antagonistic activity (GABAa) in addition to having multiple side effects. Fibrinolysis can be suppressed by targeting the three important protein domains: kringle-1 and serine protease domain of plasminogen and kringle-2 domain of tissue plasminogen activator. In the present study, combined approaches of structure-based virtual screening and molecular docking using Schrödinger Glide, AutoDock Vina, and ParDock/BAPPL+ were employed to identify potential hits from the ZINC database. Thereafter, the drug-likeness properties of the top three leads for each protein target were evaluated using Discovery Studio. Subsequently, a molecular dynamics simulation of 200ns for each protein-ligand complex was performed in GROMACS. The identified ligands are found to impart higher rigidity and stability to the protein-ligand complexes. Furthermore, the results were validated by performing the principal component analysis (PCA), and calculation of binding free energy using the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach. The identified ligands occupy smaller phase space, form stable clusters and exhibit stronger non-bonded interactions. Thus, our findings can be useful for the development of promising anti-fibrinolytic agents.

Graphical Abstract
Alternative splicing preferentially increases transcript diversity associated with stress responses in the extremophyteSchrenkiella parvula
Authors: Wijesinghege Chathura , Tran Kieu-Nga , Dassanayake Maheshi
Published: October 2022

Alternative splicing extends the coding potential of genomes by creating multiple isoforms from one gene. Isoforms can render transcript specificity and diversity to initiate multiple responses required during transcriptome adjustments in stressed environments. Although the prevalence of alternative splicing is widely recognized, how diverse isoforms facilitate stress adaptation in plants that thrive in extreme environments are unexplored. Here we examine how an extremophyte model,Schrenkiella parvula, coordinates alternative splicing in response to high salinity compared to a salt-stress sensitive model,Arabidopsis thaliana. We use Iso-Seq to generate full length reference transcripts and RNA-seq to quantify differential isoform usage in response to salinity changes. We find that single-copy orthologs whereS. parvulahas a higher number of isoforms than A. thaliana as well as S. parvula genes observed and predicted using machine learning to have multiple isoforms are enriched in stress associated functions. Genes that showed differential isoform usage were largely mutually exclusive from genes that were differentially expressed in response to salt.S. parvulatranscriptomes maintained specificity in isoform usage assessed via a measure of expression disorderdness during transcriptome reprogramming under salt. Our study adds a novel resource and insight to study plant stress tolerance evolved in extreme environments.
A taxonomic revision of the genusHydnora(Hydnoraceae)
Authors: Hatt Sebastian A. , Thorogood Chris J. , Bolin Jay F. , Musselman Lytton J. , Cameron Duncan D. , Grace Olwen M.
Published: October 2022

A systematic monograph is presented for Hydnora (Hydnoraceae), a poorly known genus of holoparasitic plants distributed across Africa, Madagascar and southern Arabia. Species ofHydnoraare characterised by their underground habit, unusual fleshy flowers and complete absence of leaves or photosynthetic tissue. This is the first detailed monograph of the genus Hydnora since 1935 and is informed by a comprehensive survey of herbarium specimens and literature. Detailed descriptions, full synonymy, distribution maps and discussion concerning confusable taxa are provided for each species, along notes on ethnobotany, ecology and conservation. We place particular emphasis on the taxonomic value of osmophore geometry and positioning in living and dried material, which are highly consistent within species. We also provide the first detailed assessment of host range across the genus.Hydnora hanningtoniiRendle andH. solmsianaDinter are reinstated from synonymy, andH. boliniiHatt is newly described here. The infrageneric classification is reviewed and a key is provided for both living and dried material. Species are accompanied by both illustrations and photographs of living and dried material where possible.
Experienced social partners hinder learning performance in naive clonal fish
Authors: Francisco Fritz A. , Lukas Juliane , Stöcker Almond , Romanczuk Pawel , Bierbach David
Published: October 2022

Social learning can facilitate information spread within groups and is generally assumed to increase learning efficiency in animals. Here, we asked how individual learning is affected by skill level of a demonstrator present during learning. We predicted that both task-naive and task-experienced individuals benefit from a task-experienced, conspecific demonstrator. We used the all-female clonal Amazon molly (Poecilia formosa) for our experiments. We further propose a model framework which lets us directly relate each research question to a single model parameter. First, following a classical conditioning paradigm over five days, half the fish were trained to find food inside a cylinder, while the others were provided with food randomly dispersed in their tank. As a result trained individuals visited the cylinder with a higher likelihood than randomly fed individuals and showed consistent individual differences in their learning performance. In a second step, we allowed these fish to observe a conspecific while we continued (for those trained) or started (for naives) individual training. We found that trained individuals did not benefit from a partner, regardless of the partners’ proficiency, but showed higher average performances compared to naives. Naive individuals showed a decrease in learning performance when paired with experienced partners but not when paired with other naive ones. Our results suggest that Amazon mollies learn a foraging task individually and differ consistently in their individual learning ability. Further, social learning depends on own, as well as the demonstrator’s skill level in a way that observing informed conspecifics may hamper own learning.

