bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of the Value of T2 Mapping in the Prediction of Eosinophilic Chronic Rhinosinusitis With Nasal Polyps
Authors: Wang Yuchen , Lou Hongfei , Xian Mu , Cui Jing , Piao Yingshi , Wang Chengshuo , Zhang Luo , Xian Junfang
Published: February 2023

Objectives

Patients with eosinophilic chronic rhinosinusitis with nasal polyps (eosCRSwNP) usually have more extensive sinus disease, severe symptoms, and poorer disease control compared with patients with non-eosCRSwNP. Separating these entities will be crucial for patient management. The purpose of this study is to investigate T1, T2, and apparent diffusion coefficient (ADC) values of the nasal polyps in patients with CRSwNP and evaluate the usefulness of these parameters for differentiating these diseases.

Methods

Sinonasal magnetic resonance imaging was performed in 36 patients with eosCRSwNP and 20 patients with non-eosCRSwNP (including T1 mapping, T2 mapping, and diffusion-weighted imaging) before surgery. The T1, T2, and ADC values were calculated and correlated with pathologically assessed inflammatory cells of nasal polyps.

Results

Significant higher T2 value, higher eosinophil count, and lower lymphocyte count of the nasal polyps were observed in eosCRSwNP than those in non-eosCRSwNP. There was no significant difference in T1 or ADC values between the 2 groups. T2 value was correlated with eosinophil count and lymphocyte count in CRSwNP. The area under the curve of T2 value for predicting eosCRSwNP was 0.78 with 89.9% sensitivity and 60.0% specificity.

Conclusion

T2 value is a promising imaging biomarker for predicting eosCRSwNP. It can help to distinguish eosCRSwNP from non-eosCRSwNP.
68Ga-PSMA and 68Ga-FAPI-04 PET/CT Findings With 18F-FDG PET/CT in a Patient With Recurrent Prostate Cancer
Authors: Tatar Gamze , Ergül Nurhan , Baloğlu Mehmet Can , Arslan Esra , Çermik Tevfik Fikret
Published: February 2023

A 79-year-old man with prostate cancer was evaluated with 68Ga–prostate-specific membrane antigen (PSMA), 68Ga-FAPI-04, and 18F-FDG PET/CT scans since a rise in prostate-specific antigen was seen at last control while receiving chemotherapy. Abnormal FDG uptakes were observed in the tumoral areas of the left half of the prostate and walls of the bladder, although PSMA and FAPI activity were absent or lower in the relevant tumoral areas. Restaging 68Ga-PSMA and 18F-FDG PET/CT scans were obtained on the patient whose progression continued after transurethral tumor resection. Herein, we present a case proving intraindividual tumor heterogeneity in prostate cancer underwent PET/CT imaging with 3 different radiopharmaceuticals.
A Drop-in Gamma Probe for Minimally Invasive Sentinel Lymph Node Dissection in Prostate Cancer
Authors: Abascal Junquera Jose M. , Harke Nina N. , Walz Jochen C. , Hadaschik Boris , Adshead Jim , Everaerts Wouter , Goffin Karolien , Grootendorst Maarten R. , Oldfield Francesca , Vyas Kunal , Fusco Antoni Mestre , Juanpere Nuria , Vidal-Sicart Sergi , Fumado Lluis
Published: February 2023

Purpose

This study evaluated the performance of a drop-in gamma probe for prostate cancer (PCa) sentinel lymph node dissection (SLND) in a pelvic phantom, porcine model, and in PCa patients as part of an ongoing prospective multicenter clinical trial.

Methods

Two design variants of the drop-in gamma probe (SENSEI; Lightpoint Medical Ltd) were assessed in the pelvic phantom, and the preferred design was evaluated in a porcine model with clinically representative volumes and 99mTc activities. In the clinical trial, radical prostatectomy, SLND, and extended pelvic lymph node dissection were performed the day after 99mTc-nanocolloid injection and imaging. Sentinel lymph nodes (SLNs) were detected with the drop-in probe and a rigid laparoscopic gamma probe (RLGP). An interim analysis was performed after 10 patients were recruited.

Results

The narrow field of view probe design outperformed the wide field of view design in the pelvic phantom (detection rate, 100% vs 50%). In the porcine model, all activity concentrations could be successfully detected. The drop-in gamma probe successfully detected SLNs in all 10 patients (detection rate, 100%). Two of the SLNs identified by the drop-in gamma probe could not be found with the RLGP. No false-negative cases and no adverse events related to the SLND procedure or the drop-in gamma probe occurred.

