bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of early palliative care in patients with head and neck cancer in Taiwan
Authors: Chen Tzu-Chun , Wang Shih-Hao , Ho Cho-Ming , Lin Hwan-Chung , Tung Chun-Liang , Chang Chih-Chia , Tsai Ching-Fang , Chen Tsung-Hsien , Fang Yi-Chun , Lin Wei-Ting , Lee Yu-Ting , Chang Yu-Sung , Lee Ming-Yang
Published: May 2024

Background:

Early palliative care (EPC) benefits some cancers, but its clinical outcomes differ depending on patients’ racial and ethnic disparities, and customs. To determine whether EPC improves symptoms, emotional distress, and quality of life among Taiwanese patients with early or advanced-stage head and neck cancer (HNC).

Methods:

Based on participants’ pathological stages, they were categorized as having early and advanced-stage HNC. Those willing and unwilling to undergo EPC were assigned to the EPC and standard groups, respectively. Their daily cancer-related symptoms were assessed using the Distress Thermometer (DT) and MD Anderson Symptom Inventory (MDASI), whose scores’ concurrent validity was evaluated using the European Organization for Research and Treatment of Core Quality of Life (EORTC-QLQ-C30) and Head and Neck 35 (EORTC-QLQ-H&N35) questionnaires.

Results:

Patients (n = 93) diagnosed with HNC at Taiwan’s Chia-Yi Christian Hospital from November 2020 to October 2022 were recruited. The patients voluntarily split into two groups: EPC groups and standard groups (23 and 11 in early-stage; 46 and 13 in advanced-stage, respectively). DT assessment showed significant emotional distress improvements for all patients with HNC who received EPC. The EORTC-QLQ-C30 questionnaire indicated that, compared to standard interventions, EPC groups significantly improved the quality of life and some symptoms for both early and advanced-stage HNC patients. However, the EORTC-QLQ-H&N35 questionnaire found no significant difference between the two groups. Furthermore, advanced-stage patients’ anticancer treatment completion rates with EPC and standard interventions were 95.35% and 75%, respectively.

Conclusion:

EPC improves symptoms, emotional distress, quality of life, and treatment completion rates in Taiwanese patients with early or advanced-stage HNC. Nonetheless, further extensive clinical studies are required for validation.
Oil and Gas Extraction Industry Workers’ Compensation Claims and Proposed Safety Interventions
Authors: Alexander Barbara M. , Ramirez-Cardenas Alejandra , Wurzelbacher Steven J. , Meyers Alysha R. , Naber Steven J.
Published: May 2024

Objective

This study analyzed Ohio workers’ compensation data to identify potential prevention strategies for common oil and gas extraction industry claims.

Methods

Claim rates for 2001–2018 were calculated per full-time equivalent employee. Descriptive analyses on free-text descriptions of lost-time (LT) claims (>7 days away from work) identified common characteristics among claims and injured workers.

Results

Among 3134 claims, 860 (27%) were LT. The industry group, drilling contractors, experienced the highest LT claims rate, whereas the cost from servicing contractors was the highest. Contact with objects and equipment caused the highest LT claims rate. The most frequent LT occupation was roustabout, and the most frequent LT work activity was material handling. Transportation incidents caused most fatalities and hospitalizations. Over half of LT claims were from short-tenured workers.

Conclusions

Both proven and innovative approaches are needed to reduce severe workers’ compensation claims in this industry.
Bioprinting in cardiovascular medicine: possibilities, challenges, and future perspectives for low and middle-income countries
Authors: Malhi Amarveer , Padda Inderbir , Mahtani Arun , Fabian Daniel , Karroum Paul , Mathews Arpita M. , Ralhan Tushar , Sethi Yashendra , Emran Talha B.
Published: May 2024

Cardiovascular diseases stemming from various factors significantly impact the quality of life and are prevalent with high mortality rates in both developed and developing countries. In cases where pharmacotherapy proves insufficient and end-stage disease ensues, a heart transplant/surgical repair becomes the only feasible treatment option. However, challenges such as a limited supply of heart donors, complications associated with rejection, and issues related to medication compliance introduce an additional burden to the healthcare system and adversely affect patient outcomes. The emergence of bioprinting has facilitated advancements in creating structures, including ventricles, valves, and blood vessels. Notably, the development of myocardial/cardiac patches through bioprinting has offered a promising avenue for revascularizing, strengthening, and regenerating various cardiovascular structures. Employment loss in developing countries as a circumstance of disability or death can severely impact a family’s well-being and means for sustainable living. Innovations by means of life sustaining treatment options can provide hope for the impoverished and help reduce disability burden on the economy of low- and middle-income countries (LMICs). Such developments can have a significant impact that can last for generations, especially in these countries. In this review, the authors delve into various types of bioprinting techniques, exploring their possibilities, challenges, and potential future applications in treating various end-stage cardiovascular conditions in LMICs.
Timing of stroke survivors' hospital readmissions to guide APRNs in primary care
Authors: Connolly Teresa , Paxton Kim , McNair Bryan
Published: May 2024

Background:

Caring for patients after a neurovascular incident is common for advanced practice registered nurses (APRNs). Most neurological readmission studies focus on a small subset of neurovascular incident groups, but advanced practice nurses in primary care attend to a diverse neurovascular population and lack time to adequately search hospital records.

