bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Telehealth Provide Timely and Equitable Quality Medical Forensic Services? Perspectives of Illinois Hospital Administrators
Authors: Pierre-Wright Marlise Jeanne , Mathey Lisa , Risser Heather J.
Published: June 2023

Introduction

Research has shown the viability of telehealth consultations to provide medical forensic services, particularly in areas with a dearth of medical examiners. This study examined Illinois hospital administrators' willingness to utilize telehealth to meet new requirements under Illinois Public Act 100-0775, which intends to increase timely access to quality forensic examiners. Consequently, as of March 2021, roughly half of Illinois hospitals unable to meet these requirements have opted not to treat some or all patients presenting for medical forensic services of sexual assault.

Methods

We surveyed and conducted in-depth interviews (between October 2020 and April 2021) with 65 hospital administrators responsible for implementing Illinois Public Act 100-0775. Descriptive statistical analysis was used to analyze survey results.

Results

Our study found limited staffing resources and difficulties educating and training new forensic medical examiners were the major barriers to providing acute medical forensic services. The overwhelming majority of respondents (95%) saw opportunities to use telehealth across all aspects of the medical forsenic evaluation. Barriers to implementing telehealth included perceived patient discomfort with telehealth technology and current legislative restrictions.

Discussion

Legislative efforts to mandate timely access to qualified medical forensic examiners can unintentionally exacerbate disparities in access to care. Illinois hospital administrators are receptive to utilizing telehealth to improve access to forensic examiners, particularly in lower-resourced hospitals.

Conclusion

One method for responding to staffing shortages and improving equitable access to forensic sexual assault services may include implementing networks of qualified forensic examiners that support on-site clinicians in lower-resourced areas via telehealth.
COVID-19 and Elective Spine Surgery: The Older Persons' Experience of Going It Alone
Authors: Strayer Andrea L. , King Barbara J.
Published: June 2023

BACKGROUND: Older people with debilitating degenerative spine disease may benefit from surgery. However, recovery is described as a circuitous process. In general, they describe feeling powerless and receiving depersonalized care during hospitalization. Institution of hospital no-visitor policies to reduce COVID-19 spread may have caused additional negative consequences. The purpose of this secondary analysis was to understand experiences of older people who underwent spine surgery during early COVID-19. METHODS: Grounded theory guided this study of people 65 years or older undergoing elective spine surgery. Fourteen individuals were recruited for 2 in-depth interviews at 2 time points: T1 during hospitalization and T2, 1 to 3 months post discharge. All participants were affected by pandemic-imposed restrictions with 4 interviews at T1 with no visitors, 10 with a 1-visitor policy, and 6 interviews at T2 rehabilitation setting with no visitors. Discriminate sampling of data in which participants described their experiences with COVID-19 visitor restrictions was used. Open and axial coding (consistent with grounded theory) was used for data analysis. RESULTS: Three categories, worry and waiting, being alone, and being isolated, emerged from the data. Participants had delays (waiting) in getting their surgery scheduled, which produced worry that they would lose more function, become permanently disabled, have increased pain, and experience more complications such as falls. Participants described being alone during their hospital and rehabilitation recovery, without physical or emotional support from family and limited nursing staff contact. Being isolated often occurred from institution policy, restricting participants to their rooms leading to boredom and, for some, panic. CONCLUSIONS: Restricted access to family after spine surgery and during recovery resulted in emotional and physical burden for participants. Our findings support neuroscience nurses advocating for family/care partner integration into patient care delivery and investigation into the effect of system-level policies on patient care and outcomes.
Characteristics, treatment and research development of bertolotti’s syndrome: a bibliometric analysis and systematic review
Authors: Zhu Wenhao , Ding Xing , Zheng Jiale , Zeng Fan , Zhang Fan , Wu Xuequn , Sun Yijun , Ma Junming , Yin Mengchen
Published: June 2023

Purpose:

Bertolotti’s syndrome is a prevalent congenital deformity. However, many physicians fail to include it in their differential diagnosis for low back pain (LBP), which results in missed diagnosis or misdiagnosis. There is still a lack of standardized treatment and management strategies for Bertolotti’s syndrome. This study aimed to review the clinical characteristics and management of Bertolotti’s syndrome and reports bibliometric insights in advancements in Bertolotti’s syndrome research.

Methods:

Studies published until September 30, 2022 were systematically reviewed according to the PRISMA guidelines. Three independent reviewers extracted the data and assessed the quality and risk of bias of the studies based on the methodological index of non-randomized studies (MINORS). SPSS, VOS viewer, and the Citespace software were used for the systematic review, visual analysis, data mining, mapping, and clustering of the retrieved articles, which presented clear and visual presentations of the structural patterns of published research in graphs.