Conclusion

The drop-in gamma probe meets the usability and performance requirements for SLND in PCa and provides performance advantages over the RLGP. The final clinical study results will confirm the performance of the technique across multiple sites.
Convergent evolution of quadrupedality in ornithischian dinosaurs was achieved through disparate forelimb muscle mechanics
Authors: Dempsey Matthew , Maidment Susannah C. R. , Hedrick Brandon P. , Bates Karl T.
Published: February 2023

The secondary evolution of quadrupedality from bipedal ancestry is a rare evolutionary transition in tetrapods yet occurred convergently at least three times within ornithischian dinosaurs. Despite convergently evolving quadrupedal gait, ornithischians exhibited variable anatomy, particularly in the forelimbs, which underwent a major functional change from assisting in foraging and feeding in bipeds to becoming principal weight-bearing components of the locomotor system in quadrupeds. Here, we use three-dimensional multi-body dynamics models to demonstrate quantitatively that different quadrupedal ornithischian clades evolved distinct forelimb musculature, particularly around the shoulder. We find that major differences in glenohumeral abduction–adduction and long axis rotation muscle leverages were key drivers of mechanical disparity, thereby refuting previous hypotheses about functional convergence in major clades. Elbow muscle leverages were also disparate across the major ornithischian lineages, although high elbow extension muscle leverages were convergent between most quadrupeds. Unlike in ornithischian hind limbs, where differences are more closely tied to functional similarity than phylogenetic relatedness, mechanical disparity in ornithischian forelimbs appears to have been shaped primarily by phylogenetic constraints. Differences in ancestral bipedal taxa within each clade may have resulted in disparate ecomorphological constraints on the evolutionary pathways driving divergence in their quadrupedal descendants.
Knowledge of Sunscreen Usage and Skin Cancer Among Malaysian Medical Students – A cross sectional study
Authors: Haris Fadzilah Hazwani Nuruljannah binti , Yea Lee How , Hewage Minduli Thirasaree Jayasree Dumingu , Azme Fathima Salima Mohamed , Soe Htoo Htoo Kyaw , Moe Soe , Htay Mila Nu Nu
Published: February 2023

Background

Excessive ultraviolet light (UV) can cause premature skin aging and potentially skin cancer. This study evaluated the knowledge, attitude of sunscreen, and skin cancer among Malaysian medical students.

Methods

This cross-sectional study was conducted from October 2022 to November 2022 among the clinical year medical students in a private medical university in Malaysia. The respondents were recruited by purposive sampling method. The content validated questionnaire was used to collect the data, and the data collection was done via online platform.

Results

There are a total of 117 responses that we collected through an online questionnaire via Google Forms. Among the respondents, 59.8% of the respondents reported of having a poor knowledge about sunscreen. However, 64.96% reported to have good knowledge about skin cancer. Approximately half of the respondents (48.7%) had a good attitude towards sunscreen. Females are more likely to use them compared to men (OR: 9.12, 95% CI: 3.52, 23.64) and there is a difference between ethnicity and the usage of sunscreen.

Conclusion

This study demonstrated limited knowledge of sunscreen among medical students. However, they are having better knowledge of skin cancer. Our results spotted the need for education about sunscreen among Malaysian medical students.
Positions of the International Society for Clinical Densitometry and their Etiology: A Scoping Review
Authors: Shepherd John
Published: February 2023

The International Society for Clinical Densitometry convenes a Position Development Conference (PDC) every 2 to 3 years to make recommendations for guidelines and standards in the field of musculoskeletal measurement and assessment. The recommendations pertain to clinically relevant issues regarding the acquisition, quality control, interpretation, and reporting of measures of various aspects of musculoskeletal health. These PDCs have been meeting since 2002 and have generated 214 Adult, 26 FRAX, 41 pediatric, and 9 general nomenclature consideration positions, for a total of 290 positions. All positions are justified by detailed documents that present the background and rationale for each position. However, the linkage to these publications is not maintained by the ISCD or any other publication such that physicians cannot easily understand the etiology of the positions. Further, the wording of many positions has changed over the years after being reviewed by subsequent PDCs. This Scoping review captures the references, changes, and timeline associated with each position through the 2019 PDC. It is meant to serve as a guide to clinicians and researchers for intelligent use and application of the positions.
Data Imputation for Clinical Trial Emulation: A Case Study on Impact of Intracranial Pressure Monitoring for Traumatic Brain Injury
Authors: Zhao Zhizhen , Liu Ruoqi , Groner Jonathan I. , Xiang Henry , Zhang Ping
Published: February 2023