Purpose:

The aim of this study was to determine readmission risk factors after a neurovascular incident to guide APRNs in the primary care setting.

Methodology:

The study is a retrospective observational study that used a crude single predictor model to determine potential risks for readmission.

Results:

A total of 876 neurovascular participants were studied. Of these, only 317 experienced at least one hospital readmission, with 703 readmissions within 1 year, indicating some were readmitted more than once. Risks for readmission varied across neurovascular events. The main reasons for readmission were because of neurological, cardiovascular, and musculoskeletal complications.

Conclusions:

Stroke readmission rates are high and require intervention by APRNs. To prevent readmission includes timely follow-up within 30 days and should also include longitudinal follow-up beyond 90 days to prevent hospital readmission.

Implications:

Future studies are needed to create guidelines for APRNs that implement rehabilitation strategies to decrease hospital readmission for the neurovascular population that focus on interdisciplinary communication.
Extended Duration Bridge to Orthotopic Heart Transplant Utilizing the Impella RP Flex
Authors: Maigrot Jean-Luc A. , Lee Ran , Higgins Andrew , Mountis Maria , Unai Shinya , Weiss Aaron J.
Published: May 2024

We present a case of a 56 year old man presenting with cardiogenic shock from isolated right ventricular failure due to arrhythmogenic right ventricular cardiomyopathy who was successfully bridged to heart transplantation after 29 days on an Impella RP Flex right ventricular assist device. This represents the longest reported duration of support with the device to date and highlights the utility of this platform in the management of severe right ventricular failure.
Advances in systemic immune inflammatory indices in non-small cell lung cancer: A review
Authors: Mao Kai-Yun , Cao Yuan-Chao , Si Mao-Yan , Rao Ding-yu , Gu Liang , Tang Zhi-Xian , Zhu Shen-yu
Published: May 2024

Lung cancer is one of the most prevalent cancers globally, with non-small cell lung cancers constituting the majority. These cancers have a high incidence and mortality rate. In recent years, a growing body of research has demonstrated the intricate link between inflammation and cancer, highlighting that inflammation and cancer are inextricably linked and that inflammation plays a pivotal role in cancer development, progression, and prognosis of cancer. The Systemic Immunoinflammatory Index (SII), comprising neutrophil, lymphocyte, and platelet counts, is a more comprehensive indicator of the host’s systemic inflammation and immune status than a single inflammatory index. It is widely used in clinical practice due to its cost-effectiveness, simplicity, noninvasiveness, and ease of acquisition. This paper reviews the impact of SII on the development, progression, and prognosis of non-small cell lung cancer.
Role of CENPF and NDC80 in the rehabilitation nursing of hepatocellular carcinoma and cirrhosis: An observational study
Authors: Jia Wei , Wu Qiaoling , Li Ruipu , Hou Shiyang , Kang Chunbo
Published: May 2024

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally and often develops on the foundation of chronic liver disease or cirrhosis. Cirrhosis is a clinically prevalent chronic progressive liver disease characterized by diffuse liver damage resulting from long-term or repeated actions of 1 or more etiological factors. However, the impact of CENPF and nuclear division cycle 80 (NDC80) genes on rehabilitation nursing of HCC and cirrhosis remains unclear. HCC and cirrhosis datasets GSE63898 and GSE89377 profile files were downloaded from the gene expression omnibus database generated on platforms GPL13667 and GPL6947, respectively. Differentially expressed genes (DEGs) screening, weighted gene co-expression network analysis (WGCNA), construction and analysis of protein–protein interaction (PPI) networks, functional enrichment analysis, gene set enrichment analysis (GSEA), survival analysis, immune infiltration analysis, and comparative toxicogenomics database (CTD) analysis were conducted. Gene expression heatmaps were plotted. miRNAs regulating central DEGs were selected through TargetScan. A total of 626 DEGs were identified. According to gene ontology (GO) analysis, they were primarily enriched in small molecule metabolic processes, drug metabolic processes, binding of identical proteins, and lipid metabolic processes. Kyoto Encyclopedia of Gene and Genome (KEGG) analysis results indicated that the target genes were mainly enriched in metabolic pathways, phagosomes, glycine, serine, and threonine metabolism. The construction and analysis of the PPI network revealed 3 core genes (NDC80, CENPF, RRM2). Gene expression heatmaps showed that core genes (CENPF, NDC80) were highly expressed in HCC and cirrhosis samples. CTD analysis found that 2 genes (CENPF and NDC80) were associated with liver, jaundice, ascites, fever, dyspepsia, and hepatic encephalopathy. CENPF and NDC80 are highly expressed in HCC and cirrhosis, and CENPF and NDC80 might be the biomarkers of rehabilitation nursing of HCC and cirrhosis.
Increased incidence of acute primary angle closure during the COVID-19 outbreak in China: A retrospective analysis
Authors: Liang Zhiqiao , Yang Kangyi , Lv Kun , Ma Yao , Hou Xianru , Liang Yong , Bao Yongzhen , Wu Huijuan
Published: May 2024

