Identifying C. elegans Lifespan Mutants by Screening for Early-Onset Protein Aggregation

Genetic screens have been widely used to identify genetic pathways that control specific biological functions. In C. elegans, forward genetic screens rely on the isolation of reproductively active mutants that can self-propagate clonal populations. Since aged individuals are unable to generate clonal populations, screens that target post-reproductive phenotypes, such as longevity, are challenging. In this work, we developed an approach that combines microfluidic technologies and image processing to perform a high-throughput, automated screen for mutants with shortened lifespan using protein aggregation as a marker for aging. We take advantage of microfluidics for maintaining a reproductively-active adult mutagenized population and for performing serial high-throughput analysis and sorting of animals with increased protein aggregation, using fluorescently labeled PAB-1 as a readout. We identified five mutants with increased aggregation levels, of which two exhibited a reduced lifespan. We demonstrate that lifespan mutants can be identified by screening for accelerated protein aggregation through quantitative analysis of fluorescently-labeled aggregates in populations that do not require conditional sterilization or manual separation of parental and progeny populations. We further analyzed the morphology of protein aggregates and reveal that patterns of aggregation in naturally-aging animals differ from mutants with increased aggregation, suggesting aggregate growth is time-dependent. This screening approach can be customized to other non-developmental phenotypes that appear during adulthood, as well as to other aging markers to identify additional longevity-regulating genetic pathways.

A Systematic Review to Guide Future Efforts in the Determination of Genetic Causes of Pregnancy Loss

Background: Pregnancy loss is the most common obstetric complication occurring in almost 30% of conceptions overall and in 12–14% of clinically recognized pregnancies. Pregnancy loss has strong genetic underpinnings, and despite this consensus, our understanding of its genetic causes remains limited. We conducted a systematic review of genetic factors in pregnancy loss to identify strategies to guide future research.Methods: To synthesize data from population-based association studies on genetics of pregnancy loss, we searched PubMed for relevant articles published between 01/01/2000-01/01/2020. We excluded review articles, case studies, studies with limited sample sizes to detect associations (N < 4), descriptive studies, commentaries, and studies with non-genetic etiologies. Studies were classified based on developmental periods in gestation to synthesize data across various developmental epochs.Results: Our search yielded 580 potential titles with 107 (18%) eligible after title/abstract review. Of these, 54 (50%) were selected for systematic review after full-text review. These studies examined either early pregnancy loss (n = 9 [17%]), pregnancy loss >20 weeks' gestation (n = 10 [18%]), recurrent pregnancy loss (n = 32 [59%]), unclassified pregnancy loss (n = 3 [4%]) as their primary outcomes. Multiple genetic pathways that are essential for embryonic/fetal survival as well as human development were identified.Conclusion: Several genetic pathways may play a role in pregnancy loss across developmental periods in gestation. Systematic evaluation of pregnancy loss across developmental epochs, utilizing whole genome sequencing in families may further elucidate causal genetic mechanisms and identify other pathways critical for embryonic/fetal survival.

Using the Symptom Patient Similarity Network to Explore the Difference between the Chinese and Western Medicine Pathways of Ischemic Stroke and its Comorbidities

Background and Objectives. The development of network medicine provides new opportunities for disease research. Ischemic stroke has a high incidence, disability, and recurrence rate, and one of the reasons is that it is often accompanied by other complex diseases, including risk factors, complications, and comorbidities. Network medicine was used to try to analyze the characteristics of IS-related diseases and find out the differences in genetic pathways between Chinese herbs and Western drugs. Methods. Individualized treatment of traditional Chinese medicine (TCM) provides a theoretical basis for the study of the personalized classification of complex diseases. Utilizing the TCM clinical electronic medical records (EMRs) of 7170 in patients with IS, a patient similarity network (PSN) with shared symptoms was constructed. Next, patient subgroups were identified using community detection methods and enrichment analyses were performed. Finally, genetic data of symptoms, herbs, and drugs were used for pathway and GO analysis to explore the characteristics of pathways of subgroups and to compare the similarities and differences in genetic pathways of herbs and drugs from the perspective of molecular pathways of symptoms. Results. We identified 34 patient modules from the PSN, of which 7 modules include 98.48% of the whole cases. The 7 patient subgroups have their own characteristics of risk factors, complications, and comorbidities and the underlying genetic pathways of symptoms, drugs, and herbs. Each subgroup has the largest number of herb pathways. For specific symptom pathways, the number of herb pathways is more than that of drugs. Conclusion. The research of disease classification based on community detection of symptom-shared patient networks is practical; the common molecular pathway of symptoms and herbs reflects the rationality of TCM herbs on symptoms and the wide range of therapeutic targets.

Aging in HIV: Can natural compounds beneficially affect its higher progression?

Aging in HIV patients is accompanied with many physical and psychological health threatening challenges. A full citation of all natural compounds and their beneficial effects in aging process in HIV-positive patients is beyond the scope of a short editorial like this and we do not intend to delve in depth of genetic pathways. However, we shortly present some useful notes below worth of ongoing research.

