Epigenetic reprogramming of a distal developmental enhancer cluster drives SOX2 overexpression in breast and lung adenocarcinoma.

Enhancer reprogramming has been proposed as a key source of transcriptional dysregulation during tumorigenesis, but the molecular mechanisms underlying this process remain unclear. Here, we identify an enhancer cluster required for normal development that is aberrantly activated in breast and lung adenocarcinoma. Deletion of the SRR124-134 cluster disrupts expression of the SOX2 oncogene, dysregulates genome-wide transcription and chromatin accessibility and reduces the ability of cancer cells to form colonies in vitro. Analysis of primary tumors reveals a correlation between chromatin accessibility at this cluster and SOX2 overexpression in breast and lung cancer patients. We demonstrate that FOXA1 is an activator and NFIB is a repressor of SRR124-134 activity and SOX2 transcription in cancer cells, revealing a co-opting of the regulatory mechanisms involved in early development. Notably, we show that the conserved SRR124 and SRR134 regions are essential during mouse development, where homozygous deletion results in the lethal failure of esophageal-tracheal separation. These findings provide insights into how developmental enhancers can be reprogrammed during tumorigenesis and underscore the importance of understanding enhancer dynamics during development and disease.

The manuscript by Abatti et al. shows that epigenetic reactivation of a pair of distal enhancers that drive Sox2 expression during development (to permit separation of the esophagus and trachea) is responsible for the tumor-promoting re-expression of SOX2 in breast and lung tumors. Intriguingly, the same transcription factors that act on the enhancers during development to either activate or repress them (i.e. FOXA1 and NFIB, respectively) are also required for altering chromatin accessibility of the enhancers and SOX2 transcription in breast and lung cancer cells. With their work, the authors unravel the exact mechanism of how developmentally active enhancers become repurposed in a tumor context and show the relevance of this repurposing event for cancer.

Ovarian angiosarcoma: A systematic review of literature and survival analysis.

Ovarian angiosarcoma (OA) is rare, with only sporadic cases reported in English literature. We performed a systematic review of cases published in the PubMed, Science Direct, and Google Scholar databases with the aim of describing the reported clinicopathological features of OA. Fifty-three articles that reported 60 patients were reviewed. Of the 60 patients, 7 (11.6 %) were diagnosed with secondary (metastatic) ovarian angiosarcoma and 53 (88.3 %) were diagnosed with primary ovarian angiosarcoma. The mean age at presentation for ovarian angiosarcoma was 38.3±17.8 years. The average tumor size for ovarian angiosarcoma was 11.9±6.1 cm. Abdominal distention was reported in 45/60 (75 %). Microscopic examination revealed necrosis in 28/60 (46.7 %), pleomorphism in 32/59 (54.2 %), mitotic figures in 44/60 (73.3 %), spindle-shaped cells in 27/36 (75 %), epithelioid-shaped cells in 20/36 (55.5 %), and mixed epithelioid and spindle-shaped cells in 12/36 (33.3 %) patients. On immunohistochemistry CD 31 was positive in 41/41 (100 %), CD 34 in 38/39 (97.4 %), and Factor VIII related antigen in 18/21 (85.7 %) patients. Metastasis was present in 43/60 (71.6 %) patients. Chemotherapy and surgery was performed in 36/52 (69.2 %). The median follow-up time for ovarian angiosarcoma was 7 months (IQR1-IQR3:2-13.5 months). 24 (48 %) of the 50 patients with available survival data were alive and 26/50 (52 %) were dead of disease. Survival analyses (KM curves) revealed that the presence of necrosis (log-rank test; p = 0.05) and absence of spindle-shaped cells (log rank test; p = 0.04) on histopathology were associated with worse outcomes, while treatment with combined chemotherapy and surgical excision was associated with better survival (P < 0.001) therefore, prompt diagnosis and early treatment with combined chemotherapy and surgical excision can prolong survival in OA.

Inferring density-dependent population dynamics mechanisms through rate disambiguation for logistic birth-death processes.