This study aimed to investigate the incidence and clinical characteristics of acute primary angle closure (APAC) during the Coronavirus Disease 2019 (COVID-19) pandemic in China. This was a retrospective study of patients diagnosed with APAC in a glaucoma clinic over a 5-year period. We compared the number of APAC cases during the COVID-19 outbreak (December 7, 2022 to January 7, 2023) with those during the same period in previous years and 2 months prior to the outbreak. We also collected data on the demographic and clinical features of APAC patients, such as age, sex, disease course, visual acuity, intraocular pressure (IOP), and lens opacity. We included 95 eyes of 88 patients with APAC were included. Of these, 65 were female and 23 were male. The mean age was 68.0 ± 8.1 years. The median disease course was 10.8 ± 9.5 days. There was a significant increase in the number of APAC cases during the COVID-19 outbreak compared with the same months over a 5-year period (44 vs 51, P < .001). A higher proportion of women developed APAC during the outbreak period than during the non-outbreak period (P < .001). Eyes with APAC in the outbreak period had a lower mean IOP than those in the preceding 6 months (40.5 ± 8.8 mm Hg vs 46.1 ± 10.1 mm Hg; P = .043). No significant differences were observed in disease duration, lens opacity, or bilateral or unilateral onset between the 2 groups. Our study suggests a potential correlation between APAC and COVID-19, marked by a significant surge in APAC cases concurrent with the COVID-19 outbreak. However, the underlying mechanisms and preventive strategies remain to be elucidated.
Defining oligometastatic state in uro-oncological cancers
Authors: Fazekas Tamás , Miszczyk Marcin , Matsukawa Akihiro , Nyirády Péter , Shariat Shahrokh F. , Rajwa Pawel
Published: May 2024

Purpose of review

Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology.

Recent findings

Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor.

Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future.
How Do Mental Disorders and Combinations of Disorders Affect the Odds of Injuries and Poisoning?
Authors: Merrill Ray M. , Ashton McKay K.
Published: May 2024

Injuries and poisoning are associated with mental disorders. The association may be stronger if comorbid mental illness is involved. This study explores whether selected mental disorders (stress, anxiety, depression, attention deficit hyperactivity disorder [ADHD], bipolar, obsessive-compulsive disorder [OCD], schizophrenia) are associated with injuries and poisoning and if the presence and frequency of comorbid mental illness affect these associations. Analyses utilize medical claims data for adult employees of a large corporation during 2017–2021. Approximately half or more of the index mental disorders experience comorbid mental illness. Odds of injury and poisoning are significantly greater for each mental disorder and tend to be significantly greater when comorbid mental illness exists (vs. the mental disorder alone), especially for the associations involving poisoning. Schizophrenia alone and in combination with other mental illness has the strongest associations with injury and poisoning. OCD is only associated with injury and poisoning, and ADHD is only associated with poisoning, if accompanied by comorbid mental illness.
Quantitative Proteomics Identifies Conserved Proteins and Altered Regulation of Mucin-16 in Low Grade Serous Ovarian Cancers
Authors: Tarney Christopher M. , Mhawech-Fauceglia Paulette , Ogata Jonathan D. , Oliver Julie , Abulez Tamara , Branton Philip A. , Movahedi-Lankarani Saeid , Hood Brian L. , Conrads Kelly A. , Rosalik Kendal , Wong Kwong-Kwok , Gershenson David M. , Lee Sanghoon , Sood Anil K. , Bast Robert C. , Darcy Kathleen M. , Phippen Neil T. , Maxwell G. Larry , Conrads Thomas P. , Bateman Nicholas W.
Published: May 2024

Background

Low-grade serous ovarian carcinoma (LGSOC) is a rare and largely chemoresistant subtype of epithelial ovarian cancer. Unlike treatment for high-grade serous ovarian cancer (HGSOC), management options for LGSOC patients are limited, in part, due to a lack of deep molecular characterization of this disease. To address this limitation, we aimed to define highly conserved proteome alterations in LGSOC by performing deep quantitative proteomic analysis of tumors collected from LGSOC (n=12) and HGSOC (n=24) patients or normal fallopian tube tissues (n=12) and validating proteins within two independent proteomic datasets of LGSOC (n=25) and HGSOC (n=49) tumors.

Results

Our efforts identified 275 protein alterations conserved between LGSOC and HGSOC tumors that exhibit high quantitative correlation between discovery and validation cohorts (Spearman Rho ≥ 0.82, P < 1E-4). Conserved proteins elevated in LGSOC tumors were enriched for pathways regulating cell adhesion and defective cellular apoptosis signaling and candidates mapping as putative drug targets included 5’-nucleotidase/ cluster of differentiation 73 (NT5E/CD73). We also identified MUC16 (CA125) as significantly elevated in LGSOC versus HGSOC tumors and confirmed this by immunohistochemistry analysis between three independent reviewers. We also find that MUC16 exhibits a more apical versus membrane-staining pattern in LGSOC tumors, suggesting unique regulation of MUC16 in this disease subtype.

