bluuebunny/crossref_metadata_2025 huggingface dataset:
From Race to Racism and Disparities to Equity
Authors: Reeder-Hayes Katherine , Roberson Mya L. , Wheeler Stephanie B. , Abdou Yara , Troester Melissa A.
Published: November 2023

Purpose

Racial disparities in outcomes of breast cancer in the United States have widened over more than 3 decades, driven by complex biologic and social factors. In this review, we summarize the biological and social narratives that have shaped breast cancer disparities research across different scientific disciplines in the past, explore the underappreciated but crucial ways in which these 2 strands of the breast cancer story are interwoven, and present 5 key strategies for creating transformative interdisciplinary research to achieve equity in breast cancer treatment and outcomes.

Design

We first review the key differences in tumor biology in the United States between patients racialized as Black versus White, including the overrepresentation of triple-negative breast cancer and differences in tumor histologic and molecular features by race for hormone-sensitive disease. We then summarize key social factors at the interpersonal, institutional, and social structural levels that drive inequitable treatment. Next, we explore how biologic and social determinants are interwoven and interactive, including historical and contemporary structural factors that shape the overrepresentation of triple-negative breast cancer among Black Americans, racial differences in tumor microenvironment, and the complex interplay of biologic and social drivers of difference in outcomes of hormone receptor positive disease, including utilization and effectiveness of endocrine therapies and the role of obesity. Finally, we present 5 principles to increase the impact and productivity of breast cancer equity research.

Results

We find that social and biologic drivers of breast cancer disparities are often cyclical and are found at all levels of scientific investigation from cells to society. To break the cycle and effect change, we must acknowledge and measure the role of structural racism in breast cancer outcomes; frame biologic, psychosocial, and access factors as interwoven via mechanisms of cumulative stress, inflammation, and immune modulation; take responsibility for the impact of representativeness (or the lack thereof) in genomic and decision modeling on the ability to accurately predict the outcomes of Black patients; create research that incorporates the perspectives of people of color from inception to implementation; and rigorously evaluate innovations in equitable cancer care delivery and health policies.

Conclusions

Innovative, cross-disciplinary research across the biologic and social sciences is crucial to understanding and eliminating disparities in breast cancer outcomes.
A Modified Suture Technique to Improve Scar Appearance in Wounds Under High Tension
Authors: Liu Hui , Lin Mao-Hui , Jiang Ling-Li , Chang Shu-Sen , Chen Wei , Nie Kai-Yu , Huang Guang-Tao , Qi Fang , Zhou Xiao-Fan , Chen Jian-Da , Deng Cheng-Liang , Wei Zai-Rong
Published: November 2023

The purpose of this study was to introduce a modified suture technique and to compare its effects on skin scar formation with 2 traditional suture methods: simple interrupted suture (SIS) and vertical mattress suture (VMS). Three groups of healthy adult female Sprague-Dawley rats were selected (6 replicates in each group), and the full-thickness skin of 5 cm × 0.2 cm was cut off on the back of the rats after anesthesia. The wounds were then sutured using 1 of the 3 methods for each group: SIS, VMS, and a newly introduced modified vertical mattress suture (M-VMS) technique with the needle reinsertion at the exit point. A traction device was installed on the back of the rats to achieve high tension wounds. The tensile distance was increased by 1 mm every day for 20 days. After 20 days of healing, the hematoxylin-eosin staining method was used for observation of scar morphology. The collagen production rate was measured by Masson staining, and the type I collagen and type III collagen were detected by the immunofluorescence method. Immunohistochemical staining was used to detect the expression of myofibroblast marker α-smooth muscle actin, and real-time quantitative polymerase chain reaction and Western blot techniques were used to detect the expressions of transforming growth factors TGFβ1, TGFβ2, and TGFβ3 to understand the mechanisms of scar formation. Results showed that the quantity and density of collagen fibers were both lower in the M-VMS group than in the other 2 groups. Immunofluorescence results showed that type I collagen was significantly lower, whereas type III collagen was significantly higher in the M-VMS group than in the other 2 groups. The expressions of α-smooth muscle actin and TGFβ1 both were lower in the M-VMS group than in the other 2 groups. The expression of TGFβ2 and TGFβ3 had no obvious difference among the 3 groups. For wounds under high tension, compared with SIS and VMS methods, the M-VMS technique we proposed can reduce scar formation due to the reduction of collagen formation, myofibroblast expression, and TGFβ1 expression.
RESTRICTIVE FLUID RESUSCITATION IN SEPTIC SHOCK PATIENTS HAS LOWER MORTALITY AND ORGAN DYSFUNCTION RATES THAN STANDARD THERAPY
Authors: Jiang Zhizhao , Luo Fenbin , Liu Yuqi , Sun Xuri , Tan Guoliang , Chen Zhiliang , Chen Yongqiang
Published: November 2023