Density dependence is important in the ecology and evolution of microbial and cancer cells. Typically, we can only measure net growth rates, but the underlying density-dependent mechanisms that give rise to the observed dynamics can manifest in birth processes, death processes, or both. Therefore, we utilize the mean and variance of cell number fluctuations to separately identify birth and death rates from time series that follow stochastic birth-death processes with logistic growth. Our nonparametric method provides a novel perspective on stochastic parameter identifiability, which we validate by analyzing the accuracy in terms of the discretization bin size. We apply our method to the scenario where a homogeneous cell population goes through three stages: (1) grows naturally to its carrying capacity, (2) is treated with a drug that reduces its carrying capacity, and (3) overcomes the drug effect to restore its original carrying capacity. In each stage, we disambiguate whether the dynamics occur through the birth process, death process, or some combination of the two, which contributes to understanding drug resistance mechanisms. In the case of limited sample sizes, we provide an alternative method based on maximum likelihood and solve a constrained nonlinear optimization problem to identify the most likely density dependence parameter for a given cell number time series. Our methods can be applied to other biological systems at different scales to disambiguate density-dependent mechanisms underlying the same net growth rate.

Population collapse and adaptive rescue during long-term chemostat fermentation.

Microbial fermentation is an essential process for research and industrial applications, yet our understanding of cellular dynamics during long-term fermentation is limited. Here, we report a reproducible phenomenon of abrupt population collapse followed by a rapid population rescue that was observed during long-term chemostat cultivations, for various strains of Escherichia coli in minimal media. Through genome resequencing and whole-genome transcriptional profiling of replicate runs over time, we identified that changes in the tRNA and carbon catabolic genes are the genetic basis of this phenomenon. Since current fermentation models are unable to capture the observed dynamics, we present an extended model that takes into account critical biological processes during fermentation, and we further validated carbon source predictions through forward experimentation. This study extends the predictability of current models for microbial fermentation and adds to our system-level knowledge of cellular adaptation during this crucial biotechnological process.

Associations among human papillomavirus, inflammation, and fatigue in patients with head and neck cancer.

BACKGROUND: Human papillomavirus (HPV) infection has contributed to an increased incidence of squamous cell carcinoma of the head and neck (SCCHN). Fatigue is a major side effect of SCCHN and its treatment. However, to the authors' knowledge, the association between HPV and fatigue has not been examined to date, nor is it known whether HPV influences biological mechanisms of fatigue, including inflammation. METHODS: Patients with SCCHN who were without distant metastasis were assessed at baseline (pre-radiotherapy) and 1 month and 3 months postradiotherapy. Fatigue was measured using the Multidimensional Fatigue Inventory. Peripheral inflammation was assessed by plasma C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor 2 (sTNFR2), and IL-6. Mixed effect models were used to examine associations. RESULTS: A total of 94 patients who were newly diagnosed were enrolled; 53% had HPV-related tumors. Patients with HPV-unrelated tumors had higher fatigue and higher plasma CRP, sTNFR2, and IL-6 over time, especially at baseline and 3 months after intensity-modulated radiotherapy compared with those with HPV-related tumors (all P < .05). However, fatigue and plasma sTNFR2 increased more significantly from baseline to 1 month after radiotherapy in the HPV-related group compared with the HPV-unrelated group (both P < .01). Controlling for significant covariates, HPV status and inflammation were found to be independent predictors of fatigue over time. CONCLUSIONS: HPV status is an important marker of vulnerability to the behavioral and immune consequences of SCCHN and its treatment, providing support for different symptom management strategies. Special emphasis should be placed on addressing marked persistent fatigue in patients with HPV-unrelated tumors, whereas attention should be paid to the large increases in fatigue during treatment among patients with HPV-related tumors. Cancer 2018. © 2018 American Cancer Society.

Disruption of Th2a and Th2b genes causes defects in spermatogenesis.