Conclusion

Our efforts define highly conserved protein alterations distinguishing LGSOC from HGSOC tumors, including CD73, as well as the novel identification that MUC16 is elevated and exhibits more apical staining pattern in LGSOC tumor tissues. These findings deepen our molecular understanding of LGSOC and provide unique insights into highly conserved proteome alterations in LGSOC tumors.
Spleen gene expression is associated with mercury content in three-spined stickleback populations
Authors: Yadav Brijesh S. , Lamaze Fabien C. , Shankregowda Aruna M. , Delahaut Vyshal , Calboli Federico C. F. , Patel Deepti M. , Kuizenga Marijn , Bervoets Lieven , Volckaert Filip A.M. , Boeck Gudrun De , Raeymaekers Joost A.M.
Published: May 2024

Mercury can be very toxic at low environmental concentrations by impairing immunological, neurological, and other vital pathways in humans and animals. Aquatic ecosystems are heavily impacted by mercury pollution, with evidence of biomagnification through the food web. We examined the effect of mercury toxicity on the spleen, one of the primary immune organs in fish, in natural populations of the three-spined stickleback (Gasterosteus aculeatusLinnaeus, 1758). Our aim was to better understand adaptation to high mercury environments by investigating transcriptomic changes in the spleen. Three stickleback populations with mean Hg muscle concentrations above and three populations with mean Hg muscle concentrations below the European Biota Quality Standard of 20 ng/g wet weight were selected from the Scheldt and Meuse basin in Belgium. We then conducted RNA sequencing of the spleen tissue of 22 females from these populations. We identified 136 differentially expressed genes between individuals from populations with high and low mean mercury content. The 129 genes that were upregulated were related to the neurological system, immunological activity, hormonal regulation, and inorganic cation transporter activity. Seven genes were downregulated and were all involved in pre-mRNA splicing. The results are indicative of our ability to detect molecular alterations in natural populations that exceed an important environmental quality standard. This allows us to assess the biological relevance of such standards, offering an opportunity to better describe and manage mercury-associated environmental health risks in aquatic populations.
NPmatch: Latent Batch Effects Correction of Omics data by Nearest-Pair Matching
Authors: Zito Antonino , Martinelli Axel , Masiero Mauro , Akhmedov Murat , Kwee Ivo
Published: May 2024

Motivation

Batch effects (BEs) are a predominant source of noise in omics data and often mask real biological signals. BEs remain common in existing datasets. Current methods for BE correction mostly rely on specific assumptions or complex models, and may not detect and adjust BEs adequately, impacting downstream analysis and discovery power. To address these challenges we developed NPmatch, a nearest-neighbor matching-based method that adjusts BEs satisfactorily and outperforms current methods in a wide range of datasets.

Results

We assessed distinct metrics and graphical readouts, and compared our method to commonly used BE correction methods. NPmatch demonstrates overall superior performance in correcting for BEs while preserving biological differences than existing methods. Altogether, our method proves to be a valuable BE correction approach to maximize discovery in biomedical research, with applicability in clinical research where latent BEs are often dominant.

Data availability and implementation

NPmatch is freely available on Github (https://github.com/bigomics/NPmatch) and on Omics Playground (https://bigomics.ch/omics-playground). The datasets underlying this article are the following: GSE120099, GSE82177, GSE162760, GSE171343, GSE153380, GSE163214, GSE182440, GSE163857, GSE117970, GSE173078, GSE10846. All these datasets are publicly available and can be freely accessed on the Gene Expression Omnibus (GEO) repository.
Distraction Impact of Concurrent Conversation on Event-Related Potential Based Brain-Computer Interfaces
Authors: Kim Minju , Kim Sung-Phil
Published: May 2024

Objective

This study investigates the impact of conversation on the performance of visual event-related potential (ERP)-based brain-computer interfaces (BCIs), considering distractions in real life environment. The research aims to understand how cognitive distractions from speaking and listening activities affect ERP-BCI performance.

Approach

The experiment employs a dual-task paradigm where participants control a smart light using visual ERP-BCIs while simultaneously conducting speaking or listening tasks.