Result:

A total of 118 articles, describing a total of 419 patients with Bertolotti’s syndrome, were included. There was an upward trend with a steady increase in the number of publications. The world map distribution showed that most publications were predominantly from North America and Asia. The most cited articles were published in the following journals: Spine, The Journal of Bone and Joint Surgery, and Radiology. The mean age of the patients was 47.7 years, and 49.6% of them were male. A total of 159 (96.4%) patients had low back pain symptoms. The mean symptom duration was 41.4 months (74.8%), and most of the patients had Castellvi type II. Disc degeneration was the most reported comorbid spinal diseases. The mean MINORS score was 4.16±3.95 points (range, 1−21). A total of 265 (68.3%) patients underwent surgical treatments. Minimally invasive surgical techniques, prevalence, image classification, and disc degeneration were the current main research areas of Bertolotti’s syndrome.

Conclusions:

The steady increase in the number of publications demonstrated the increased attention of researchers on this topic. Our results showed a significant prevalence of Bertolotti’s syndrome in patients with LBP and a long symptom duration before the initiation of treatment. Surgical treatments were commonly used to treat patients with Bertolotti’s syndrome after a non-effective conservative treatment. Minimally invasive surgical techniques, prevalence, image classification, and disc degeneration are the major research areas of Bertolotti’s syndrome.
Nonischemic Donor Heart Preservation: New Milestone in Heart Transplantation History
Authors: Pradegan Nicola , Gallo Michele , Fabozzo Assunta , Toscano Giuseppe , Tarzia Vincenzo , Gerosa Gino
Published: June 2023

Heart transplantation is considered the gold standard for the treatment of advanced end-stage heart failure. However, standard donors after brain death are decreasing, whereas patients on the heart transplant waitlist are constantly rising. The introduction of the ex vivo machine perfusion device has been a turning point; in fact, these systems are able to significantly reduce ischemic times and have a potential effect on ischemia-related damage reduction. From a clinical standpoint, these machines show emerging results in terms of heart donor pool expansion, making marginal donors and donor grafts after circulatory death suitable for donation. This article aims to review mechanisms and preclinical and clinical outcomes of currently available ex vivo perfusion systems, and to explore the future fields of application of these technologies.
Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer
Authors: Wu Rongrong , Oshi Masanori , Asaoka Mariko , Yan Li , Benesch Matthew G.K. , Khoury Thaer , Nagahashi Masayuki , Miyoshi Yasuo , Endo Itaru , Ishikawa Takashi , Takabe Kazuaki
Published: June 2023

Objective:

To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes.

Summary Background Data:

Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells.

Methods:

In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated.

Results:

The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts.

Conclusions:

Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.
Duration of antimicrobial treatment for complicated intra-abdominal infections after definitive source control: A systematic review, meta-analysis, and practice management guideline from the Eastern Association for the Surgery of Trauma
Authors: Ra Jin H. , Rattan Rishi , Patel Nimitt J. , Bhattacharya Bishwajit , Butts Christopher A. , Gupta Shailvi , Asfaw Sofya H. , Como John J. , Sahr Sheryl M. , Bugaev Nikolay
Published: June 2023

BACKGROUND

Recent studies have evaluated outcomes associated with duration of antimicrobial treatment for complicated intra-abdominal infections (cIAI). The goal of this guideline was to help clinicians better define appropriate antimicrobial duration in patients who have undergone definitive source control for cIAI.

METHODS

A working group of Eastern Association for the Surgery of Trauma (EAST) performed a systematic review and meta-analyses of the available data pertaining to the duration of antibiotics after definitive source control of cIAI in adult patients. Only studies that compared patients treated with short vs. long duration antibiotic regimens were included. The critical outcomes of interest were selected by the group. Noninferiority of short compared with long duration of antimicrobial treatment was defined as an indicator for a potential recommendation in favor of shorter antibiotics course. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of the evidence and to formulate recommendations.

RESULTS

Sixteen studies were included. The short duration ranged from 1 dose to ≤10 days, with an average of 4 days, and the long duration ranged >1 day to 28 days, with an average of 8 days. There were no differences between short and long duration of antibiotics in terms of mortality (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.56–1.44), rate of surgical site infection (OR, 0.88; 95% CI, 0.56–1.38); persistent/recurrent abscess (OR, 0.76; 95% CI, 0.45–1.29); unplanned interventions (OR, 0.53; 95% CI, 0.12–2.26); hospital length of stay (mean difference, −2.62 days; CI, −7.08 to 1.83 days); or readmissions (OR, 0.92; 95% CI, 0.50–1.69). The level of evidence was assessed as very low.