Randomized clinical trial emulation using real-world data is significant for treatment effect evaluation. Missing values are common in the observational data. Handling missing data improperly would cause biased estimations and invalid conclusions. However, discussions on how to address this issue in causal analysis using observational data are still limited. Multiple imputation by chained equations (MICE) is a popular approach to fill in missing data. In this study, we combined multiple imputation with propensity score weighted model to estimate the average treatment effect (ATE). We compared various multiple imputation (MI) strategies and a complete data analysis on two benchmark datasets. The experiments showed that data imputations had better performances than completely ignoring the missing data, and using different imputation models for different covariates gave a high precision of estimation. Furthermore, we applied the optimal strategy on a medical records data to evaluate the impact of ICP monitoring on inpatient mortality of traumatic brain injury (TBI). The experiment details and code are available athttps://github.com/Zhizhen-Zhao/IPTW-TBI.
Range-wide differential adaptation and genomic vulnerability in critically endangered Asian rosewoods
Authors: Hung Tin Hang , So Thea , Thammavong Bansa , Chamchumroon Voradol , Theilade Ida , Phourin Chhang , Bouamanivong Somsanith , Hartvig Ida , Gaisberger Hannes , Jalonen Riina , Boshier David H. , MacKay John J.
Published: February 2023

In the billion-dollar global illegal wildlife trade, rosewoods have been the world’s most trafficked wild product since 20051.Dalbergia cochinchinensisandD. oliveriare the most sought-after rosewoods in the Greater Mekong Subregion2. They are exposed to significant genetic risks and the lack of knowledge on their adaptability limits the effectiveness of conservation efforts. Here we present genome assemblies and range-wide genomic scans of adaptive variation, together with predictions of genomic vulnerability to climate change. Adaptive genomic variation was differentially associated with temperature and precipitation-related variables between the species, although their natural ranges overlap. The findings are consistent with differences in pioneering ability and in drought tolerance3. We predict their genomic offsets will increase over time and with increasing carbon emission pathway but at a faster pace inD. cochinchinensisthan inD. oliveri. These results and the distinct gene-environment association in the eastern coastal edge suggest species-specific conservation actions: germplasm representation across the range inD. cochinchinensisand focused on vulnerability hotspots inD. oliveri. We translated our genomic models into a seed source matching application,seedeR, to rapidly inform restoration efforts. Our ecological genomic research uncovering contrasting selection forces acting in sympatric rosewoods is of relevance to conserving tropical trees globally and combating risks from climate change.

Significant statement

In the billion-dollar global illegal wildlife trade, rosewoods have been the world’s most trafficked wild product since 2005, withDalbergia cochinchinensisandD. oliveribeing the most sought-after and endangered species in Southeast Asia. Emerging efforts for their restoration have lacked a suitable evidence base on adaptability and adaptive potential. We integrated range-wide genomic data and climate models to detect the differential adaptation betweenD. cochinchinensisandD. oliveriin relevance to temperature- and precipitation-related variables and projected their vulnerability until 2100. We highlighted the stronger local adaptation in the coastal edge of the species ranges suggesting conservation priority. We developed genomic resources including chromosome-level genome assemblies and a web-based application seedeR for genomic model-enabled assisted migration and restoration.
Genomic evidence for West Antarctic Ice Sheet collapse during the Last Interglacial
Authors: Lau Sally C. Y. , Wilson Nerida G. , Golledge Nicholas R. , Naish Tim R. , Watts Phillip C. , Silva Catarina N. S. , Cooke Ira R. , Allcock A. Louise , Mark Felix C. , Linse Katrin , Strugnell Jan M.
Published: February 2023

The marine-based West Antarctic Ice Sheet (WAIS) is considered vulnerable to irreversible collapse under future climate trajectories and its tipping point may even lie within the mitigated warming scenarios of 1.5–2 °C of the United Nations Paris Agreement. Knowledge of ice loss during similarly warm past climates, including the Last Interglacial, when global sea levels were 5–10 m higher than today, and global average temperatures of 0.5–1.5 °C warmer than preindustrial levels, could resolve this uncertainty. Here we show, using a panel of genome-wide, single nucleotide polymorphisms of a circum-Antarctic octopus, persistent, historic signals of gene flow only possible with complete WAIS collapse. Our results provide the first empirical evidence that the tipping point of WAIS loss could be reached even under stringent climate mitigation scenarios.

One-Sentence Summary

Historical gene flow in marine animals indicate the West Antarctic Ice Sheet collapsed during the Last Interglacial.
On Pre-trained Language Models for Antibody
Authors: Wang Danqing , Ye Fei , Hao Zhou
Published: February 2023