Main results

The findings reveal that speaking notably degrades BCI accuracy and the amplitude of ERP components, while increases the latency variability of ERP components and occipital alpha power. In contrast, listening and simple syllable repetition tasks have a lesser impact on these variables. The results suggest that speaking activity significantly distracts visual attentional processes critical for BCI operation

Significance

This study highlights the need to take distractions by daily conversation into account of the design and implementation of ERP-BCIs.
Transcriptome Analysis ofAegle marmelos(L.) Corrêa Fruit and Leaf Tissues: An Underexploited Fruit Tree
Authors: Kaushik Prashant
Published: May 2024

Aegle marmelos(L) Correa is both a horticultural and medicinally important tree in South-East Asia. Both of its fruits and leaves have several medicinal values including treatment of certain chronic diseases. Despite its importance, the genomic resource of this tree is very scarce. The objectives of this work were to conduct a de novo transcriptome assembly of leaf tissue from A.marmelos, locally known as bael in India. Comparison studies were conducted between the fruit transcriptome and leaf transcriptome ofA. marmelos. This is the first time that the fruit transcriptomeof A. marmeloshas been reported in the literature. There were 47 million clean reads were generated for fruit tissue and 34 million clean reads of leaf tissue. The reads were assembled to 61, 860 unigenes. Around 83% of fruit transcripts were mapped to the original assembly whereas 89% of leaf transcripts were mapped to the original assembly. Whereas, in terms of molecular function, the gene ontology (GO) terms were related to binding, cellular activity and transporter activity and genes expressed only in leaf and fruit tissue were 14,578 and 11086, respectively, Overall, RNA sequencing may be an effective method for determining the pathway and genes in the underexploited fruit crops.
Decreased brain pH correlated with progression of Alzheimer’s disease neuropathology: a systematic review and meta-analyses of postmortem studies
Authors: Hagihara Hideo , Miyakawa Tsuyoshi
Published: May 2024

Background

Altered brain energy metabolism is implicated in Alzheimer’s disease (AD). Limited and conflicting studies on brain pH changes, indicative of metabolic alterations associated with neural activity, warrant a comprehensive investigation into their relevance in this neurodegenerative condition. Furthermore, the relationship between these pH changes and established AD neuropathological evaluations, such as Braak staging, remains unexplored.

Methods

We conducted quantitative meta-analyses on postmortem brain and cerebrospinal fluid pH in patients with AD and non-AD controls, using publicly available demographic data. We collected raw pH data from studies in the NCBI GEO, PubMed, and Google Scholar databases.

Results

Our analysis of 17 datasets (457 patients and 315 controls) using a random-effects model showed a significant decrease in brain and cerebrospinal fluid pH in patients compared to controls (Hedges’g= –0.54,p< 0.0001). This decrease remained significant after considering postmortem interval, age at death, and sex. Notably, pH levels were negatively correlated with Braak stage, indicated by the random-effects model of correlation coefficients from 15 datasets (292 patients and 159 controls) (adjustedr= –0.26,p< 0.0001). Furthermore, brain pH enhanced the discriminative power of theAPOEε4 allele, the most prevalent risk gene for AD, in distinguishing patients from controls in a meta-analysis of four combined datasets (95 patients and 87 controls).

Conclusions

The significant decrease in brain pH in AD underlines its potential role in disease progression and diagnosis. This decrease, potentially reflecting neural hyperexcitation, could enhance our understanding of neurodegenerative pathology and aid in developing diagnostic strategies.
Application of graph models to the identification of transcriptomic oncometabolic pathways in human hepatocellular carcinoma
Authors: Barace Sergio , Santamaría Eva , Infante Stefany , Arcelus Sara , De la Fuente Jesús , Goñi Enrique , Tamayo Ibon , Ochoa Idoia , Sogbe Miguel , Sangro Bruno , Hernaez Mikel , Ávila Matías A. , Argemi Josepmaria
Published: May 2024

Whole tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly coexpressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph models. Using The Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-Glycan, Mevalonate and Sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of Acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines.
Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+cell therapy to induce fetal hemoglobin for sickle cell disease
Authors: Katta Varun , O’Keefe Kiera , Li Yichao , Mayurathan Thiyagaraj , Lazzarotto Cicera R. , Wood Rachael K. , Levine Rachel M. , Powers Alicia , Mayberry Kalin , Manquen Garret , Yao Yu , Zhang Jingjing , Jang Yoonjeong , Nimmagadda Nikitha , Dempsey Erin A. , Lee GaHyun , Uchida Naoya , Cheng Yong , Fazio Frank , Lockey Tim , Meagher Mike , Sharma Akshay , Tisdale John F. , Zhou Sheng , Yen Jonathan S. , Weiss Mitchell J. , Tsai Shengdar Q.
Published: May 2024

Sickle cell disease (SCD) is a common severe blood disorder, caused by one major point mutation in theHBBgene. Current pharmacotherapies are only partially effective and potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of autologous patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers a potentially curative approach to treat SCD and circumvents some problems associated with allogeneic HSCT. Although the FDA has released guidelines for evaluating genome editing risks, it remains unclear how to best to assess the preclinical safety and efficacy of genome-edited cellular drug products to prepare for a clinical trial. Here we describe rigorous pre-clinical characterization and optimization of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared targets in the γ-globin promoter andBCL11Aerythroid-specific enhancer, identified a lead candidate that potently induces HbF, and tested our approach in mobilized CD34+HSPCs from normal donors and individuals with SCD. We observed efficient editing, induction of HbF to levels predicted to be therapeutic, and reduction of sickling in red blood cells derived from edited HSPCs. With single-cell western and RNA-seq analyses, we defined the heterogeneity and specificity of HbF induction andHBG1/HBG2transcription. With CHANGE-seq for sensitive and unbiased genome-wide off-target discovery followed by multiplexed targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new discoveries onex vivogenome editing of HSCs towards clinical trials for treating SCD and other blood disorders.
Quantitative fluorescent nanoparticle tracking analysis and nano-flow cytometry enable advanced characterization of single extracellular vesicles
Authors: Mladenović Danilo , Brealey Joseph , Peacock Ben , Zarovni Nataša
Published: May 2024