CONCLUSION

The group made a recommendation for shorter (four or less days) versus longer duration (eight or more days) of antimicrobial treatment in adult patients with cIAIs who had definitive source control.

LEVEL OF EVIDENCE

Systematic Review and Meta-Analysis; Level III.
Incidence, outcomes and costs of severe sepsis and septic shock in geriatric trauma patients: Analysis of 2,563,463 hospitalizations at 3,284 hospitals
Authors: Fakhry Samir M. , Shen Yan , Wyse Ransom J. , Dunne James R. , Berg Gina M. , Garland Jeneva M. , Ludwig Ashley , Shillinglaw William C. , Hightower Todd D. , Hunt Darrell L. , Watts Dorraine D.
Published: June 2023

BACKGROUND

Severe sepsis/septic shock (sepsis) is a leading cause of death in hospitalized trauma patients. Geriatric trauma patients are an increasing proportion of trauma care but little recent, large-scale, research exists in this high-risk demographic. The objectives of this study are to identify incidence, outcomes and costs of sepsis in geriatric trauma patients.

METHODS

Patients at short-term, nonfederal hospitals 65 years or older with ≥1 injury International Classification of Diseases, Tenth Revision, Clinical Modification code were selected from 2016 to 2019 Centers for Medicare & Medicaid Services Medicare Inpatient Standard Analytical Files. Sepsis was defined as International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes R6520 and R6521. A log-linear model was used to examine the association of Sepsis with mortality, adjusting for age, sex, race, Elixhauser score, and Injury Severity Score. Dominance analysis using logistic regression was used to determine the relative importance of individual variables in predicting Sepsis. Institutional review board exemption was granted for this study.

RESULTS

There were 2,563,436 hospitalizations from 3,284 hospitals (62.8% female; 90.4% White; 72.7% falls; median ISS, 6.0). Incidence of Sepsis was 2.1%. Sepsis patients had significantly worse outcomes. Mortality risk was significantly higher in septic patients (adjusted risk ratio, 3.98, 95% confidence interval, 3.92–4.04). Elixhauser score contributed the most to the prediction of Sepsis, followed by ISS (McFadden's R
2 = 9.7% and 5.8%, respectively).

CONCLUSION

Severe sepsis/septic shock occurs infrequently among geriatric trauma patients but is associated with increased mortality and resource utilization. Pre-existing comorbidities influence Sepsis occurrence more than Injury Severity Score or age in this group, identifying a population at high risk. Clinical management of geriatric trauma patients should focus on rapid identification and prompt aggressive action in high-risk patients to minimize the occurrence of sepsis and maximize survival.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
The undisclosed disclosures: The dollar-outcome relationship in resuscitative endovascular balloon occlusion of the aorta
Authors: Bhogadi Sai Krishna , Colosimo Christina , Hosseinpour Hamidreza , Nelson Adam , Rose Maya I. , Calvillo Antonia R. , Anand Tanya , Ditillo Michael , Magnotti Louis J. , Joseph Bellal
Published: June 2023

BACKGROUND

Despite its rapid evolution, resuscitative endovascular balloon occlusion of the aorta (REBOA) remains a controversial intervention that continues to generate active research. Proper conflict of interest (COI) disclosure helps to ensure that research is conducted objectively, without bias. We aimed to identify the accuracy of COI disclosures in REBOA research.

METHODS

Literature search was performed using the keyword “REBOA” on PubMed. Studies on REBOA with at least one American author published between 2017 and 2022 were identified. The Centers for Medicare and Medicaid Services Open Payments database was used to extract information regarding payments to the authors from the industry. This was compared with the COI section reported in the manuscripts. Conflict of interest disclosure was defined as inaccurate if the authors failed to disclose any amount of money received from the industry. Descriptive statistics were performed.

RESULTS

We reviewed a total of 524 articles, of which 288 articles met the inclusion criteria. At least one author received payments in 57% (165) of the articles. Overall, 59 authors had a history of payment from the industry. Conflict of interest disclosure was inaccurate in 88% (145) of the articles where the authors received payment.

CONCLUSION

Conflict of interest reports are highly inaccurate in REBOA studies. There needs to be standardization of reporting of conflicts of interest to avoid potential bias.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Brain structure reflects empathy and psychopathy in incarcerated males
Authors: Radecki Marcin A. , Sampaolo Erika , Lettieri Giada , Handjaras Giacomo , Harenski Carla L. , Palumbo Sara , Pellegrini Silvia , Pietrini Pietro , Kiehl Kent A. , Cecchetti Luca
Published: June 2023