Background: The influence of restrictive fluid resuscitation and the early administration of vasopressors on the clinical outcomes in patients with septic shock are not fully understood. The purpose of this study was to evaluate the effects of restrictive fluid management on mortality and organ dysfunction in patients with septic shock.Methods: This study included consecutive patients with septic shock in need of fluid resuscitation. Based on the fluid management provided in the initial resuscitation phase, a comparison was made between a restrictive group and a standard fluid management group. The primary outcome was in-hospital death, whereas secondary outcomes included organ dysfunction and other adverse events.Results: A total of 238 patients were included in this study. Restrictive fluid management was administered to 59.2% of patients, whereas 40.8% received standard fluid management. Restrictive resuscitation was associated with a lower in-hospital mortality rate (24.8% vs. 52.6%), as well as a shorter median intensive care unit stay (8.0 vs. 11.0 days). The restrictive strategy was associated with a significantly lower prevalence of new-onset acute kidney injury (25.5% vs. 51.5%) and a decrease in the incidence of renal replacement therapy (20.6% vs. 40.2%). The standard group had a higher risk of the need for mechanical ventilation and a significantly lower median number of days without a ventilator than the restrictive group. The median duration of vasopressor-free days in the restrictive group was significantly longer than that in the standard group (25.0 vs. 18.0). The administration rate of inotropes in the restrictive group was significantly lower than that in the standard group. A multivariate logistic regression model showed that restrictive fluid management (odds ratio [OR], 0.312; 95% confidence interval [CI], 0.098–0.994) and vasopressor-free days (OR, 0.807; 95% CI, 0.765–0.851) protect against in-hospital death, whereas Acute Physiology and Chronic Health Evaluation II scores (OR, 1.121; 95% CI, 1.018–1.234) were independent risk factors for in-hospital death.Conclusions: Restrictive fluid resuscitation and early vasopressor protocol in patients with septic shock are associated with better outcomes, indicating that this regimen is feasible and safe.
Astragaloside IV modulates gut macrophages M1/M2 polarization by reshaping gut microbiota and SCFA in sepsis
Authors: Yang Tao , Xie Shuhua , Cao Lei , Li Man , Ding Ling , Wang Lei , Pang Shenyue , Wang Zhifen , Geng Licheng
Published: November 2023

M1 macrophage-mediated inflammation is critical in sepsis. We previously found protective role of Astragaloside IV (AS-IV) in sepsis-associated gut impairment, whose specific mechanism remains unknown. Gut microbiota modulates gut homeostatic balance to avoid excessive inflammation. Here, we aimed to investigate effects of AS-IV on gut macrophages polarization and potential roles of gut microbiota and short chain fatty acids (SCFA) in septic gut damage. Mice were pre-treated by AS-IV gavage for 7 days before cecal ligation and puncture (CLP). M1 polarization of gut lamina propria macrophages (LpMs) was promoted by CLP, accompanied by abnormal cytokines release and intestinal barrier dysfunction. NLRP3 inflammasome was activated in M1 LpMs. 16S rRNA sequencing demonstrated gut microbiota imbalance. The levels of acetate, propionate and butyrate in fecal samples decreased. Notably, AS-IV reversed LpMs M1/M2 polarization, lightened gut inflammation and barrier injury, reduced NLRP3 inflammasome expression in LpMs, restored the diversity of gut microbiome and increased butyrate levels. Similarly, these benefits were mimicked by fecal microbiota transplantation (FMT) or exogenous butyrate supplementation. In Caco-2 and THP-1 co-cultured model, lipopolysaccharide (LPS) and interferon-γ (IFN-γ) caused THP-1 M1 polarization, Caco-2 barrier impairment, abnormal cytokines release and high NLRP3 inflammasome expression in THP-1 cells, all of which were mitigated by butyrate administration. However, these protective effects of butyrate were abrogated by NLRP3 gene overexpression in THP-1. In conclusion, AS-IV can ameliorate sepsis-induced gut inflammation and barrier dysfunction by modulating M1/M2 polarization of gut macrophages, whose underlying mechanism may be restoring gut microbiome and SCFA to restrain NLRP3 inflammasome activation.
Complex Syntax Production in Informational Writing by Students With Language Impairment From Diverse Linguistic Backgrounds
Authors: Hall-Mills Shannon , Wood Carla
Published: November 2023