The variant histones TH2A and TH2B are abundant in the testis, but their roles in spermatogenesis remain elusive. Here, we show that male mutant mice lacking both Th2a and Th2b genes were sterile, with few sperm in the epididymis. In the mutant testis, the lack of TH2B was compensated for by overexpression of H2B, whereas overexpression of H2A was not observed, indicating a decrease in the total histone level. Mutant mice exhibited two defects: incomplete release of cohesin at interkinesis after meiosis I and histone replacement during spermiogenesis. In the mutant testis, secondary spermatocytes at interkinesis accumulated and cohesin was not released normally, suggesting that the retained cohesion of sister chromatids delayed the subsequent entry into meiosis II. In addition, impaired chromatin incorporation of TNP2 and degenerated spermatids were observed in the mutant testis. These results suggest that a loss of TH2A and TH2B function in chromatin dynamics or a decrease in the total histone levels causes defects in both cohesin release and histone replacement during spermatogenesis.

Picture This: Exploring the Lived Experience of High-Functioning Stroke Survivors Using Photovoice.

An increasing number of high-functioning stroke survivors are present with minimal functional impairments and are often discharged with reduced access to community reintegration. Our objectives were to explore the lived experience of high-functioning stroke survivors and to identify gaps in community and rehabilitation services. Photovoice was used with five high-functioning stroke survivors to photo-document their experiences. A modified inductive thematic analysis was used, and meanings behind the photographs were elicited through four focus group sessions followed by photography exhibitions. Five themes emerged: lack of understanding and consideration for persons with disability, emotional and behavioral impacts after stroke, self-reliance and dependence on others, importance of appropriate and accessible services, and financial determinants of quality of life. By including service users' voices; investing in adapted, community-based programs; and providing educational programs for creating attitudinal change among service providers, the polarization between who can and cannot access services will be reduced.

Sleep deprivation alters pubertal timing in humans and rats: the role of the gut microbiome.

STUDY OBJECTIVES: Evidence implied that sleeping duration is associated with the timing of puberty and that sleep deprivation triggers early pubertal onset in adolescents. Sleep deprivation can affect metabolic changes and gut microbiota composition. This study investigated the effects of sleep deprivation on pubertal onset and gut microbiota composition in animal models and a human cohort. METHODS: This study comprised 459 boys and 959 girls from the Taiwan Pubertal Longitudinal Study. Sleep duration was evaluated using the self-report Pittsburgh Sleep Quality Index questionnaire. Early sexual maturation was defined by pediatric endocrinologist assessments. Mediation analyses were done to examine the association between sleep parameters, obesity, and early sexual maturation. Besides, Sprague Dawley juvenile rats were exposed to 4 weeks of chronic sleep deprivation. Vaginal opening (VO) and preputial separation (PS) were observed every morning to determine pubertal onset in female and male rats. RESULTS: The sleep-deprived juvenile rats in the sleep-deprived-female (SDF) and sleep-deprived-male (SDM) groups experienced delayed VO (mean VO days: 33 days in control; 35 days in SDF; p-value < 0.05) and PS (mean PS days: 42 days in control; 45 days in SDM; p-value < 0.05), respectively. Relative to their non-sleep-deprived counterparts, the sleep-deprived juvenile rats exhibited lower body weight and body fat percentage. Significant differences in relative bacterial abundance at genus levels and decreased fecal short-chain-fatty-acid levels were identified in both the SDF and SDM groups. In the human cohort, insufficient sleep increased the risk of early sexual maturation, particularly in girls (OR, 1.44; 95% CI: 1.09 to 1.89; p-value < 0.01). Insufficient sleep also indirectly affected early sexual maturation in girls, with obesity serving as the mediator. CONCLUSIONS: Overall, sleep deprivation altered the timing of puberty in both animal and human models but in different directions. In the rat model, sleep deprivation delayed the pubertal onset in juvenile rats through gut dysbiosis and metabolic changes, leading to a low body weight and body fat percentage. In the human model, sleep deprivation led to fat accumulation, causing obesity in girls, which increased the risk of early puberty.

Effects of Resveratrol on Muscle Inflammation, Energy Utilisation, and Exercise Performance in an Eccentric Contraction Exercise Mouse Model.