Abstract

Antibodies are vital proteins offering robust protection for the human body from pathogens. The development of general protein and antibody-specific pre-trained language models both facilitate antibody prediction tasks. However, few studies comprehensively explore the representation capability of distinct pre-trained language models on different antibody problems. Here, to investigate the problem, we aim to answer the following key questions: (1) How do pre-trained language models perform in antibody tasks with different specificity? (2) How many benefits will the model gain if we introduce the specific biological mechanism to the pre-training process? (3) Do the learned antibody pre-trained representations make sense in real-world antibody problems, like drug discovery and immune process understanding? Previously, no benchmark available largely hindered the study to answer these questions. To facilitate the investigation, we provide anAnTibodyUnderstandingEvaluation (ATUE) benchmark. We comprehensively evaluate the performance of protein pre-trained language models by empirical study along with conclusions and new insights. OurATUEand code is released athttps://github.com/dqwang122/EATLM.
Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis
Authors: Patel Jay R. , Joel Marina Z. , Lee Kevin K. , Kambala Anusha , Cornman Hannah , Oladipo Olusola , Taylor Matthew , Deng June , Parthasarathy Varsha , Cravero Karen , Marani Melika , Zhao Ryan , Sankararam Sreenidhi , Li Ruixiang , Pritchard Thomas , Rebecca Vito , Kwatra Madan M. , Jin Ho Won , Dong Xinzhong , Kang Sewon , Kwatra Shawn G.
Published: February 2023

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multi-center PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.
A mouse model with high clonal barcode diversity for joint lineage, transcriptomic, and epigenomic profiling in single cells
Authors: Li Li , Bowling Sarah , Yu Qi , McGeary Sean E. , Alcedo Karel , Lemke Bianca , Ferreira Mark , Klein Allon M. , Wang Shou-Wen , Camargo Fernando D.
Published: February 2023

Cellular lineage histories along with their molecular states encode fundamental principles of tissue development and homeostasis. Current lineage-recording mouse models have limited barcode diversity and poor single-cell lineage coverage, thus precluding their use in tissues composed of millions of cells. Here, we developed DARLIN, an improved Cas9 barcoding mouse line that utilizes terminal deoxynucleotidyl transferase (TdT) to enhance insertion events over 30 CRISPR target sites, stably integrated into 3 distinct genomic loci. DARLIN is inducible, has an estimated ~1018lineage barcodes across tissues, and enables detection of usable barcodes in ~60% of profiled single cells. Using DARLIN, we examined fate priming within developing hematopoietic stem cells (HSCs) and revealed unique features of HSC migration. Additionally, we adapted a method to jointly profile DNA methylation, chromatin accessibility, gene expression, and lineage information in single cells. DARLIN will enable widespread high-resolution study of lineage relationships and their molecular signatures in diverse tissues and physiological contexts.
Accelerating High-Performance Classification of Bacterial Proteins Secreted via Non-Classical Pathways: no needing for deepness
Authors: Oliveira Luiz Gustavo de Sousa , Lanes Gabriel Chagas , Santos Anderson Rodrigues dos
Published: February 2023

Understanding protein secretion pathways is paramount in studying diseases caused by bacteria and their respective treatments. Most such paths must signal ways to identify secretion. However, some proteins, known as non-classical secreted proteins, do not have signaling ways. This study aims to classify such proteins from predictive machine-learning techniques. We collected a set of physical-chemical characteristics of amino acids from the AA index site, bolding known protein motifs, like hydrophobicity. We developed a six-step method (Alignment, Preliminary classification, mean outliers, two Clustering algorithms, and Random choice) to filter data from raw genomes and compose a negative dataset in contrast to a positive dataset of 141 proteins from the literature. Using a conventional Random Forest machine-learning algorithm, we obtained an accuracy of 91% on classifying non-classical secreted proteins in a validation dataset with 14 positive and 92 negative proteins - sensitivity and specificity of 91 and 86%, respectively, performance compared to state of the art for non-classical secretion classification. However, this work’s novelty resides in the fastness of executing non-CSP classification: instead of dozens of seconds to just one second considering a few dozen protein samples or only ten seconds to classify one hundred thousand proteins. Such fastness is more suitable for pan-genomic analyses than current methods without losing accuracy. Therefore, this research has shown that selecting an appropriate descriptors’ set and an expressive training dataset compensates for not using an advanced machine learning algorithm for the secretion by non-classical pathways purpose. Available athttps://github.com/santosardr/non-CSPs.
Rapid withdrawal from a threatening animal is movement-specific and mediated by reflex-like neural processing
Authors: Railo Henry , Kraufvelin Nelli , Santalahti Jussi , Laine Teemu
Published: February 2023