The primary objective of this study was to compare the syntactic complexity of informational texts produced by fifth-grade students (a) with and without language impairment and (b) with and without native English-speaking proficiency on a curriculum-based reading and writing task. Expository writing samples produced by 114 children enrolled in the fifth grade were analyzed at the utterance level for five features of complex syntax, including the frequency of utterances containing complex syntax and specific clause types (conjoined, subordinate, relative, full complement). For each of the four groups, we report frequency counts, means, standard deviations, and ranges of performance across the five syntax measures. Multivariate analysis of variance revealed there were significant group differences on measures. Specifically, children with typical language development, regardless of English proficiency level, wrote more words, utterances, and different word roots than their peers with language impairment. When productivity (i.e., text length) in the writing samples was controlled, multivariate analysis of variance revealed there was a significant difference between groups in use of relative clauses, but not for the use of conjoined, subordinate, or full complement clauses. In particular, English proficient students with language impairment produced a greater proportion of utterances with relative clauses. A post hoc correlation analysis showed moderate, positive correlations among writing cohesion and variables of complex syntax. We consider multiple implications for clinical practice and further research.
Comparison Between Cz-C3/C4 and C3-C4 Montages to Protect Against Peripheral Stimulation in Transcranial Facial Motor-Evoked Potential Monitoring
Authors: Matsuoka Ryuta , Hamada Naoya , Nishimura Nobuyuki , Mitsui Takaaki , Shiraishi Yuki , Hayami Hiromichi , Fukutome Kenji , Tei Rinsei , Shin Yasushi , Aketa Shuta , Kato Daizo , Kita Takashi , Motoyama Yasushi
Published: November 2023

Introduction:

In facial motor-evoked potential monitoring, efforts to reduce peripheral stimulation are necessary because it can cause false-negatives. The effects of peripheral stimulation on Cz-C3/C4 and C3-C4 montages were compared.

Methods:

Facial motor-evoked potentials were recorded from bilateral orbicularis oculi (Oculi) and oris (Oris) muscles. The double-train approach combining single-pulse and five-train pulse stimulation was used to determine the effect of peripheral stimulation. If the five-train pulse produced a significant waveform, it was defined as “total success.” In total success cases, “true success” was defined as a case in which no waveform appeared after the single pulse at the threshold level of the five-train pulse. The total and true success rates and the threshold value of Oculi and Oris were compared between Cz-C3/C4 and C3-C4 montages.

Results:

Thirty-six muscles each of Oculi and Oris of 18 patients were used for the analysis. True success was more likely to be obtained by the Cz-C3/C4 montage than the C3-C4 montage in Oculi (42% vs. 22%, p = 0.039). Both Oculi and Oris had higher thresholds to elicit facial motor-evoked potentials with the Cz-C3/C4 montage (Oculi: 101.7 vs. 71.4 mA, p = 0.038; Oris: 94.8 vs. 73.1 mA, p = 0.016).

Conclusions:

Cz-C3/4 montage is more effective at reducing peripheral stimulation compared with the C3-4 montage. This effect was primarily seen in the orbicularis oculi muscle. It should be noted that the Cz-C3/C4 montage has a higher threshold than the C3-C4 montage in facial muscles. In facial motor-evoked potential monitoring, the Cz-C3/C4 montage may be more suitable to eliminate peripheral stimulation.
Providing a scaffold for considering theoretical frameworks in evidence implementation projects: the JBI approach to evidence implementation
Authors: Munn Zachary , McArthur Alexa , Klugar Miloslav , Stannard Daphne , Cooper Adam S. , Enuameh Yeetey , Porritt Kylie
Published: November 2023

There are many theories, models, and frameworks that have been proposed in the field of implementation science. Despite this, many evidence implementation or practice improvement projects do not consider these theories, models, or frameworks in their improvement efforts. The JBI approach is one example of an implementation theory, model, or framework. This approach has been developed particularly with health care professionals in mind and is designed to clearly guide pragmatic evidence implementation efforts based on the best available evidence. In this paper, we discuss how the JBI approach to evidence implementation can interact with and support theory-informed, pragmatic evidence implementation projects.
Mycobacterium bovis and its impact on human and animal tuberculosis
Authors: Sawyer Jason , Rhodes Shelley , Jones Gareth J. , Hogarth Philip J. , Vordermeier H. Martin
Published: November 2023

Graphical abstract

Mycobacterium bovis

is a slow-growing (16–20 h generation time), Gram-positive and acid-fast bacterium member of the