Whether brain structure could reflect empathy and psychopathy in the same antisocial population is unknown. In White adult males from prison (N = 549, Mage= 34 ± 11 years), we measured empathy with the Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales of the Interpersonal Reactivity Index, and psychopathic traits with the Psychopathy Checklist–Revised or Youth Version (PCL-R/YV). A subsample (N = 278, Mage= 36 ± 11 years) underwent MRI, from which we derived cortical thickness (CT) and surface area (SA). CT did not relate to IRI-PT or IRI-EC, while SA of the left inferior temporal gyrus (L ITG) related negatively to IRI-PT and positively to PCL-R and PCL-R item 8 (Callousness/Lack of Empathy). L-ITG SA predicted scores on IRI-PT – but not IRI-EC – in an out-of-sample test (R2= 0.030). Mapping onto the histological BigBrain gradient, higher scores on IRI-PT – but not IRI-EC – entailed a progressive SA reduction from Bin 1 (sensorimotor) to Bin 5 (limbic). Psychopaths (PCL-R/YV ≥ 30, N = 73/39) had: (1) reduced IRI-PT and IRI-EC scores (Cohen’s Ds = -0.423, – 0.564, respectively); (2) increased L-ITG SA (Cohen’s D = 0.560); (3) increased global SA (Cohen’s D = 0.480); and (4) reduced SA covariance between the left precentral and left isthmus-cingulate cortices. There were no group differences in global, modular, or nodal SA covariance, as indexed by canonical graph-theoretical metrics. We provide novel insights into the brain correlates of empathy and psychopathy in incarcerated males.
Harmonization techniques for machine learning studies using multi-site functional MRI data
Authors: El-Gazzar Ahmed , Thomas Rajat Mani , van Wingen Guido
Published: June 2023

In recent years, the collection and sharing of resting-state functional magnetic resonance imaging (fMRI) datasets across multiple centers have enabled studying psychiatric disorders at scale, and prompted the application of statistically powerful tools such as deep neural networks. Yet, multi-center datasets introduce non-biological heterogeneity that can confound the biological signal of interest and produce erroneous findings. To mitigate this problem, the neuroimaging community has adopted harmonization techniques previously proposed in other domains to remove site-effects from fMRI data. The reported success of these approaches in improving the generalization of the models have varied significantly. It remains unclear whether harmonization techniques could boost the final outcome of multi-site fMRI studies, to what extent, and which approaches are best suited for this task. In an attempt to objectively answer these questions, we conduct a standardized rigorous evaluation of seven different harmonization techniques from the neuroimaging and computer vision literature on two large-scale multi-site datasets (N= 2169 andN= 2366) to diagnose autism spectrum disorder and major depression disorder from static and dynamic representations of fMRI data. Interestingly, while all harmonization techniques removed site-effects from the data, they had little influence on disorder classification performance in standard k-fold and leave-one-site-out validation settings over a well-tuned baseline. Further investigation shows that the baseline model implicitly learns site-invariant features which could well explain its competitiveness with explicit harmonization techniques and suggest orthogonality between latent disease features and site discrminative features. However, additional experiments show that harmonization methods could be critical to report faithful results in settings where there is high intra-site class imbalance and the learning algorithm is prone to overfit on spurious features confounding the final outcome of the study.
The tRNA Gm18 Methyltransferase TARBP1 Promotes Hepatocellular Carcinoma Progression via Metabolic Reprogramming of Glutamine
Authors: Shi Xiaoyan , Zhang Yangyi , Wang Yuci , Wang Jie , Gao Yang , Wang Ruiqi , Wang Liyong , Xiong Minggang , Ou Ningjing , Liu Qi , Ma Honghui , Cai Jiabin , Chen Hao
Published: June 2023

Cancer cells rely on metabolic reprogramming to sustain the prodigious energetic requirements for rapid growth and proliferation. Glutamine metabolism is frequently dysregulated in cancers and is being exploited as a potential therapeutic target. In current study, we identified TARBP1 (TAR (HIV-1) RNA Binding Protein 1) as a novel driver gene critical for glutamine metabolic reprogramming in tumor through the CRISPRi/Cas9 screening. Ourin vivoandin vitroassays demonstrated that TARBP1 is the methyltransferase of Guanosine 2’-O-methylation targeting position 18 (G18) of tRNAGln(TTG/CTG)and tRNASer(TGA/GCT), and loss of Gm18 modification diminishes the stability of tRNAs. Therefore, TARBP1 is critical for maintaining efficient translation of mRNA, in particular the glutamine transportor-ASCT2 (also known as SCL1A5). Importantly, TARBP1 is frequently amplified and overexpressed in HCC, consequentially promotes the protein synthesis of ASCT2 and glutamine import to fuel the growth of cancer cell, which is associated with poor patient survival. Taken together, this study reveals the critical role of TARBP1 in HCC progression through glutamine metabolic reprogramming and provides a potential target for tumor therapy.
Lost in the WASH. The functional human WASH complex 1 gene is on chromosome 20
Authors: Cerdán-Vélez Daniel , Tress Michael L.
Published: June 2023

The WASH1 gene produces a protein that forms part of the developmentally important WASH complex. The WASH complex activates the Arp2/3 complex to initiate branched actin networks at the surface of endosomes. As a curiosity, the human reference gene set includes nine WASH1 genes. How many of these are pseudogenes and how many arebona fidecoding genes is not clear.