Highlights

Naturally clonal fish learn operant conditioning tasks

Individuals show consistent differences in learning abilities

Experienced social partners are not helpful during learning
Explainable Machine Learning to Identify Patient-specific Biomarkers for Lung Cancer
Authors: Sobhan Masrur , Mondal Ananda Mohan
Published: October 2022

Background

Lung cancer is the leading cause of death compared to other cancers in the USA. The overall survival rate of lung cancer is not satisfactory even though there are cutting-edge treatment methods for cancers. Genomic profiling and biomarker gene identification of lung cancer patients may play a role in the therapeutics of lung cancer patients. The biomarker genes identified by most of the existing methods (statistical and machine learning based) belong to the whole cohort or population. That is why different people with the same disease get the same kind of treatment, but results in different outcomes in terms of success and side effects. So, the identification of biomarker genes for individual patients is very crucial for finding efficacious therapeutics leading to precision medicine.

Methods

In this study, we propose a pipeline to identify lung cancer class-specific and patient-specific key genes which may help formulate effective therapies for lung cancer patients. We have used expression profiles of two types of lung cancers, lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and Healthy lung tissues to identify LUAD- and LUSC-specific (class-specific) and individual patient-specific key genes using an explainable machine learning approach, SHaphley Additive ExPlanations (SHAP). This approach provides scores for each of the genes for individual patients which tells us the attribution of each feature (gene) for each sample (patient).

Result

In this study, we applied two variations of SHAP - tree explainer and gradient explainer for which tree-based classifier, XGBoost, and deep learning-based classifier, convolutional neural network (CNN) were used as classification algorithms, respectively. Our results showed that the proposed approach successfully identified class-specific (LUAD, LUSC, and Healthy) and patient-specific key genes based on the SHAP scores.

Conclusion

This study demonstrated a pipeline to identify cohort-based and patient-specific biomarker genes by incorporating an explainable machine learning technique, SHAP. The patient-specific genes identified using SHAP scores may provide biological and clinical insights into the patient’s diagnosis.
Social rank influences relationships between hormones and oxidative stress in a cichlid fish
Authors: Culbert Brett M. , Border Shana E. , Fialkowski Robert J. , Bolitho Isobel , Dijkstra Peter D.
Published: October 2022

An individual’s social environment can have widespread effects on their physiology, including effects on oxidative stress and hormone levels. Many studies have posited that variation in oxidative stress experienced by individuals of different social ranks might be due to endocrine differences, however, few studies have evaluated this hypothesis. Here, we assessed whether a suite of markers associated with oxidative stress in different tissues (blood, plasma, liver, or gonads) had social rank-specific relationships with circulating testosterone or cortisol levels in males of a cichlid fish,Astatotilapia burtoni. Across all fish, blood DNA damage (a global marker of oxidative stress) and gonadal synthesis of reactive oxygen species (as indicated by NADPH-oxidase (NOX) activity) were lower when testosterone was high. High DNA damage in both the blood and gonads was associated with high cortisol in subordinates, but low cortisol in dominants. Additionally, high cortisol was associated with greater production of reactive oxygen species (greater NOX activity) in both the gonads (dominants only) and liver (dominants and subordinates). In general, high testosterone was associated with lower oxidative stress across both social ranks, whereas high cortisol was associated with lower oxidative stress in dominants and higher oxidative stress in subordinates. Taken together, our results show that differences in the social environment can lead to contrasting relationships between hormones and oxidative stress.
Type 2 Inflammation Drives an Airway Basal Stem Cell Program Through Insulin Receptor Substrate Signaling
Authors: Wang Xin , Hallen Nils R. , Lee Minkyu , Samuchiwal Sachin , Ye Qihua , Buchheit Kathleen M. , Maxfield Alice Z. , Roditi Rachel E. , Bergmark Regan W. , Bhattacharyya Neil , Ryan Tessa , Gakpo Deb , Raychaudhuri Soumya , Dwyer Dan , Laidlaw Tanya M. , Boyce Joshua A. , Gutierrez-Arcelus Maria , Barrett Nora A.
Published: October 2022

Background

Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a type 2 (T2) inflammatory disease associated with an increased number of airway basal epithelial cells (BCs). Recent studies have identified transcriptionally distinct BCs, but functional data are lacking and the molecular pathways that support or inhibit human BC proliferation and differentiation are largely unknown.