Mycobacterium tuberculosis

complex pathogen group (MTBC). They are characterized by a complex, protective cell wall containing mycolic acids. The MTBCs are the causative agents of tuberculosis (TB). Following initial infection, subsequent pathological changes, and the progress of infection depend on the interplay between host defence mechanisms and mycobacterial virulence factors and the balance between the immunologic protective responses and the damaging inflammatory processes. Progression of the disease is characterized by the formation of typical caseous tuberculous granuloma (inflammatory mononuclear cell aggregates) because of the host's immune response to infection. The transmission and epidemiology of

Mycobacterium bovis

are complex and vary depending on the situation and ecosystem. In the UK, the spread of BTB in the UK cattle herd can occur by transmitting the disease from cattle to cattle and between badgers but also between badgers and cattle. The disease is thought to be primarily a respiratory disease with spread between individuals through mechanisms such as coughing or transfer of bacteria in respiratory secretions. It is also thought that environmental contamination may also lead to some transmission. The protective cell wall of the organism is believed to allow the organism to survive outside an animal host, which can then transfer to new hosts following subsequent environmental exposure. In some situations, ingestion of pathogens in food can lead to infection. The relative contribution of these routes and precise transmission mechanisms needs to be better understood.
AlzGenPred: A CatBoost based method using network features to classify the Alzheimer’s Disease associated genes from the high throughput sequencing data
Authors: Shukla Rohit , Singh Tiratha Raj
Published: November 2023

Background and Objective

AD is a progressive neurodegenerative disorder characterized by memory loss. Due to the advancement in next-generation sequencing technologies, an enormous amount of AD-associated genomics data is available. However, the information about the involvement of these genes in AD association is still a research topic because all these algorithms are based on statistical techniques. Therefore, AlzGenPred is developed to identify the AD-associated genes from a large set of data.

Methods

To develop the AlzGenPred, we have compiled a benchmark dataset consisting of 1086 AD and non-AD genes and used them as positive and negative datasets. We have generated several features including the fused features and evaluated them through machine learning methods. Then hyperparameter tuning approach was also applied and the final model was selected. The proposed method was validated by using the AlzGene and transcriptomics datasets and proposed as a standalone tool.

Results

Total 13504 features belonging to eight different encoding schemes of these sequences were generated and evaluated by using 16 ML algorithms. It reveals that network-based features can classify AD genes while sequence-based features are not able to classify them. Then we generated 24 different fused features (6020 D) using sequence-based features and fed them into a two-step lightGBM-based recursive feature selection method. It increased up to 5-7% accuracy. After that selected eight fused features with CKSAAP were used for the hyperparameter tuning. They showed <70% accuracy. Therefore, network-based features were used to generate the CatBoost-based ML method called AlzGenPred with 96.55% accuracy and 98.99% AUROC. The developed method is tested on the AlzGene dataset where it showed 96.43% accuracy. Then the model is validated using the transcriptomics dataset also.

Conclusion

The validation of AlzGenPred using the AlzGene dataset and transcriptomics dataset obtained from Human, mouse, and ES-derived neural cells revealed that it can classify the omics data and can sort the AD-associated genes. These predicted genes can be directly used in the wet lab for further testing which will reduce labor cost and time expenses. The AlzGenPred is developed as a standalone package and is available for users athttps://www.bioinfoindia.org/alzgenpred/andhttps://github.com/shuklarohit815/AlzGenPred.
Clinical Utility of Ultrasonography BI-RADS in the Evaluation of Breast Cancer in Patients with Palpable Breast Masses: A Diagnostic Test Accuracy Original Article
Authors: Gami Vismit , Desai Dev , Shah Sahil , Rana Devang
Published: November 2023

Introduction

Diagnosing and staging breast cancer with an easy and widely useable method that can be employed worldwide in the poorest and wealthiest settings is important.

Mammography is a technique that might not be available in faraway clinics and it is technically challenging whereas USG can be available in most remote areas and small hospitals far from tertiary care hospitals. Even a trainee Radiology resident can use USG BIRADS and can be used diagnostically for that, it is important to define its, diagnostic accuracy with Sensitivity, Specificity, and other diagnostic parameters.

Aims

To determine the Diagnostic accuracy of USG BIRADS compared to the gold standard Histopathology report

Methodology

A Retrospective cohort study was conducted at a tertiary care hospital. a total of 84 female patients presenting to Surgical OPD with complaints of a breast lump or pain were enrolled from their records. Their Breast USG results were analyzed to identify their BIRADS stage correctly and then their corresponding Histopathology report was considered the gold standard to compare the USG results against. Excel, SPSS, and Revman were used to conduct analysis and create results.