Eight of the nine WASH1 genes reside in rearrangement and duplication-prone subtelomeric regions. Many of these subtelomeric regions had gaps in the GRCh38 human genome assembly, but the recently published T2T-CHM13 assembly from the Telomere to Telomere (T2T) Consortium has filled in the gaps. As a result, the T2T Consortium has added four new WASH1 paralogues in previously unannotated subtelomeric regions.

Here we show that one of these four novel WASH1 genes,LOC124908094, is the gene most likely to produce the functional WASH1 protein. We also demonstrate that the other twelve WASH1 genes derived from a singleWASH8Ppseudogene on chromosome 12. These 12 genes include WASHC1, the gene currently annotated as the functional WASH1 gene.

We proposeLOC124908094should be annotated as a coding gene and all functional information relating to theWASHC1gene on chromosome 9 should be transferred toLOC124908094. The remaining WASH1 genes, includingWASHC1, should be annotated as pseudogenes. This work confirms that the T2T assembly has added at least one functionally relevant coding gene to the human reference set. It remains to be seen whether other important coding genes are missing from the GRCh38 reference assembly.
Retrieval of developmental social memories requires activation of the adult-born granule cell-CA2 circuit in mice
Authors: Laham Blake J. , Gore Isha R. , Brown Casey J. , Gould Elizabeth
Published: June 2023

Adult-born granule cells (abGCs) project to the CA2 region of the hippocampus, but it remains unknown how this circuit affects behavioral function. Here we show that abGC input to the CA2 of adult mice is involved in the retrieval of remote developmental memories of the mother. Ablation of abGCs impaired the ability to discriminate between a caregiving mother and a novel mother, while this ability returned after new neurons were regenerated. Chemogenetic inhibition of projections from abGCs to the CA2 also temporarily prevented the retrieval of remote mother memories. These findings were observed when abGCs were 4-6 weeks old, but not when they were 10-12 weeks old. We also found that abGCs are necessary for differential CA2 network activity, including theta-gamma coupling and sharp wave-ripples, in response to novel versus familiar social stimuli. Taken together, these findings suggest that abGCs are necessary for neuronal oscillations associated with discriminating between social stimuli, thus enabling retrieval of remote developmental memories of the mother by their adult offspring.
Genetic and transcriptomic analysis of hyphal constriction based on a novel assay method in the rice blast fungus
Authors: Cho Eunbyeol , Lee Song Hee , Jeong Minsoo , De Mandal Surajit , Park Sook-Young , Nam Seung Won , Byeun Do Gyeung , Choi Jung Kyu , Lee Yong-Hwan , Shin Jae-Ho , Jeon Junhyun
Published: June 2023

An ability of fungi to undergo hyphal constriction is important for fungal ecology and diseases. In the rice blast fungus,Magnaporthe oryzae, hyphal constriction is required to traverse host cell junctions through pit fields. However, little is known about genetic underpinnings of hyphal constriction, except the requirement of a mitogen-activated protein kinase, Pmk1. Here we demonstrate that a simplein vitroassay based on nitrocellulose membrane allows investigation of the genetic basis for hyphal constriction. Using the assay, we found that the constriction limit ofM. oryzaehypha lies between 0.22 and 0.3 μm, and that a histone modification might be involved in hyphal constriction. RNA-seq experiments combining our assay and Δpmk1showed that hyphal constriction relies on transcriptional changes of genes implicated primarily in membrane and cell wall-related cellular processes in Pmk1-dependent and/or Pmk1-independent manner. Furthermore, our assays with diverse fungal species suggest correlation between hyphal constriction and fungal lifestyles. Our study reveals that hyphal constriction can be induced without host-derived cues and provides molecular and evolutionary insights into a fundamental process to infection of host plant.
A survey of CIN measures across mechanistic models
Authors: Lynch Andrew R. , Bradford Shermineh , Zhou Amber S. , Oxendine Kim , Henderson Les , Horner Vanessa L. , Weaver Beth A. , Burkard Mark E.
Published: June 2023