The Role of Genetic Pathways in the Development of Chemoradiation Resistance in Nasopharyngeal Carcinoma (NPC) Patients

Management of nasopharyngeal carcinoma (NPC) remains elusive despite new developments and advancement that has been made in the current management approaches. A patient’s survival and prognosis remain dismal especially for a late-stage disease. This is highly attribute to the chemoradiation resistance. Arrays of genes and molecular mechanisms underlie the development of chemoradiation resistance in NPC. Imperatively, unravelling the true pathogenesis of chemoradiation resistance is crucial as these significant proteins and genes can be modulated to produce an effective therapeutic target. It is pivotal to identify the chemoradiation resistance at the very beginning in order to combat the chemoradiation resistance efficiently. Intense research in the genetic ecosphere is critical, as the discovery and development of novel therapeutic targets can be used for screening, diagnosis, and treating the chemoradiation resistance aggressively. This will escalate the management trajectory of NPC patients. This article highlights the significance of genetic and molecular factors that play critical roles in the chemoradiation resistance and how these factors may be modified for next-generation targeted therapy products.

(Non)Parallel developmental pathways to vertebrate appendage reduction and loss

This is the pre-peer reviewed version of the following article: (Non)Parallel developmental mechanisms in vertebrate appendage reduction and loss , which has been published in final form at https://doi.org/10.1002/ece3.8226. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Appendages have been reduced or lost hundreds of times independently during vertebrate evolution. This suggests that selection routinely favors appendage reduction. How often are the same developmental and genetic pathways used during loss by independent lineages? We reviewed the developmental and evolutionary literatures of appendage reduction in 12 genera spanning fish, reptiles, birds, and mammals. We found that appendage reduction and loss resulted from modified gene expression in each case but one. However, the genes for which expression was modified were rarely shared. Our findings suggest that adaptive loss of complex traits might proceed relatively easily through changes in gene expression along multiple developmental pathways.

(Non)Parallel developmental pathways to vertebrate appenda

This is the pre-peer reviewed version of the following article: (Non)Parallel developmental mechanisms in vertebrate appendage reduction and loss , which has been published in final form at https://doi.org/10.1002/ece3.8226. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Appendages have been reduced or lost hundreds of times independently during vertebrate evolution. This suggests that selection routinely favors appendage reduction. How often are the same developmental and genetic pathways used during loss by independent lineages? We reviewed the developmental and evolutionary literatures of appendage reduction in 12 genera spanning fish, reptiles, birds, and mammals. We found that appendage reduction and loss resulted from modified gene expression in each case but one. However, the genes for which expression was modified were rarely shared. Our findings suggest that adaptive loss of complex traits might proceed relatively easily through changes in gene expression along multiple developmental pathways.

Expansion and application of dye tracers for measuring solid food intake and food preference in Drosophila

The Drosophila model is used to investigate the effects of diet on physiology as well as the effects of genetic pathways, neural systems and environment on feeding behavior. We previously showed that Blue 1 works well as a dye tracer to track consumption of agar-based media in Drosophila in a method called Con-Ex. Here, we describe Orange 4 as a novel dye for use in Con-Ex studies that expands the utility of this method. Con-Ex experiments using Orange 4 detect the predicted effects of starvation, mating status, strain, and sex on feeding behavior in flies. Orange 4 is consumed and excreted into vials linearly with time in Con-Ex experiments, the number of replicates required to detect differences between groups when using Orange 4 is comparable to that for Blue 1, and excretion of the dye reflects the volume of consumed dye. In food preference studies using Orange 4 and Blue 1 as a dye pair, flies decreased their intake of food laced with the aversive tastants caffeine and NaCl as determined using Con-Ex or a more recently described modification called EX-Q. Our results indicate that Orange 4 is suitable for Con-Ex experiments, has comparable utility to Blue 1 in Con-Ex studies, and can be paired with Blue 1 to assess food preference via both Con-Ex and EX-Q.

Genetic Characterization, Current Model Systems and Prognostic Stratification in PAX Fusion-Negative vs. PAX Fusion-Positive Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents and accounts for approximately 2% of soft tissue sarcomas in adults. It is subcategorized into distinct subtypes based on histological features and fusion status (PAX-FOXO1/VGLL2/NCOA2). Despite advances in our understanding of the pathobiological and molecular landscape of RMS, the prognosis of these tumors has not significantly improved in recent years. Developing a better understanding of genetic abnormalities and risk stratification beyond the fusion status are crucial to developing better therapeutic strategies. Herein, we aim to highlight the genetic pathways/abnormalities involved, specifically in fusion-negative RMS, assess the currently available model systems to study RMS pathogenesis, and discuss available prognostic factors as well as their importance for risk stratification to achieve optimal therapeutic management.

Intermittent and Periodic Fasting, Hormones, and Cancer Prevention

The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have been shown to have both acute and long-term effects on these hormones. Here, we review the effects of nutrients and fasting on hormones and genes established to affect aging and cancer. We describe the link between dietary interventions and genetic pathways affecting the levels of these hormones and focus on the mechanisms responsible for the cancer preventive effects. We propose that IF and PF can reduce tumor incidence both by delaying aging and preventing DNA damage and immunosenescence and also by killing damaged, pre-cancerous and cancer cells.