Results

36 of these 84 patients belonged to BIRADS 1, 2, and 5 where Sensitivity, Specificity, and PPV were calculated at 100%. No one was diagnosed with BIRADS III from USG reports. For USG BIRADS 4, in total 48 patients Sensitivity was 0.667, specificity was 0.883, and PPV was 0.364.

Conclusion

Patients whose USG shows Benign growth or can be diagnosed in BIRADS 1, 2, 3, and 5 can be counted as accurate and precise. When the USG diagnosis describes the patient to be in BIRADS 4, the sensitivity and PPV show poor results showing a very low probability of the patient being truly positive when the diagnosis gives a positive result.
Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum
Authors: Mulloy SM , Aback EM , Gao R , Engel S , Pawaskar K , Win C , Moua A , Hillukka L , Lee AM
Published: November 2023

Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kgi.p.ethanol inducedFosexpression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.
KSR1 knockout mouse model demonstrates MAPK pathway’s key role in cisplatin- and noise-induced hearing loss
Authors: Ingersoll Matthew A. , Lutze Richard D. , Kelmann Regina G. , Kresock Daniel F. , Marsh Jordan D. , Quevedo Rene V. , Zuo Jian , Teitz Tal
Published: November 2023

Hearing loss is a major disability in everyday life and therapeutic interventions to protect hearing would benefit a large portion of the world population. Here we found that mice devoid of the protein kinase suppressor of RAS 1 (KSR1) in their tissues (germline KO mice) exhibit resistance to both cisplatin- and noise- induced permanent hearing loss compared to their wild-type KSR1 littermates. KSR1 is expressed in the cochlea and is a scaffold protein that brings in proximity the mitogen-activated protein kinase (MAPK) proteins BRAF, MEK and ERK and assists in their activation through a phosphorylation cascade induced by both cisplatin and noise insults in the cochlear cells. Deleting the KSR1 protein tempered down the MAPK phosphorylation cascade in the cochlear cells following both cisplatin and noise insults and conferred hearing protection of up to 30 dB SPL in three tested frequencies in mice. Treatment with dabrafenib, an FDA- approved oral BRAF inhibitor, downregulated the MAPK kinase cascade and protected the KSR1 wild-type mice from both cisplatin- and noise-induced hearing loss. Dabrafenib treatment did not enhance the protection of KO KSR1 mice, as excepted, providing evidence dabrafenib works primarily through the MAPK pathway. Thus, either elimination of the KSR1 gene expression or drug inhibition of the MAPK cellular pathway in mice resulted in profound protection from both cisplatin- and noise-induce hearing loss. Inhibition of the MAPK pathway, a cellular pathway that responds to damage in the cochlear cells, can prove a valuable strategy to protect and treat hearing loss.

Significance Statement

Ten percent of the world population suffers from hearing loss but this impairment may be preventable. We show that mice devoid of the KSR1 protein (KO) exhibit resistance to cisplatin- and noise-induced permanent hearing loss compared to wild-type littermates that harbor the protein. Removing KSR1 tempers down the MAPK phosphorylation cascade of BRAF-MEK-ERK induced in the cochlea following cisplatin and noise insults. Treatment of KSR1 wild-type mice following cisplatin or noise with an FDA-approved BRAF inhibitor, dabrafenib, protected the hearing and, importantly, did not confer additional protection to the KO KSR1 mice. Hence, the MAPK pathway has a unique role in responding to cochlear damage, and removing KSR1 gene expression or drug inhibition of the pathway results in hearing protection.
Endothelial stiffening induced by CD36-mediated lipid uptake leads to endothelial barrier disruption and contributes to atherosclerotic lesions
Authors: Aguilar Victor , Master Elizabeth Le , Paul Amit , Ahn Sang Joon , Lazarko Dana , Febbraio Maria , Lee James , Levitan Irena
Published: November 2023

Background

To determine the impact of endothelial stiffening induced by CD36-mediated lipid uptake in the disruption of aortic endothelial barrier and development of atherosclerosis in mouse models of obesity and hypercholesterolemia.