Current state-of-the-art tools for analyzing extracellular vesicles (EVs) offer either highly sensitive but unidimensional bulk measurements of EV components, or high-resolution multiparametric single particle analyses which lack standardization and appropriate reference materials. This limits the accuracy of assessment of marker abundance and overall marker distribution among individual EVs, and finally, the understanding of true EV heterogeneity.

In this study, we aimed to define the standardized operating procedures and reference material for fluorescent characterization of EVs with two commonly used EV analytical platforms - nanoparticle tracking analysis (NTA) and nano-flow cytometry (nFCM).

For the first time, we achieved quantitative fluorescence analyses on ZetaView NTA and NanoAnalyzer nFCM instruments, by utilizing yellow-green FluoSpheres (FS) with assigned ERF (equivalent reference fluorophore) values. This standardization technique allowed for fluorescent EV signal to be expressed in ERF units (indicative of bound fluorescent antibodies per EV), thus enabling measurement of target protein marker abundance on individual EVs, and in the whole EV population. The NTA’s and nFCM’s limits of quantification (LoQ) were evaluated at 115 and 75 Alexa Fluor 488 (AF488) molecules, respectively. To complement these shortcomings, in-line bulk fluorescence measurements in a plate reader were performed. This provided absolute marker quantification, and more insightful analyses of EV heterogeneity and marker stoichiometry.

The standardization method outlined in this work unlocks the full analytical potential of NTA and nFCM, enabling cross-platform data comparison. At the same time, it highlights some of the technical challenges and considerations, and thus contributes to the ongoing efforts towards development of EV analytical tools.
Mathematical Methodology for Dynamic Models of Insecticide Selection Assuming a Polygenic Basis of Resistance
Authors: Hobbs Neil Philip , Hastings Ian Michael
Published: May 2024

Mathematical models for evaluating insecticide resistance management (IRM) have primarily assumed insecticide resistance (IR) is monogenic. Modelling using a quantitative genetics framework to model polygenic IR has less frequently been used. We introduce a complex mathematical model for polygenic IR with a focus on public health insecticide deployments for vector control. Conventional polygenic models assume selection differentials are constant over the course of selection. We instead propose calculating the selection differentials dynamically depending on the level of IR and the amount of insecticide encountered. Dynamically calculating the selection differentials increases biological and operational realism, allowing for the evaluation of strategies of policy relevance, including reduced dose mixtures or the deployment of long-lasting insecticide-treated nets and indoor residual spraying in combination. The dynamic calculations of insecticide selection allow for two methods: 1) Truncation (“polytruncate”) – where only the most resistant individuals in the population survive, and 2) Probabilistic (“polysmooth”) – where an individual’s survival probability is dependent on their own level of IR. We describe in detail the calculation and calibration of these models. The models (“polytruncate” and “polysmooth”) are compared against a previous polygenic model (“polyres”) and the monogenic literature for the IRM strategies of rotations, sequences and full-dose mixtures. We demonstrate consistency in results of full-dose mixtures remaining the best IRM strategy, with sequences and rotations being similar in their efficacy between the two selection processes, and consistency in “global conclusions” with previous models. Consistency between the “polysmooth”, “polytruncate” and previous models helps provide confidence in their predictions, as operational interpretations are not overly impacted by model assumptions. This increases confidence in the application of these dynamic models to investigate more complex IRM strategies and scenarios, and their future applications will investigate more scenario specific evaluations of IRM strategies.
Mechano-metabolism of metastatic breast cancer cells in 2D and 3D microenvironments
Authors: Jaganathan Anuja , Toth Joshua , Chen Xingyu , Basir Ramin , Pieuchot Laurent , Shen Yihui , Reinhart-King Cynthia , Shenoy Vivek B.
Published: May 2024