Chromosomal instability (CIN) is the persistent reshuffling of cancer karyotypes via chromosome mis-segregation during cell division. In cancer, CIN exists at varying levels that have differential effects on tumor progression. However, mis-segregation rates remain challenging to assess in human cancer despite an array of available measures. We evaluated measures of CIN by comparing quantitative methods using specific, inducible phenotypic CIN models of chromosome bridges, pseudobipolar spindles, multipolar spindles, and polar chromosomes. For each, we measured CIN fixed and timelapse fluorescence microscopy, chromosome spreads, 6-centromere FISH, bulk transcriptomics, and single cell DNA sequencing (scDNAseq). As expected, microscopy of tumor cells in live and fixed samples correlated well (R=0.77; p<0.01) and sensitively detect CIN. Cytogenetics approaches include chromosome spreads and 6-centromere FISH, which also correlate well (R=0.77; p<0.01) but had limited sensitivity for lower rates of CIN. Bulk genomic DNA signatures and bulk transcriptomic scores, CIN70 and HET70, did not detect CIN. By contrast, single-cell DNA sequencing (scDNAseq) detects CIN with high sensitivity, and correlates very well with imaging methods (R=0.83; p<0.01). In summary, single-cell methods such as imaging, cytogenetics, and scDNAseq can measure CIN, with the latter being the most comprehensive method accessible to clinical samples. To facilitate comparison of CIN rates between phenotypes and methods, we propose a standardized unit of CIN: Mis-segregations per Diploid Division (MDD). This systematic analysis of common CIN measures highlights the superiority of single-cell methods and provides guidance for measuring CIN in the clinical setting.

Significance

Cancer relies on genomic changes to drive evolution. One type of change, Chromosomal INstability (CIN), promotes plasticity and heterogeneity of chromosome sets via ongoing errors in mitosis. The rate of these errors informs patient prognosis, drug response, and risk of metastasis. However, measuring CIN in patient tissues is challenging, hindering the emergence of CIN rate as a prognostic and predictive clinical biomarker. To advance clinical measures of CIN, we quantitatively tested the relative performance of several CIN measures in tandem using four well-defined, inducible CIN models. This survey revealed poor sensitivity in several common CIN assays and highlights the primacy of single-cell approaches. Further, we propose a standard, normalized unit of CIN, permitting comparison across methods and studies.
Ground-state pluripotent stem cells are characterized by Rac1-dependent Cadherin-enriched F-actin protrusions
Authors: Liu Shiying , Meng Yue , Kanchanawong Pakorn
Published: June 2023

Pluripotent Stem Cells (PSCs) exhibit extraordinary differentiation potentials that can be propagatedin vitroand thus are commonly utilized in regenerative medicine. While different types of PSCs exist which correspond to different stages of pluripotency during embryogenesis, important aspects of their biology in terms of their cellular architecture and mechanobiology have been less well understood, thereby limiting their tissue engineering application potentials. Since the actin cytoskeleton is a primary determinant of cell mechanical properties, here we sought to investigate how the actin cytoskeleton may be differentially regulated in different states of pluripotency. Comparing ground-state naïve mESCs and the corresponding converted prime epiblast stem cells (EpiSCs), we observed the actin cytoskeleton is drastically reorganized during the naïve to prime pluripotency transition. Strikingly, we reported a distinctive actin organization that appears to be unique to the ground state mESCs, whereby the isotropic cortical networks are decorated with prominent actin-enriched structures which contain cadherin-based cell-cell junctional components, despite not locating at cell-cell junctions. We termed these structures “cadheropodia” and showed they arise from the cis-association of E-cadherin extracellular domain. Our measurements revealed that cadheropodia is under low mechanical tension and exhibits minimal calcium dependence, consistent with its putative dependence on cis-interaction. Further, we identified Rac1 as a negative regulator of cadheropodia whereby active Rac1 induces its fragmentation and dissociation of β-catenin. Taken together, we described a novel actin-based structures in the ground-state mESCs, which may have potential roles in ground-state pluripotency and serve as useful structural markers to distinguish heterogeneous population of pluripotent stem cells.
Comprehensive Characterization and Global Transcriptome Analyses of Human Fetal Liver Terminal Erythropoiesis
Authors: Han Yongshuai , Wang Shihui , Wang Yaomei , Huang Yumin , Gao Chengjie , Guo Xinhua , Chen Lixiang , Zhao Huizhi , An Xiuli
Published: June 2023