Objective

To determine the role of T2 cytokines in regulating airway BCs

Methods

Single cell and bulk RNA-sequencing of sinus and lung airway epithelial cells was analyzed. Human sinus BCs were stimulated with IL-4 and IL-13 in the presence and absence of IL4R inhibitors. Confocal analysis of human sinus tissue and murine airway was performed. Murine BC subsets were sorted for RNA sequencing and functional assays. Fate labeling was performed in a murine model of tracheal injury and repair.

Results

Here we find two subsets of BCs in human and murine respiratory mucosa distinguished by the expression of BC adhesion molecule (BCAM). BCAM expression identifies airway stem cells among P63+KRT5+NGFR+ BCs. In the sinonasal mucosa, BCAMhiBCs expressingTSLP,IL33,CCL26,and the canonical BC transcription factorTP63are increased in patients with CRSwNP. In cultured BCs, IL-4/13 increases expression ofBCAMandTP63through an Insulin Receptor Substrate (IRS)-dependent signaling pathway that is increased in CRSwNP.

Conclusions

These findings establish BCAM as a marker of airway stem cells among the BC pool and demonstrate that airway epithelial remodeling in T2 inflammation extends beyond goblet cell metaplasia to the support of a BC stem state poised to perpetuate inflammation.

CAPSULE SUMMARY

Type 2 cytokines drive an airway stem cell program through IRS signaling

KEY MESSAGES

Two subsets of airway BCs have distinct transcriptional signatures and function

High levels of BCAM expression mark the earliest BC progenitor

IL-4 and IL-13 upregulate BCAM and P63 in an IRS-dependent fashion which prevents BC differentiation to secretory epithelial cells

BCAMhiBCs are increased in CRSwNP
Intermittent hypoxia therapy engages multiple longevity pathways to double lifespan inC.elegans
Authors: Pitt Jason N. , Chavez Eduardo , Provencher Kathryn M. , Chen Michelle , Tran Christina , Tran Jennifer , Huang Karen , Vaid Anuj , Abadir Marian L , Arang Naheed , Leiser Scott F. , Roth Mark B. , Kaeberlein Matt
Published: October 2022

Genetic activation of the hypoxia response robustly extends lifespan inC. elegans, while environmental hypoxia shows more limited benefit. Here we describe an intermittent hypoxia therapy (IHT) able to double the lifespan of wildtype worms. The lifespan extension observed in IHT does not require HIF-1 but is partially blocked by loss of DAF-16/FOXO. RNAseq analysis shows that IHT triggers a transcriptional state distinct from continuous hypoxia and affects down-stream genes of multiple longevity pathways. We performed a temperature sensitive forward genetic screen to isolate mutants with delayed nuclear localization of DAF-16 in response to IHT and suppression of IHT longevity. One of these mutations mapped to the enzyme Inositol Polyphosphate MultiKinase (IPMK-1).ipmk-1mutants, likedaf-16mutants, partially suppress the benefits of IHT, while other effectors of phosphatidyl inositol signaling pathways (PLCβ4, IPPK, Go/iα) more robustly suppress IHT longevity.

One-Sentence Summary

Intermittent hypoxia therapy is frequency dependent, HIF independent, and requires FOXO, PLCβ, Go/iα, IPMK, and IPPK.
Single-cell Landscape Analysis Unravels Molecular Programming of the Human B Cell Compartment in Chronic GVHD
Authors: Poe Jonathan C , Fang Jiyuan , Zhang Dadong , Lee Marissa R , DiCioccio Rachel A , Su Hsuan , Qin Xiaodi , Zhang Jennifer , Visentin Jonathan , Bracken Sonali J , Ho Vincent T , Wang Kathy S , Rose Jeremy J , Pavletic Steven Z , Hakim Frances T , Jia Wei , Suthers Amy N , Curry-Chisolm Itaevia , Horwitz Mitchell E , Rizzieri David A , McManigle William , Chao Nelson J , Cardones Adela R , Xie Jichun , Owzar Kouros , Sarantopoulos Stefanie
Published: October 2022