Approach and Results

Endothelial-specific inducible downregulation of CD36 results in abrogating the stiffening of aortic endothelium induced by a short-term (6-8 weeks) high-fat Western diet in intact freshly isolated mouse aortas of Cdh5.CreERT2CD36fl/flmice, as assessed by atomic force microscopy. No effect was observed on the stiffness of aortic vascular wall assessed in the same groups of mice by echocardiography. Prevention of WD-induced endothelial stiffening by the downregulation of endothelial CD36 was associated with a protective effect against endothelial barrier disruption, assessed by morphological analysis of VE-cadherin junctions and penetration of Evans blue dye into the aortic wall. These protective effects were independent of the changes in the serum lipid profiles. Furthermore, endothelial specific downregulation of CD36 in hypercholesterolemic Cdh5.CreERT2CD36fl/flLDLR-/-mice also led to significant decrease in endothelial stiffening after 4-5 months of high fat diet and a significant decrease in the areas of atherosclerotic lesion. In both models, significant endothelial stiffening was observed specifically in male mice, while female mice exhibited less endothelial stiffening and less severe atherosclerosic phenotype, consistent with endothelial stiffening playing an important role in aortic vascular disease in a sex-dependent way. Mechanistically, we showin vitrothat CD36-mdiated uptake of long chain saturated fatty acids, particularly palmitic acid, induces endothelial stiffening via activation of RhoA/ROCK pathway. Moreover, palmitic acid-induced endothelial stiffening critically depends on the expression of a RhoA inhibitory protein, Rho-GDI-1.

Conclusions

We conclude that stiffening of the aortic endothelium by CD36-mediated uptake of fatty acids contributes significantly to WD-induced vascular dysfunction and atherosclerosis. We further propose that fatty acids may activate RhoA by inducing its dissociation from Rho-GDI-1.
Mem-GAN: A Pseudo Membrane Generator for Single-cell Imaging in Fluorescent Microscopy
Authors: Wang Yixin , Ding Jiayuan , Wu Lidan , Wardhani Aster , Danaher Patrick , Lu Qiaolin , Wen Hongzhi , Tang Wenzhuo , Chang Yi , Lei Yu Leo , Tang Jiliang , Xie Yuying
Published: November 2023

Motivation

Fluorescent microscopy imaging is vital to capturing single-cell spatial data, characterizing tissue organization and facilitating comprehensive analysis of cellular state. Advancements in fluorescent microscopy imaging technologies have enabled precise downstream cellular analysis, particularly in cell segmentation. Accurate segmentation of individual cells allows better profiling and understanding of cell properties and behaviors. The majority of existing segmentation methods predominantly concentrate on enhancing segmentation algorithms, and their effectiveness strongly relies on the input stained image quality. Factors such as high cellular density, indistinct cell boundaries, and staining artifacts can result in uneven and low-quality staining, particularly causing missing or unclear membrane staining. These artifacts adversely impact the efficacy of the subsequent cell segmentation methods.

Results

To tackle this insufficient membrane staining, we propose a novel approach, Mem-GAN, to generate high-quality membranes for cells with missing or weak membranes. Inspired by advanced style transfer techniques in computer vision, Mem-GAN styles the content of the cells with missing or weak membranes into cells with integrated membrane staining. Considering the differences in membrane morphology between epithelial/tumor cells and immune cells, Mem-GAN deals with tumor and immune cells separately, not only enhancing membrane staining for cells with partially weak membrane signals but also generating membranes for cells with only nuclear channels. The proposed Mem-GAN is evaluated using the publicly available CosMx dataset. Experimental results demonstrate significant improvements in image staining quality, more accurate representation of membrane morphology characteristics, and better performance in downstream segmentation tasks. Mem-GAN is flexibly adapted and applied to other spatially resolved transcriptomics datasets, such as MERFISH and FISHseq. Our work provides a new perspective on tackling the challenges in cell segmentation from fluorescent microscopy image restoration.

Availability and implementation

The implementation of Mem-GAN is open-source and available at the github repositoryhttps://github.com/OmicsML/Mem-GAN. The interactive webserver-based demo of Mem-GAN can be accessed athttps://omicsml.ai/memgan.
An encyclopedia of enhancer-gene regulatory interactions in the human genome
Authors: Gschwind Andreas R. , Mualim Kristy S. , Karbalayghareh Alireza , Sheth Maya U. , Dey Kushal K. , Jagoda Evelyn , Nurtdinov Ramil N. , Xi Wang , Tan Anthony S. , Jones Hank , Ma X. Rosa , Yao David , Nasser Joseph , Avsec Žiga , James Benjamin T. , Shamim Muhammad S. , Durand Neva C. , Rao Suhas S. P. , Mahajan Ragini , Doughty Benjamin R. , Andreeva Kalina , Ulirsch Jacob C. , Fan Kaili , Perez Elizabeth M. , Nguyen Tri C. , Kelley David R. , Finucane Hilary K. , Moore Jill E. , Weng Zhiping , Kellis Manolis , Bassik Michael C. , Price Alkes L. , Beer Michael A. , Guigó Roderic , Stamatoyannopoulos John A. , Aiden Erez Lieberman , Greenleaf William J. , Leslie Christina S. , Steinmetz Lars M. , Kundaje Anshul , Engreitz Jesse M.
Published: November 2023

Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1–6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 element-gene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancer-promoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
Evaluating diversionary feeding as a method to resolve conservation conflicts in a recovering ecosystem
Authors: Bamber Jack A. , Kortland Kenny , Sutherland Chris , Payo-Payo Ana , Lambin Xavier
Published: November 2023

1. The recovery of mammalian predators of conservation concern in Europe is a success story, but their impact on some prey species of conservation concern may cause conservation dilemmas. This calls for effective intervention strategies that mitigate predator impacts without compromising their recovery.

2. We evaluated diversionary feeding as a management intervention tool to reduce depredation on nests of rapidly declining Western capercaillies in Scotland. We studied the influence of diversionary feeding provision on the fates of artificial nests deployed using a replicated and representative randomised landscape-scale experiment. This comprised 30 paired control (no diversionary feeding) and treatment (diversionary feeding applied) sites, 60 in total, each containing six artificial nests distributed across 600 km2. The experiment was replicated over two years, and in the second year, the control-treatment pairs were reversed, yielding 60 treatment and 60 control sites and 720 artificial nests.

3. Diversionary feeding substantially reduced depredation of artificial nests, translating into an 83% increase in predicted nest survival over 28 days of incubation. The increase in survival was mostly accounted for by a reduction in the probability that a pine marten, the main nest predator, consumed or cached eggs. Diversionary food also significantly reduced nest predation by badgers, although the magnitude of this effect varied by year.

4. Diversionary feeding is an easily employable method shown in this study to reduce predator impact (functional) without lethal (numerical) intervention. Managers should proceed with its application for conserving capercaillie in Scotland without delay.
Cis- andtrans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia
Authors: Head S. Taylor , Dezem Felipe , Todor Andrei , Yang Jingjing , Plummer Jasmine , Gayther Simon , Kar Siddhartha , Schildkraut Joellen , Epstein Michael P.
Published: November 2023

Transcriptome-wide association studies (TWAS) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have only considered regulatory effects of risk associated SNPs thought to act incison a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWAS of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of bothcis- andtrans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such asACAP3, whose associations are predominantly driven bytrans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents a first look into the role oftrans-eQTLs in the complex molecular mechanisms underlying these diseases.
Spatial distribution of insular cliff vegetation and future scenarios in a climate change perspective
Authors: Capó Miquel , Cortés-Fernández Iván , Borràs Joshua
Published: November 2023

Cliff ecology has been studied for decades, providing good information about its high biodiversity values and their vulnerability to climate change. At the same time, literature shows how insular ecosystems are evolutionarily enhanced to present biodiversity hotspots with high endemicity rates, but they are also severely affected by anthropogenic effects. Together, insular cliff communities combine both biodiversity uniqueness and high vulnerability to global change, but few studies have evaluated these particular ecosystems. In this study, our aim was to provide novel information on the spatial distribution of insular cliff vegetation, taking the Balearic islands as a study case, assessing which environmental and climatic variables contribute to the definition of habitat conditions. Also, we used the predictions found in the WorldClim database to predict how the spatial distribution model vary. The map obtained showed that the mountains and coast were the most suitable habitats, especially the mountain ranges of the island of Mallorca. In particular, the high peaks of Serra de Tramuntana englobe the most fitted conditions for rupicolous species. Regarding the future climatic scenarios, in both the pessimistic and optimistic models, the spatial distribution of cliff vegetation remain intact in the mountain ranges where the habitat suitability was high, but disappear or reduce in other less favorable zones for the period 2021-2040. However, the extension of the distribution will be reduced in mid- and long-term periods, until 2081-2100, when the well-suited areas are only predicted to be in high-elevation mountains from the north of Mallorca island. These results emphasize the high vulnerability of these habitats to climate change due to their vulnerability to aridity and the strict requirements for habitat suitability (e.g., high slopes). From this, future studies should focus on single-species analysis to evaluate if any cliff specialist species can be at risk of extinction due to climate change.
Impact of Evolutionary Relatedness on Species Diversification and Tree Shape
Authors: Qin Tianjian , Valente Luis , Etienne Rampal
Published: November 2023