Responses to potentially dangerous stimuli are among the most basic animal behaviors. While research has shown that threats automatically capture the attention of human participants, research has failed to demonstrate automatic behavioral responses to threats in humans. Using a novel naturalistic paradigm, we show that two species of animals humans often report fearing trigger rapid withdrawal responses: participants withdrew their arm from photos of snakes and spiders faster, and with higher acceleration when compared to bird and butterfly stimuli. The behavior was specific to withdrawal as approach movements or button-press/release tasks failed to detect a similar difference. Moreover, between-participant differences in how aversive they found the stimuli predicted the participant’s withdrawal speed, indicating that the paradigm was also sensitive to trait-level differences between individuals. Using electroencephalography (EEG), we show that the fast withdrawal was mediated by two attentional processes. First, fast withdrawal responses were associated with early amplification of sensory signals (40-110 ms after stimulus). Second, a later correlate of feature-based attention (early posterior negativity, EPN, 200-240 ms after stimulus) revealed the opposite pattern: Stronger EPN was associated with slower behavioral responses, suggesting that the deployment of attention towards the threatening stimulus features, or failure to “disengage” attention from the stimulus, was detrimental for withdrawal speed. Altogether, the results suggest that rapid behavioral withdrawal from a threatening animal is mediated by reflex-like attentional processing, and later, conscious attention to stimulus features may hinder escaping the treat.
A Novel Explainable Fuzzy Clustering Approach for fMRI Dynamic Functional Network Connectivity Analysis
Authors: Ellis Charles A. , Miller Robyn L. , Calhoun Vince D.
Published: February 2023

Resting state functional magnetic resonance imaging (rs-fMRI) dynamic functional network connectivity (dFNC) analysis has illuminated brain network interactions across many neuropsychiatric disorders. A common analysis approach involves using hard clustering methods to identify transitory states of brain activity, and in response to this, other methods have been developed to quantify the importance of specific dFNC interactions to identified states. Some of these methods involve perturbing individual features and examining the number of samples that switch states. However, only a minority of samples switch states. As such, these methods actually identify the importance of dFNC features to the clustering of a subset of samples rather than the overall clustering. In this study, we present a novel approach that more capably identifies the importance of each feature to the overall clustering. Our approach uses fuzzy clustering to output probabilities of each sample belonging to states and then measures their Kullback-Leibler divergence after perturbation. We show the viability of our approach in the context of schizophrenia (SZ) default mode network analysis, identifying significant differences in state dynamics between individuals with SZ and healthy controls. We further compare our approach with an existing approach, showing that it captures the effects of perturbation upon most samples. We also find that interactions between the posterior cingulate cortex (PCC) and the anterior cingulate cortex and the PCC and precuneus are important across methods. We expect that our novel explainable clustering approach will enable further progress in rs-fMRI analysis and to other clustering applications.
Instant polarized light microscopy pi (IPOLπ) for quantitative imaging of collagen architecture and dynamics in ocular tissues
Authors: Lee Po-Yi , Schilpp Hannah , Naylor Nathan , Watkins Simon C. , Yang Bin , Sigal Ian A
Published: February 2023

Collagen architecture determines the biomechanical environment in the eye, and thus characterizing collagen fiber organization and biomechanics is essential to fully understand eye physiology and pathology. We recently introduced instant polarized light microscopy (IPOL) that encodes optically information about fiber orientation and retardance through a color snapshot. Although IPOL allows imaging collagen at the full acquisition speed of the camera, with excellent spatial and angular resolutions, a limitation is that the orientation-encoding color is cyclic every 90 degrees (π/2 radians). In consequence, two orthogonal fibers have the same color and therefore the same orientation when quantified by color-angle mapping. In this study, we demonstrate IPOLπ, a new variation of IPOL, in which the orientation-encoding color is cyclic every 180 degrees (π radians). Herein we present the fundamentals of IPOLπ, including a framework based on a Mueller-matrix formalism to characterize how fiber orientation and retardance determine the color. The improved quantitative capability of IPOLπ enables further study of essential biomechanical properties of collagen in ocular tissues, such as fiber anisotropy and crimp. We present a series of experimental calibrations and quantitative procedures to visualize and quantify ocular collagen orientation and microstructure in the optic nerve head, a region in the back of the eye. There are four important strengths of IPOLπ compared to IPOL. First, IPOLπ can distinguish the orientations of orthogonal collagen fibers via colors, whereas IPOL cannot. Second, IPOLπ requires a lower exposure time than IPOL, thus allowing faster imaging speed. Third, IPOLπ allows visualizing non-birefringent tissues and backgrounds from tissue absorption, whereas both appear dark in IPOL images. Fourth, IPOLπ is cheaper and less sensitive to imperfectly collimated light than IPOL. Altogether, the high spatial, angular, and temporal resolutions of IPOLπ enable a deeper insight into ocular biomechanics and eye physiology and pathology.

Highlights

We introduce IPOLπ, addressing IPOL limitations for characterizing eye collagen.

IPOLπ orientation-encoded color cycle is 180° (π radians) instead of 90° in IPOL.

IPOLπ requires a lower exposure time than IPOL, allowing faster imaging speed.

IPOLπ visualizes non-birefringent tissues and backgrounds from brightness.