The fetal liver (FL) is the key erythropoietic organ during fetal development, but knowledge on human FL erythropoiesis is very limited. In this study, we sorted primary erythroblasts from FL cells and performed RNA sequencing analyses. We found that temporal gene expression patterns reflected changes in function during primary human FL terminal erythropoiesis. Notably, expression of genes enriched in proteolysis and autophagy was upregulated in orthochromatic erythroblasts (OrthoE), suggesting involvement of these pathways in enucleation. We also performed RNA sequencing ofin vitrocultured erythroblasts derived from FL CD34+cells. Comparison of transcriptomes between the primary and cultured erythroblasts revealed significant differences, indicating impacts of the culture system on gene expression. Notably, lipid metabolism gene expression was increased in cultured erythroblasts. We further immortalized erythroid cell lines from FL and cord blood (CB) CD34+cells (FL-iEry and CB-iEry, respectively). FL-iEry and CB-iEry are immortalized at the proerythroblast stage and can be induced to differentiate into OrthoE, but their enucleation ability is very low. Comparison of transcriptomes between OrthoE with and without enucleation capability revealed downregulation of pathways involved in chromatin organization and mitophagy in OrthoE without enucleation capacity, indicating that defects in chromatin organization and mitophagy contribute to the inability of OrthoE to enucleate. Additionally, the expression levels ofHBE1,HBZ, andHBG2were upregulated in FL-iEry compared with CB-iEry, and this was accompanied by downregulation ofBCL11Aand upregulation ofLIN28BandIGF2BP1. Our study provides new insights into human FL erythropoiesis and rich resources for future studies.
Reconstructing visual illusory experiences from human brain activity
Authors: Cheng Fan , Horikawa Tomoyasu , Majima Kei , Tanaka Misato , Abdelhack Mohamed , Aoki Shuntaro C. , Hirano Jin , Kamitani Yukiyasu
Published: June 2023

Visual illusions provide significant insights into the brain’s interpretation of the world given sensory inputs. However, the precise manner in which brain activity translates into illusory experiences remains largely unknown. Here we leverage a brain decoding technique combined with deep neural network (DNN) representations to reconstruct illusory percepts as images from brain activity. The reconstruction model was trained on natural images to establish a link between brain activity and perceptual features and then tested on two types of illusions: illusory lines and neon color spreading. Reconstructions revealed lines and colors consistent with illusory experiences, which varied across the source visual cortical areas. This framework offers a way to materialize subjective experiences, shedding new light on the brain’s internal representations of the world.
Predicting cued and oddball visual search performance from neural representational similarity
Authors: Yeh Lu-Chun , Thorat Sushrut , Peelen Marius V.
Published: June 2023

Capacity limitations in visual tasks can be observed when the number of task-related objects increases. An influential idea is that such capacity limitations are determined by competition at the neural level: two objects that are encoded by shared neural populations interfere more in behavior (e.g., visual search) than two objects encoded by separate neural populations. However, the neural representational similarity of objects varies across brain regions and across time, raising the question of where and when competition determines task performance. Furthermore, it is unclear whether the association between neural representational similarity and task performance is common or unique across tasks. Here, we used neural representational similarity derived from fMRI, MEG, and deep neural networks (DNN) to predict performance on two visual search tasks involving the same objects and requiring the same responses but differing in instructions: cued visual search and oddball visual search. Separate groups of human participants (both sexes) viewed the individual objects in neuroimaging experiments to establish the neural representational similarity between those objects. Results showed that performance on both search tasks could be predicted by neural representational similarity throughout the visual system (fMRI), from 80 msec after onset (MEG), and in all DNN layers. Stepwise regression analysis, however, revealed task-specific associations, with unique variability in oddball search performance predicted by early/posterior neural similarity, and unique variability in cued search task performance predicted by late/anterior neural similarity. These results reveal that capacity limitations in superficially similar visual search tasks may reflect competition at different stages of visual processing.

Significance Statement

Visual search for target objects is slowed down by the presence of distractors, but not all distractors are equally distracting – the more similar a distractor is to the target, the more it slows down search. Here, we used fMRI, MEG, and a deep neural network to reveal where, when, and how neural similarity between targets and distractors predicts visual search performance across two search tasks: oddball visual search (locating the different-looking object) and cued visual search (locating the cued object). Results also revealed brain regions, time points, and feature levels that predicted task-unique performance. These results provide a neural basis for similarity theories of visual search and show that this neural basis differs across visual search tasks.
POLARIS is a copper-binding peptide required for ethylene signalling control in Arabidopsis.
Authors: Mudge Anna M , Mehdi Saher , Michaels Will E , Oroza-Puente Beatriz , Shen Weiran , Tomlinson Charlie , Wei Wenbin , Hoppen Claudia , Uzun Buket , Roy Dipan , Hetherington Flora M , Topping Jennifer F , Sadanandom Ari , Groth Georg , Robinson Nigel J , Lindsey Keith
Published: June 2023