Eccentric contraction can easily cause muscle damage and an inflammatory response, which reduces the efficiency of muscle contraction. Resveratrol causes anti-inflammatory effects in muscles, accelerates muscle repair, and promotes exercise performance after contusion recovery. However, whether resveratrol provides the same benefits for sports injuries caused by eccentric contraction is unknown. Thus, we explored the effects of resveratrol on inflammation and energy metabolism. In this study, mice were divided into four groups: a control group, an exercise group (EX), an exercise with low-dose resveratrol group (EX + RES25), and an exercise with high-dose resveratrol group (EX + RES150). The results of an exhaustion test showed that the time before exhaustion of the EX + RES150 group was greater than that of the EX group. Tumour necrosis factor-α (Tnfα) mRNA expression was lower in the EX + RES150 group than in the EX group. The energy utilisation of the EX + RES150 group was greater than that of the EX + RES25 group in different muscles. High-dose resveratrol intervention decreased Tnfα mRNA expression and enhanced the mRNA expressions of sirtuin 1, glucose transporter 4, AMP-activated protein kinase α1, and AMP-activated protein kinase α2 in muscles. These results revealed that high-dose resveratrol supplementation can reduce inflammation and oxidation and improve energy utilisation during short-duration high-intensity exercise.

Maternal Omega-3 Supplementation During Pregnancy, but Not Childhood Supplementation, Reduces the Risk of Food Allergy Diseases in Offspring.

BACKGROUND: Omega-3 supplementation has been reported to modulate immune responses and prevent food allergies among children; however, findings are inconsistent, and the timing of supplementation, which is critical, has not been thoroughly investigated. OBJECTIVE: To assess optimal timing (maternal vs childhood intake) of omega-3 supplementation for reducing food allergy risk among children in 2 periods (the first 3 years and beyond 3 years of age). METHODS: We performed a meta-analysis to assess the effects of maternal or childhood omega-3 supplementation on preventing the development of infant food allergies and food sensitizations. The PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were searched for related studies published until October 30, 2022. We conducted dose-response and subgroup analyses to investigate the effects of omega-3 supplementation. RESULTS: We found that maternal omega-3 supplementation during pregnancy and lactation was significantly associated with decreased risks of infant egg sensitization (relative risk [RR]: 0.58, 95% confidence interval [95% CI]: 0.47-0.73, P < .01) and peanut sensitization (RR: 0.62, 95% CI: 0.47-0.80, P < .01) among children. Similar results were found in subgroup analyses for food allergy, egg sensitization, and peanut sensitization during the first 3 years of age and peanut sensitization and cashew nut sensitization beyond 3 years of age. Dose-response analysis showed a linear relationship between maternal omega-3 supplementation and infant egg sensitization risk during early life. By contrast, intake of omega-3 polyunsaturated fatty acid during childhood did not appear to significantly protect against food allergies. CONCLUSIONS: Maternal omega-3 supplementation during pregnancy and lactation, rather than childhood intake, reduces the risk of infant food allergy and food sensitization.

Dietary nitrate, nitrite, and nitrosamine in association with diabetes: a systematic review and meta-analysis.

CONTEXT: Diabetes is a global health concern, and diet is a contributing factor to diabetes. Findings regarding the connection between nitrate, nitrite, and nitrosamine and diabetes risk are inconsistent. OBJECTIVE: The aim was to examine the effects of these dietary compounds on diabetes risk. DATA SOURCES: The data were sourced from PubMed, EMBASE, Scopus, and Web of Science until February 28, 2023. Studies that reported individual-level consumption of these compounds were included. Review articles or ecological studies were excluded. DATA EXTRACTION: The number of events and total observations were recorded. DATA ANALYSIS: The pooled odds ratio (OR) was calculated and displayed in a forest plot. Subgroup and sensitivity analyses were predefined. A dose-response meta-analysis was conducted to determine the exposure intervals that may increase the risk of disease. Six observational reports that met the inclusion criteria were included, involving 108 615 individuals. Participants in the highest quantile of nitrite intake had a greater risk of diabetes compared with those in the lowest quantile (OR, 1.61; 95% confidence interval [CI], 1.08-2.39; I2 = 74%, P = 0.02). Higher nitrosamine consumption tended to increase diabetes risk (OR, 1.52; 95% CI, 0.76-3.04; I2 = 76%; P = 0.24). The relationship was stronger for type 1 (OR, 1.79; 95% CI, 1.20-2.67; I2 = 58%; P < 0.01) than for type 2 diabetes (OR, 1.42; 95% CI, 0.86-2.37; I2 = 71%; P = 0.17). Additionally, nitrite consumption had a dose-dependent association with both phenotypes. No association was found between diabetes risk and high nitrate intake (OR, 1.01; 95% CI, 0.87-1.18; I2 = 28%; P = 0.87). CONCLUSION: Attention should be paid to the consumption of nitrite-containing foods. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42023394462 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=394462).