IPOLπ is cheaper and less sensitive to imperfectly collimated light than IPOL.
In vivo Modulation of Intraocular and Intracranial Pressures Causes Nonlinear and Non-monotonic Deformations of the Lamina Cribrosa and Scleral Canal
Authors: Zhu Ziyi , Waxman Susannah , Wang Bo , Wallace Jacob , Schmitt Samantha E. , Tyler-Kabara Elizabeth , Ishikawa Hiroshi , Schuman Joel S. , Smith Matthew A. , Wollstein Gadi , Sigal Ian A.
Published: February 2023

Purpose

To evaluate changes in monkey optic nerve head (ONH) morphology under acutely controlled intraocular pressure (IOP) and intracranial pressure (ICP).

Methods

Seven ONHs from six monkeys were imaged via optical coherence tomography while IOP and ICP were maintained at one of 16 conditions. These conditions were defined by 4 levels for each pressure: low, baseline, high and very high. Images were processed to determine scleral canal area, aspect ratio, and planarity and anterior lamina cribrosa (ALC) shape index and curvature. Linear mixed effect models were utilized to investigate the effects of IOP, ICP and their interactions on ONH morphological features. The IOP-ICP interaction model was compared with one based on translaminar pressure difference (TLPD).

Results

We observed complex, eye-specific, non-linear patterns of ONH morphological changes with changes in IOP and ICP. For all ONH morphological features, linear mixed effects models demonstrated significant interactions between IOP and ICP that were unaccounted for by TLPD. Interactions indicate that the effects of IOP and ICP depend on the other pressure. The IOP-ICP interaction model was a higher quality predictor of ONH features than a TLPD model.

Conclusions

In vivo modulation of IOP and ICP causes nonlinear and non-monotonic changes in monkey ONH morphology that depend on both pressures and is not accounted for by a simplistic TLPD. These results support and extend prior findings.

Translational Relevance: A better understanding of ICP’s influence on the effects of IOP can help inform the highly variable presentations of glaucoma and effective treatment strategies.
Optimizing the design of spatial genomic studies
Authors: Jones Andrew , Cai Diana , Li Didong , Engelhardt Barbara E.
Published: February 2023

Spatially-resolved genomic technologies have shown promise for studying the relationship between the structural arrangement of cells and their functional behavior. While numerous sequencing and imaging platforms exist for performing spatial transcriptomics and spatial proteomics profiling, these experiments remain expensive and labor-intensive. Thus, when performing spatial genomics experiments using multiple tissue slices, there is a need to select the tissue cross sections that will be maximally informative for the purposes of the experiment. In this work, we formalize the problem of experimental design for spatial genomics experiments, which we generalize into a problem class that we callstructured batch experimental design. We propose approaches for optimizing these designs in two types of spatial genomics studies: one in which the goal is to construct a spatially-resolved genomic atlas of a tissue and another in which the goal is to localize a region of interest in a tissue, such as a tumor. We demonstrate the utility of these optimal designs, where each slice is a two-dimensional plane, on several spatial genomics datasets.
In Silico Evaluation of Biomarker Genes for Melanoma Carcinoma
Authors: Kwatra Bharat , Khan Mohammed Moin
Published: February 2023

ABSTRACTS

Melanoma skin cancer is a primary cutaneous malignancy. Melanoma cancer of the skin cell is one of the major skin cancer worldwide, ranking first in frequency. Melanoma skin cancer has been strongly associated with psoriasis. Here, we use computational methods in an effort to identify possible biomarkers for psoriasis related Melanoma skin cancer. To do this, we downloaded gene expression microarray data from the GEO (Gene Expression Omnibus) database in the GSE series: GSE14905 and pre-processed it in the Bioconductor repository for R. The data was screened for DEGs using a rigorous methodology, which included the use of statistical testing methodologies and tools (Differentially Expressed Genes). Psoriasis has 6749 up-regulated genes and 7142 down-regulated genes. Psoriasis DEGs were combined with the NCG dataset resulting 874 up-regulated genes and 74 down-regulated genes for an in depth analysis of how differential expression can lead to malignancy. we used stringDB diseases dataset in Cytoscape to generate network of melanoma proteins, which were further mapped to DEGs and igraph to construct a GRN. In addition, module level analysis was carried out because of the benefits it provides in terms of stability and comprehension of intricate GRNs, resulting 17 biomarkers (17 up-regulated). There is an emphasis on the network’s topology as well. The findings suggest that the network has a hierarchical structure. Additionally, survival analysis of 8 biomarkers results obtained from intersection mapping of skin cancer stringDB and biomarkers, was carried out. Significant enrichment of KEGG pathways was found. They also illuminate the interplay between biomarkers whose upregulation may lead to melanoma skin cancer. These findings may inform future investigations and the identification of potential therapeutic targets for this condition as well as shows the potential link between psoriasis and melanoma.
Organoid generation from mouse mammary tumors captures the genetic heterogeneity of clinically relevant copy number alterations
Authors: Lake Katherine E. , Colonetta Megan M. , Smith Clayton A. , Martinez-Algarin Kenneth , Saunders Kaitlyn , Mohta Sakshi , Pena Jacob , McArthur Heather L. , Reddy Sangeetha M. , Roussos-Torres Evanthia T. , Chen Elizabeth H. , Chan Isaac S.
Published: February 2023