Ethylene signalling represents one of the classic hormonal pathways in plants, with diverse roles in development and stress responses. The dimeric ethylene receptor localizes to the endoplasmic reticulum (ER) and contains Cu(I) ions essential for ethylene binding and signal transduction. We previously discovered that mutants in the Arabidopsis gene POLARIS (PLS), encoding a 36 amino acid peptide, exhibit enhanced ethylene signalling responses, suggestive of reduced receptor activity, but the role and activity of the peptide in this signalling cascade has not been defined. Here we report PLS binds copper as a 1:2 thiol-dependent Cu(I):PLS2 complex, with an affinity of 3.79 (+/-1.5) x1019 M-2, via two cysteine residues also found in the related species Camelina sativa. These residues are also essential for biological function. This affinity precludes PLS as a cytosolic Cu chaperone. We demonstrate that PLS localizes to endomembranes and interacts with the transmembrane domain of receptor protein ETR1. PLS-ETR1 binding is increased in the presence of copper, and this interaction provides a Cu-dependent mechanism for mediating a repression of ethylene responses. PLS transcription is up-regulated by auxin and down-regulated by ethylene, and so PLS-ETR1 interactions also provide a mechanism to modulate ethylene responses in high auxin tissues.
CFSA: Comparative Flux Sampling Analysis as a Guide for Strain Design
Authors: van Rosmalen R.P. , Moreno-Paz S. , Duman-Özdamar Z.E. , Suarez-Diez M.
Published: June 2023

Genome-scale metabolic models of microbial metabolism have extensively been used to guide the design of microbial cell factories, still, many of the available strain design algorithms often fail to produce a reduced list of targets for improved performance that can be implemented and validated in a step-wise manner. We present Comparative Flux Sampling Analysis (CFSA), a strain design method based on the extensive comparison of complete metabolic spaces corresponding to maximal or near-maximal growth and production phenotypes. The comparison is complemented by statistical analysis to identify reactions with altered flux that are suggested as targets for genetic interventions including up-regulations, down-regulations and gene deletions. We applied CFSA to the production of lipids byCutaneotrichosporon oleaginosusand naringenin bySaccharomyces cerevisiaeidentifying engineering targets in agreement with previous studies as well as new interventions. CFSA is an easy-to-use, robust method that suggests potential metabolic engineering targets for growth-uncoupled production that can be applied to the design of microbial cell factories.
The role of Kölliker-Fuse nucleus in breathing variability
Authors: John S. , Barnett W. , Abdala A. , Zoccal D. , Rubin J. , Molkov Y.
Published: June 2023

The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apneas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupneic as well as RTT-like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT-like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late-expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing.

Key points

The Kölliker-Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation. Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modeling to explore different dynamical regimes of KF activity and their compatibility with experimental observations. By analyzing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT-like respiratory patterns and proposes potential KF local circuit organizations. Two models are presented that simulate both normal breathing and RTT-like breathing patterns. These models provide plausible hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.
Thermodynamics of Quantum Information in Noisy Polarizers
Authors: Aifer Maxwell , Myers Nathan M. , Deffner Sebastian
Published: June 2023

Among the emerging technologies with prophesied quantum advantage, quantum communications has already led to fascinating demonstrations—including quantum teleportation to and from satellites. However, all optical communication necessitates the use of optical devices, the comprehensive quantum thermodynamic description of which is still severely lacking. In the present analysis, we prove several versions of Landauer’s principle for noisy polarizers, namely, absorbing linear polarizers and polarizing beam splitters. As main results, we obtain statements of the second law quantifying the minimal amount of heat that is dissipated in the creation of linearly polarized light. Our findings are illustrated with an experimentally tractable example, namely, the temperature dependence of a quantum eraser.

Published by the American Physical Society
2023
Entrustable professional activities: a model for job activity competency framework with microcredentials
Authors: Ma Terence , Ten Cate Olle
Published: June 2023

Purpose

Job competency frameworks are based on the listing skills required for a job. The assumption is that if a candidate is presumed to have the skills, then the candidate should be able to do the job. Thus, employers hope to identify prospective employees having the required skills. However, this may differ from knowing whether the employee is ready to be trusted to do the job activities with minimal or no supervision. The authors pose the question how employers might know about the capability of prospective employees to perform the job activities for which the employees are being hired.

Design/methodology/approach

In health professions education, a job activity-based framework has been developed called “entrustable professional activities” (EPAs, activities to be entrusted). This paper reviews the job activity framework and EPAs used in medical education, considering how this might support preparation for work in other sectors of the labor market.

Findings

The authors describe the EPA framework, some implementation issues and how EPAs lead to a type of microcredential being awarded to individuals as the individuals demonstrate that the individuals can be entrusted with specific job activities.

Originality/value

The focus of this paper is to demonstrate that a medical education model could potentially be adopted by other industries to provide employers with information regarding the ability of a prospective employee in performing the job activities required. Such an approach would address employer's concerns about the job readiness of potential employees.