Slowdowns in lineage accumulation are often observed in phylogenies of extant species. One explanation is the presence of ecological limits to diversity and hence to diversification. Previous research has examined whether and how species richness (SR) impacts diversification rates, but rarely considered the evolutionary relatedness (ER) between species, although ER can affect the degree of interaction between species, which likely sets these limits. To understand the influences of ER on species diversification and the interplay between SR and ER, we present a simple birth-death model in which the speciation rate depends on the ER. We use different metrics of ER that operate at different scales, ranging from branch/lineage-specific to clade-wide scales. We find that the scales at which an effect of ER operates yield distinct patterns in various tree statistics. When ER operates across the whole tree, we observe smaller and more balanced trees, with speciation rates distributed more evenly across the tips than in scenarios with lineage-specific ER effects. Importantly, we find that negative SR dependence of speciation masks the impact of ER on some of the tree statistics. Our model allows diverse evolutionary trajectories for producing imbalanced trees, which are commonly observed in empirical phylogenies but have been challenging to replicate with earlier models.
Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease
Authors: Summa K.C. , Jiang P. , González-Rodríguez P. , Huang X. , Lin X. , Vitaterna M.H. , Dan Y. , Surmeier D.J. , Turek F.W.
Published: November 2023

Disrupted sleep has a profound adverse impact on lives of Parkinson’s disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD – the MCI-Park mouse – was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities mirror those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.
RPPA survey of cancer hotspot panel proteins and cell markers in matched tumor-normal human breast and kidney samples reveals a weak correlation between proteins expression and public transcriptome repositories
Authors: Paal Krisztina , Konrad Csaba , Karnok Noemi , Bui David , Chinopoulos Christos
Published: November 2023

Despite the tremendous global effort in discovering and cataloguing somatic mutations in cancer-related genes and the impact they exert on human cancers, the effects of these mutations on the levels of protein expression are inadequately addressed. Here, we semi-quantitated the expression of 48 (out of 50) proteins represented by the most widely used cancer hotspot panel, the Ion AmpliSeq™ Cancer Hotspot Panel v2, and 14 cell markers commonly used as ‘house-keeping’ proteins, using reverse phase protein array (RPPA) technology in 586 human breast- and 192 kidney matched tumor-normal samples. We further correlated our RPPA data with gene chip data from the Gene Expression Omnibus repository fetched through the TNMplot portal. Nearly half of proteins expression exhibited a negative correlation from their gene expression, while several of the remaining were only moderately correlated. Our data complement the vast information obtained elsewhere by transcriptomic analysis of the respective genes and gene products, potentially assisting in harmonizing proteomic with NGS outputs.
Structural and biochemical requirements for secretory component interactions with dimeric Immunoglobulin A
Authors: Kumar Bharathkar Sonya , Stadtmueller Beth M.
Published: November 2023

Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody that protects host epithelial barriers and promotes microbial homeostasis. SIgA production occurs when plasma cells assemble two copies of monomeric IgA and one joining-chain (JC) to form dimeric (d) IgA, which is bound by the polymeric Ig receptor (pIgR) on the basolateral surface of epithelial cells and transcytosed to the apical surface. There, pIgR is proteolytically cleaved, releasing SIgA, a complex of the dIgA and the pIgR ectodomain, called secretory component (SC). The pIgR’s five Ig-like domains (D1-D5) undergo a conformational change upon binding dIgA, ultimately contacting four IgA heavy chains and the JC in SIgA. Here we report structure-based mutational analysis combined with surface plasmon resonance binding assays that identify key residues in mouse SC D1 and D3 that mediate SC binding to dIgA. Residues in D1 CDR3 are likely to initiate binding whereas residues that stabilize the D1-D3 interface are likely to promote the conformation change and stabilize the final SIgA structure. Additionally, we find that the JC’s three C-terminal residues play a limited role in dIgA assembly but a significant role in pIgR/SC binding to dIgA. Together results inform new models for the intricate mechanisms underlying IgA transport across epithelia and functions in the mucosa.

KEY POINTS

The secretory component D1 CDR3 loop plays an important role in binding to dIgA.

The formation of SC D1-D3 interface stabilizes SIgA.

JC C-terminal residues influence dIgA assembly and mediate pIgR binding to dIgA.
PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F
Authors: Ivanchenko Maryna V. , Hathaway Daniel M. , Mulhall Eric M. , Booth Kevin T. , Wang Mantian , Peters Cole W. , Klein Alex J. , Chen Xinlan , Li Yaqiao , György Bence , Corey David P.
Published: November 2023

Usher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore a novel approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.