Breast cancer metastases exhibit many different genetic alterations, including copy number amplifications. Using publicly available datasets, we identify copy number amplifications in metastatic breast tumor samples and using our organoid-based metastasis assays, and we validate FGFR1 is amplified in collectively migrating organoids. Because the heterogeneity of breast tumors is increasingly becoming relevant to clinical practice, we demonstrate our organoid method captures genetic heterogeneity of individual tumors.
PerturbSci-Kinetics: Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens
Authors: Xu Zihan , Sziraki Andras , Lee Jasper , Zhou Wei , Cao Junyue
Published: February 2023

Here we describedPerturbSci-Kinetics, a novel combinatorial indexing method for capturing three-layer single-cell readout (i.e.,whole transcriptomes, nascent transcriptomes, sgRNA identities) across hundreds of genetic perturbations. ThroughPerturbSci-Kineticsprofiling of pooled CRISPR screens targeting a variety of biological processes, we were able to decipher the complexity of RNA regulations at multiple levels (e.g.,synthesis, processing, degradation), and revealed key regulators involved in miRNA and mitochondrial RNA processing pathways. Our technique opens the possibility of systematically decoding the genome-wide regulatory network underlying RNA temporal dynamics at scale and cost-effectively.
The viral packaging motor potentiates late gene expression in Kaposi’s sarcoma-associated herpesvirus
Authors: McCollum Chloe O. , Didychuk Allison L. , Liu Dawei , Murray-Nerger Laura A. , Cristea Ileana M. , Glaunsinger Britt A.
Published: February 2023

β- and γ-herpesviruses transcribe their late genes in a manner distinct from host transcription. This process is directed by a complex of viral transcriptional activator proteins that hijack cellular RNA polymerase II and an unknown set of additional factors. We employed proximity labeling coupled with mass spectrometry, followed by CRISPR and siRNA screening to identify proteins functionally associated with the Kaposi’s sarcoma-associated herpesvirus (KSHV) late gene transcriptional complex. These data revealed that the catalytic subunit of the viral DNA packaging motor, ORF29, is both dynamically associated with the viral transcriptional activator complex and potentiates late gene expression. Through genetic mutation and deletion of ORF29, we establish that its catalytic activity potentiates viral transcription and is required for robust accumulation of essential late proteins during infection. Thus, we propose an expanded role for ORF29 that encompasses its established function in viral packaging and its newly discovered contributions to viral transcription and late gene expression in KSHV.

Author summary

β- and γ-herpesviruses express a class of genes essential for completion of the viral life cycle late during infection. A specialized complex of viral transcriptional activator proteins drives expression of these late genes in a manner dependent on viral genome replication, although the mechanisms and regulation of this process are largely unknown. Here, we identified factors that physically and functionally associate with the late gene transcription complex and unexpectedly found that the viral DNA packaging motor in Kaposi’s sarcoma-associated herpesvirus (KSHV) contributes to late gene expression. We show that the catalytic activity of this protein is not only required for genomic packaging but also for the robust expression of late genes to ensure the successful production of progeny virions. Thus, late gene transcription is mechanistically linked to the conserved processes of viral genome replication and packaging.
Outdoor Physical Activity as a Confounder for Vitamin D Status: A Scoping Review Protocol
Authors: Corr Patrick G. , Badawi Alia M. , Vu Stephanie H. , Frame Leigh A.
Published: February 2023

Background

Vitamin D (vitD) has been correlated with a number of health outcomes and disease states; however, these relationships are likely confounded by the role of outdoor physical activity (PA). Currently, there are few studies that consider confounders to vitD status and the potentially spurious relationships between PA and vitD status.

Methods

This scoping review will employ Arksey and O’Malley’s five-stage approach. Publications will be identified through five databases (CINAHL, Cochrane Library, PubMed, Scopus, and SportDISCUS) and reviewed in Covidence.

Results

The findings are expected to help identify what information is presently available regarding the correlation between outdoor PA and vitD status. The results of this scoping review will help to inform a quantitative analysis of the National Institutes of Health (NIH) All of Us database.