Cells regulate their shape and metabolic activity in response to the mechano-chemical properties of their microenvironment. To elucidate the impact of matrix stiffness and ligand density on the bioenergetics of mesenchymal cells, we developed a nonequilibrium, active chemo-mechanical model that accounts for the mechanical energy of the cell and matrix, chemical energy from ATP hydrolysis, interfacial energy, and mechano-sensitive regulation of stress fiber assembly through signaling. By integrating the kinetics and energetics of these processes, we define the cell “metabolic potential” that, when minimized, provides testable predictions of cell contractility, shape, and ATP consumption. Specifically, we show that the morphology of MDA-MB-231 breast cancer cells in 3D collagen changes from spherical to elongated to spherical with increasing matrix stiffness, which is consistent with experimental observations. On 2D hydrogels, our model predicts a hemispherical-to-spindle-to-disc shape transition with increasing gel stiffness. In both cases, we show that these shape transitions emerge from competition between the energy of ATP hydrolysis associated with increased contractility that drives cell elongation and the interfacial energy that favors a rounded shape. Furthermore, our model can predict how increased energy demand in stiffer microenvironments is met by AMPK activation, which is confirmed experimentally in both 2D and 3D microenvironments and found to correlate with the upregulation of mitochondrial potential, glucose uptake, and ATP levels, as well as provide estimates of changes in intracellular adenosine nucleotide concentrations with changing environmental stiffness. Overall, we present a framework for relating adherent cell energy levels and contractility through biochemical regulation of underlying physical processes.

Statement of Significance

Increasing evidence indicates that cellular metabolism is regulated by mechanical cues from the extracellular environment. Forces transmitted from the microenvironment activate mechanotransduction pathways in the cell, which trigger a cascade of biochemical events that impact cytoskeletal tension, cellular morphology and energy budget available to the cell. Using a nonequilibrium free energy-based theory, we can predict the ATP consumption, contractility, and shape of mesenchymal cancer cells, as well as how cells regulate energy levels dependent on the mechanosensitive metabolic regulator AMPK. The insights from our model can be used to understand the mechanosensitive regulation of metabolism during metastasis and tumor progression, during which cells experience dynamic changes in their microenvironment and metabolic state.
Applying Cell Painting in Non-Tumorigenic Breast Cells to Understand Impacts of Common Chemical Exposures
Authors: Tapaswi Anagha , Cemalovic Nicholas , Polemi Katelyn M , Sexton Jonathan Z , Colacino Justin A
Published: May 2024

There are a substantial number of chemicals to which individuals in the general population are exposed which have putative, but still poorly understood, links to breast cancer. Cell Painting is a high-content imaging-basedin vitroassay that allows for rapid and unbiased measurements of the concentration-dependent effects of chemical exposures on cellular morphology. We optimized the Cell Painting assay and measured the effect of exposure to 16 human exposure relevant chemicals, along with 21 small molecules with known mechanisms of action, for 48 hours in non- tumorigenic mammary epithelial cells, the MCF10A cell line. Through unbiased imaging analyses using CellProfiler, we quantified 3042 morphological features across approximately 1.2 millio n cells. We used benchmark concentration modeling to quantify significance and dose-dependent directionality to identify morphological features conserved across chemicals and find features that differentiate the effects of toxicants from one another. Benchmark concentrations were compared to chemical exposure biomarker concentration measurements from the National Health and Nutrition Examination Survey to assess which chemicals induce morphological alterations at human-relevant concentrations. Morphometric fingerprint analysis revealed similar phenotypes between small molecules and prioritized NHANES-toxicants guiding further investigation. A comparison of feature fingerprints via hypergeometric analysis revealed significant feature overlaps between chemicals when stratified by compartment and stain. One such example was the similarities between a metabolite of the organochlorine pesticide DDT (p,p’-DDE) and an activator of canonical Wnt signaling CHIR99201. As CHIR99201 is a known Wnt pathway activator and its role in ꞵ-catenin translocation is well studied, we studied the translocation of ꞵ-catenin following p’-p’ DDE exposure in an orthogonal high-content imaging assay. Consistent with activation of Wnt signaling, low dose p’,p’-DDE (25nM) significantly enhances the nuclear translocation of ꞵ-catenin. Overall, these findings highlight the ability of Cell Painting to enhance mode-of-action studies for toxicants which are common exposures in our environment but have previously been incompletely characterized with respect to breast cancer risk.
Haplotype-resolved genomes and population genetics to analyze glandular secretory trichome formation mechanism in oregano
Authors: Sun Meiyu , Miao Jiahui , Liu Ningning , Zhang Yanan , Zhang Jinzheng , Wang Di , Xia Fei , Bai Hongtong , Li Hui , Shi Lei
Published: May 2024

Oregano is an important economic plant which has valuable medicinal and aromatic properties. Oregano essential oil, containing carvacrol and thymol, is a preferred material to replace antibiotics in feed additives. Glandular secretory trichome (GST) density has positively correlated with the production of these compounds. Here, two haplotype-resolved genomes were assembled and annotated which contained 15 chromosomes with the total length of 606.75 and 612.74 Mb, respectively. Oregano had experienced two whole-genome duplications corresponding to the divergence ∼5.120/4.564 and ∼66.857/69.923 Mya, respectively. Many transcription factors and genes were found related to GSTs formation mechanism such as R2R3-MYB- and HD-ZIP IV-encoding genes. 2,669,410 SNPs, 569,093 InDels, 14,839 DUPs, 110 INVs, 3,976 TRANSs, and 1,426 CNVs were detected among two haplotype-resolved genomes. Two high density genetic linkage maps consisted of 15 LGs and spanned 2,279.28 and 2,322.83 cM, respectively. GADS, GABS, and GTS of F2segregating populations showed obvious superparental dominance. One/one, one/one, and two/four QTLs for GADS, GABS, and GTS were independently mapped on two genetic maps, respectively. Five candidate genes showed extreme difference in two bulked segregant pools. Our study not only provides significant insight into the GSTs formation mechnism, but also will facilitate molecular breeding in oregano.