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT) chronic graft-versus-host disease (cGVHD), a B cell-mediated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B Cell Receptor (BCR)-activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells under selective pressure of alloantigens, we performed scRNA-Seq analysis on high numbers of purified B cells from allo-HCT patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation and memory. We found striking transcriptional differences in the memory B cell compartment after allo-HCT compared to healthy or infected individuals. To identify intrinsic properties when B-cell tolerance is lost after allo-HCT, we then assessed clusters for differentially expressed genes (DEGs) between patients with vs. without autoimmune-like manifestations (Active cGVHD vs. No cGVHD, respectively). DEGs were found in Active cGVHD in both naive and BCR-activated clusters, suggesting functional diversity. Some DEGs were also differentially expressed across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides new understanding of B-cell memory in the face of chronic alloantigen stimulation.
Neurofeedback training can modulate task-relevant memory replay rate in rats
Authors: Gillespie Anna K. , Astudillo Maya Daniela A. , Denovellis Eric L. , Desse Sachi , Frank Loren M.
Published: October 2022

Hippocampal replay – the time-compressed, sequential reactivation of ensembles of neurons related to past experience – is a key neural mechanism of memory consolidation. Replay typically coincides with a characteristic pattern of local field potential activity, the sharp-wave ripple (SWR). Reduced SWR rates are associated with cognitive impairment in multiple models of neurodegenerative disease, suggesting that a clinically viable intervention to promote SWRs and replay would prove beneficial. We therefore developed a neurofeedback paradigm for rat subjects in which SWR detection triggered rapid positive feedback in the context of a memory-dependent task. This training protocol increased the prevalence of task-relevant replay during the targeted neurofeedback period by changing the temporal dynamics of SWR occurrence. This increase was also associated with neural and behavioral forms of compensation after the targeted period. These findings reveal short-timescale regulation of SWR generation and demonstrate that neurofeedback is an effective strategy for modulating hippocampal replay.
DNA-encoded library (DEL)-enabled discovery of proximity-inducing small molecules
Authors: Mason Jeremy W. , Hudson Liam , Westphal Matthias V. , Tutter Antonin , Michaud Gregory , Shu Wei , Ma Xiaolei , Coley Connor W. , Clemons Paul A. , Bonazzi Simone , Berst Frédéric , Zécri Frédéric J. , Briner Karin , Schreiber Stuart L.
Published: October 2022

Molecular glues and bifunctional compounds that induce protein–protein associations provide a powerful and general mechanism to modulate cell circuitry. We sought to develop a platform for the direct discovery of compounds able to induce association of any two pre-selected proteins, using the first bromodomain of BRD4 and the VHL–elongin C–elongin B (VCB) complex as a test system. Leveraging the screening power of DNA-encoded libraries (DELs), we synthesized ∼one million DNA-encoded compounds that possess a VHL-targeting fragment, a variety of connectors, and a diversity element generated by split- and-pool combinatorial chemistry. By screening our DEL against BRD4BD1in the presence and absence of VCB, we could identify VHL-bound molecules that simultaneously bind BRD4. For highly barcode-enriched library members, ternary complex formation leading to BRD4 degradation was confirmed in cells. Furthermore, a ternary complex crystal structure was obtained for the most enriched library member. Our work provides a foundation for adapting DEL screening to the discovery of proximity-inducing small molecules.

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Local gradient analysis of human brain function using the Vogt-Bailey Index
Authors: Farrugia Christine , Galdi Paola , Irazu Irati Arenzana , Scerri Kenneth , Bajada Claude J.
Published: October 2022

In this work, we take a closer look at the Vogt-Bailey (VB) index, proposed in Ref. [1] as a tool for studying local functional homogeneity in the human cortex. We interpret the VB index in terms of the minimum ratio cut, a parameter that indicates whether a network can easily be disconnected into two parts having a comparable number of nodes. In our case, the nodes of the network consist of a brain vertex/voxel and its nearest neighbours, and a given edge is weighted according to the affinity of the nodes it connects (as reflected by the modified Pearson correlation between their fMRI time series). Consequently, the minimum ratio cut quantifies the degree of small-scale similarity in brain activity: the greater the similarity, the ‘heavier’ the edges and the more difficult it is to disconnect the network, hence the higher the value of the minimum ratio cut. We compare the performance of the VB index with that of the Regional Homogeneity (ReHo) algorithm, commonly used to assess whether voxels in close proximity have synchronised fMRI signals, and find that the VB index is uniquely placed to detect sharp changes in the (local) functional organization of the human cortex.
Effects of Neurofeedback training on performance in laboratory tasks: A systematic review
Authors: Chiasson Payton , Boylan Maeve R. , Elhamiasl Mina , Pruitt Joseph M. , Ranjan Saurabh , Riels Kierstin , Sahoo Ashish K. , Mirifar Arash , Keil Andreas
Published: October 2022