Discussion

It is unclear what effect outdoor PA may have on the relationship between vitD status and health outcomes and if any portion of this relationship is spurious. This scoping review will initiate an exploration of the relationship between vitD and PA to determine the strength and magnitude of potential confounders. Ultimately, we seek to reassess previous findings and determine the true effect of vitD alone by isolating the effect of outdoor PA.
Autonomous Screening for Laser Photocoagulation in Fundus Images Using Deep Learning
Authors: Bressler Idan , Aviv Rachelle , Margalit Danny , Rom Yovel , Ianchulev Sean , Dvey-Aharon Zack
Published: February 2023

Background

Diabetic retinopathy is a leading cause of blindness in adults worldwide. AI with autonomous deep learning algorithms has been increasingly used in the analysis of retinal images particularly for the screening of referrable DR. An established treatment for proliferative DR is pan-retinal or focal laser photocoagulation. Training AI autonomous models to discern laser patterns can be important in disease management and follow-up.

Methods

A deep learning model was trained for laser treatment detection using the EyePACs dataset. Data was randomly assigned, by participant, into development (n= 18,945) and validation (n= 2,105) sets. Analysis was conducted at the single image, eye, and patient levels. The model was then used to filter input images for three independent AI models for various retinal indications, and changes in model efficacy were measured using AUC and MAE.

Findings

On the task of laser photocoagulation detection: AUC of 0.981 (CI 95% 0.971-0.87) was achieved at the patient level. AUC of 0.950 (CI 95% 0.943-0.956) was achieved at the image level. AUC of 0.979 (CI 95% 0.972-0.984) was achieved at the eye level.

When analyzing independent AI models, efficacy was shown to improve across the board on images of untreated eyes. DME detection on images with artifacts was AUC 0.932 (CI 95% 0.905-0.951) vs. AUC 0.955 (CI 95% 0.948-0.961) on those without. Participant sex detection on images with artifacts was AUC 0.872 (CI 95% 0.830-0.903) compared to AUC 0.922 (CI 95% 0.916-0.927) on those without. Participant age detection on images with artifacts was MAE 5.33 vs. MAE 3.81 on those without.

Interpretation

The proposed model for laser treatment detection achieved high performance on all analysis metrics and has been demonstrated to positively affect the efficacy of different AI models, suggesting that laser detection can generally improve AI powered applications for fundus images.

Funding

Provided by AEYE Health Inc.
A systematic review on machine learning approaches in the diagnosis of rare genetic diseases
Authors: Roman-Naranjo P , Parra-Perez AM , Lopez-Escamez JA
Published: February 2023

Background

The diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases.

Methods

We performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis.

Findings

Our search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations.

Conclusions

ML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases.
Coinfection withStrongyloidesand SARS-CoV-2: protocol for a systematic review
Authors: Rosca Elena C , Heneghan Carl , Spencer Elizabeth A , Plüddemann Annette , Maltoni Susanna , Gandini Sara , Onakpoya Igho J , Evans David H , Conly John M , Jefferson Tom
Published: February 2023

Rationale for the review

COVID-19 treatment can worsen parasitic disease in patients with coinfection. Consequently, there is a need to investigate the infection with SARS-CoV-2 andStrongyloides. We aim to systematically review clinical and laboratory features of COVID-19 andStrongyloidescoinfection, to investigate possible interventions and outcomes in this pathology. Also, we aim to identify difficulties in managing the parasitic disease manifestations in this context and to emphasize research gaps requiring further attention.

Methods

We will search two electronic databases – LitCOVID, and WHO COVID-19 and will include studies on SARS-CoV-2 andStrongyloidescoinfection. We will adapt the WHO-UMC system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID-19 patients determined acute strongyloidiasis manifestations.

Expected results

We will present the evidence in three distinct packages: study description, methodological quality assessment and data extracted. We will summarize the evidence and will draw conclusions as to the quality of the evidence.
Spatial enhancer activation determines inhibitory neuron identity
Authors: Dvoretskova Elena , Ho May C. , Kittke Volker , Neuhaus Florian , Vitali Ilaria , Lam Daniel D. , Delgado Irene , Feng Chao , Torres Miguel , Winkelmann Juliane , Mayer Christian
Published: February 2023

The mammalian telencephalon contains a tremendous diversity of GABAergic projection neuron and interneuron types, that originate in a germinal zone of the embryonic basal ganglia. How genetic information in this transient structure is transformed into different cell types is not yet fully understood. Using a combination ofin vivoCRISPR perturbation, lineage tracing, and ChIP-seq in mice, we found that the transcription factor MEIS2 favors the development of projection neurons through genomic binding sites in regulatory enhancers of projection neuron specific genes. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity towards these sites. In interneuron precursors, the activation of projection neuron specific enhancers by MEIS2 and DLX5 is repressed by the transcription factor LHX6. When MEIS2 carries a mutation associated with intellectual disability in humans, it is less effective at activating enhancers involved in projection neuron development. This suggests that GABAergic differentiation may be impaired in patients carrying this mutation. Our research supports a model (“Differential Binding‘) where the spatial specific composition of transcription factors atcis-regulatory elements determines differential gene expression and cell fate decisions in the ganglionic eminence.