One Sentence Summary

Oregano essential oil is a preferred material to replace antibiotics which will use to study the glandular secretory trichome formation mechanism and analyze the source of essential oil.
WITHDRAWN: Neural Network and Random Forest Algorithms as Catalysts in QSAR/QSAAR Modeling: Targeting Carbonic Anhydrase for Antituberculosis Drug Design
Authors: Bhowmik Ratul , Manaithiya Ajay , Ray Rajarshi , Carta Fabrizio , Supuran Claudiu T , Parkkila Seppo , Aspatwar Ashok
Published: May 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Rational Design of Live Biotherapeutic Products for the Prevention ofClostridioides difficileInfection
Authors: Ke Shanlin , Villafuerte Gálvez Javier A , Sun Zheng , Cao Yangchun , Pollock Nira R , Chen Xinhua , Kelly Ciarán P , Liu Yang-Yu
Published: May 2024

Clostridioides difficileinfection (CDI) is one of the leading causes of healthcare- and antibiotic-associated diarrhea. While fecal microbiota transplantation (FMT) has emerged as a promising therapy for recurrent CDI, its exact mechanisms of action and long-term safety are not fully understood. Defined consortia of clonal bacterial isolates, known as live biotherapeutic products (LBPs), have been proposed as an alternative therapeutic option. However, the rational design of LBPs remains challenging. Here, we employ a computational pipeline and three independent metagenomic datasets to systematically identify microbial strains that have the potential to inhibit CDI. We first constructed the CDI-related microbial genome catalog, comprising 3,741 non-redundant metagenome-assembled genomes (nrMAGs) at the strain level. We then identified multiple potential protective nrMAGs that can be candidates for the design of microbial consortia targeting CDI, including strains fromDorea formicigenerans,Oscillibacter welbionis, andFaecalibacterium prausnitzii. Importantly, some of these potential protective nrMAGs were found to play an important role in the success of FMT, and the majority of the top protective nrMAGs can be validated by various previously reported findings. Our results demonstrate a computational framework for the rational selection of microbial strains targeting CDI, paving the way for the computational design of microbial consortia against other enteric infections.
Managed honey bee colony losses and causes during the active beekeeping season 2022/2023 in nine Sub-Saharan African countries
Authors: Nganso Beatrice Tchuidjang , Ayalew Workneh , Wubie Abebe J. , Assefa Freweini , Belayhun Lulseged , Ndungu Nelly N. , Toroitich Daniel , Otieno-Ayayo Z. Ngalo , Wambua Mbatha B. , Oyieyo Yudah O. , Elie Ntirenganya , Sikirou Rachidatou , Idrissou Souradji B. , Mwiza Willy , Turner Simon , Bobadoye Bridget O. , Fameni Sidonie T. , Gaboe Sayemie , Agbodzavu Mawufe K. , Mafwila Patrick , Tasse Taboue Geraud C. , Emily Kimathi , Henri Tonnang Z.E. , Niassy Saliou , Fonkou Simplice N. , Pirk Christian W.W. , Gray Alison , Brodschneider Robert , Soroker Victoria , Subramanian Sevgan
Published: May 2024

This study reports for the first-time managed honey bee colony loss rates and associated risk factors during the active beekeeping season 2022/2023 in nine Sub-Saharan African countries, namely Kenya, Ethiopia, Rwanda, Uganda, Benin, Liberia, Nigeria, Cameroon and Democratic Republic of the Congo. The sustainability of bee swarm catches as a main honey bee colony source tool for operation expansion by African beekeepers was also evaluated in Kenya and Ethiopia. In this survey, the 1,786 interviewed beekeepers across these countries collectively managing 41,761 colonies registered an overall loss rate of 21.3%, which varied significantly among countries (from 9.7 to 45.3%) and hive types (from 10.6% in hives with movable frames to 17.9% in frameless hives). The perceived causes of losses in order of significance were issues beyond the beekeeper control (mainly theft, drought, and bushfire), absconding and pests (mainly wax moth, small and large hive beetles, ants and Varroa destructor mite), but this pattern varied greatly across countries. Among the management practices and characteristics, migratory operations and professional beekeepers experienced lower losses than stationary operations and semi-professionals and hobby beekeepers. Insights into the number of bee swarms caught revealed significant decreases in swarm availability over the past three years in Kenya. The opposite situation was observed in some regions of Ethiopia. These trends require further investigation. Overall, this comprehensive survey sheds light on the complexities and challenges beekeepers faced in Sub-Saharan Africa, pointing to the need for targeted interventions and sustained research to support the resilience and growth of the apicultural sector.