Neurofeedback procedures are attracting increasing attention in the neuroscience community. Based on the principle that participants, through suitable feedback, may learn to affect specific aspects of their brain activity, neurofeedback has been applied to basic research, translational, and clinical science alike. A large segment of the extant empirical research as well as review articles have focused on the extent to which neurofeedback interventions affect mental health outcomes, cognitive capacity, aging, and other complex behaviors. Another segment has aimed to characterize the extent to which neurofeedback affects the targeted neural processes. At this time, there is no current systematic review of the effects of neurofeedback on healthy participants’ performance in experimental tasks. Such a review is relevant in this rapidly evolving field because changes in experimental task performance are traditionally considered a hallmark of changing neurocognitive processes, often established in neurotypical individuals. This systematic review addresses this gap in the literature using the PRISMA method, building on earlier reviews on the same topic. Empirical studies using EEG or fMRI to alter brain processes linked to established, well-defined cognitive and affective laboratory tasks were reviewed. Substantial variability was found regarding the nature of the control for placebo effects, the implementation of the feedback, and the neural targets of feedback. Importantly, only a minority of the studies reported statistically meaningful effects of neurofeedback on performance in cognitive and affective tasks. Examining effect sizes and p-values in a subset of studies found no evidence for reporting bias, while also not finding systematic relations between study characteristics such as sample size or experimental control on the one hand and efficacy on the other. Implications for future work are discussed.
Transposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat
Authors: Zhang Yuyun , Li Zijuan , Liu Jinyi , Zhang Yu’e , Ye Luhuan , Peng Yuan , Wang Haoyu , Diao Huishan , Ma Yu , Wang Meiyue , Xie Yilin , Tang Tengfei , Zhuang Yili , Teng Wan , Tong Yiping , Zhang Wenli , Lang Zhaobo , Xue Yongbiao , Zhang Yijing
Published: October 2022

The success of common wheat as the global staple crop is derived from genome diversity and redundancy as a result of allopolyploidization [1-3], giving rise to the major question how the divergent and convergent transcription among different subgenomes are achieved and harmonized in a single cell. The regulatory information is largely encoded in DNA regulatory elements (REs) interpreted by sequence specific transcription factors (TFs). Here, we created a catalog of genome-wide TF-binding sites (TFBS) to assemble an extensive wheat regulatory network comprising connections among 189 TFs and 3,714,431 REs, which enhances the understanding of wheat regulatory mechanisms on an unprecedented scale. A significant fraction of subgenome-divergent TFBS are derived from recent subgenome-asymmetric expansion of particular transposable element (TE) families. In contrary, TFBS derived from ancient TE expansion largely underwent parallel purifying selection during independent evolution of each subgenome, despite extensive unbalanced turnover of flanking TEs. Altogether, the subgenome-convergent and -divergent regulation in common wheat is orchestrated via differential evolutionary selection on paleo- and neo-TEs.
Adaptive Sampling as tool for Nanopore direct RNA-sequencing
Authors: Vries Isabel S. Naarman-de , Gjerga Enio , Gandor Catharina L.A. , Dieterich Christoph
Published: October 2022

ONT long-read sequencing provides real-time monitoring and controlling of individual nanopores. Adaptive sampling enriches or depletes specific sequences in Nanopore DNA sequencing, but was not applicable to direct sequencing of RNA so far.

Here, we identify essential parameter settings for direct RNA sequencing (DRS). We demonstrate the superior performance of depletion over enrichment and show that adaptive sampling efficiently depletes specific transcripts in transcriptome-wide sequencing applications. Specifically, we applied our adaptive sampling approach to polyA+ RNA samples from human cardiomyocytes and mouse whole heart tissue. Herein, we show more than 2.5-fold depletion of highly abundant mitochondrial-encoded transcripts that in normal sequencing account for up to 40% of sequenced bases in heart tissue samples.