The role of dietary magnesium deficiency in inflammatory hypertension.

Nearly 30% of adults consume less than the estimated average daily requirement of magnesium (Mg2+), and commonly used medications, such as diuretics, promote Mg2+ deficiency. Higher serum Mg2+ levels, increased dietary Mg2+ in-take, and Mg2+ supplementation are each associated with lower blood pressure, suggesting that Mg2+-deficiency contributes to the pathogenesis of hypertension. Antigen-presenting cells, such as monocytes and dendritic cells, are well-known to be involved in the pathogenesis of hypertension. In these cells, processes implicated as necessary for increased blood pressure include activation of the NLRP3 inflammasome, IL-1ß production, and oxidative modification of fatty acids such as arachidonic acid, forming isolevuglandins (IsoLGs). We hypothesized that increased blood pressure in response to dietary Mg2+-depletion leads to increased NLRP3, IL-1ß, and IsoLG production in antigen presenting cells. We found that a Mg2+-depleted diet (0.01% Mg2+ diet) increased blood pressure in mice compared to mice fed a 0.08% Mg2+ diet. Mg2+-depleted mice did not exhibit an increase in total body fluid, as measured by quantitative magnetic resonance. Plasma IL-1ß concentrations were increased (0.13 ± 0.02 pg/mL vs. 0.04 ± 0.02 pg/mL). Using flow cytometry, we observed increased NLRP3 and IL-1ß expression in antigen-presenting cells from spleen, kidney, and aorta. We also observed increased IsoLG production in antigen-presenting cells from these organs. Primary culture of CD11c+ dendritic cells confirmed that low extracellular Mg2+ exerts a direct effect on these cells, stimulating IL-1ß and IL-18 production. The present findings show that NLRP3 inflammasome activation and IsoLG-adduct formation are stimulated when dietary Mg2+ is depleted. Interventions and increased dietary Mg2+ consumption may prove beneficial in decreasing the prevalence of hypertension and cardiovascular disease.

Diagnostic Accuracy of Female Pelvic Ultrasonography in Differentiating Precocious Puberty From Premature Thelarche: A Systematic Review and Meta-analysis.

Background: The gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and may create an unpleasant experience for participants. Moreover, some overlaps may occur between PP and premature thelarche (PT) in the early stage of PP. Female pelvic ultrasonography may provide additional information to help differentiate PP from PT and subsequently initiate early treatment. In this study, we aimed to first directly compare pelvic ultrasonography parameters between PP and PT groups and secondly, investigate their diagnostic accuracy compared with the GnRH stimulation test. Methods: A systematic search of the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed up to March 31, 2021. All types of studies, except for case reports and review articles, were included. The GnRH stimulation test was used to confirm PP diagnosis. Those whose organic conditions might cause PP were excluded. The mean, standard deviation, sensitivity, and specificity of each parameter were documented. Forest plots were constructed to display the estimated standardized mean differences (SMDs) from each included study and the overall calculations. A bivariate model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Results: A total of 13 studies were included for analysis. The SMDs (95% confidence interval - CI) in ovarian volume, fundal-cervical ratio, uterine length, uterine cross-sectional area, and uterine volume between PP and PT groups were 1.12 (0.78-1.45; p < 0.01), 0.90 (0.07-1.73; p = 0.03), 1.38 (0.99-1.78; p < 0.01), 1.06 (0.61-1.50; p < 0.01), and 1.21 (0.84-1.58; p <0.01), respectively. A uterine length of 3.20 cm yielded a pooled sensitivity of 81.8% (95% CI 78.3%-84.9%), specificity of 82.0% (95% CI 61.0%-93.0%), PLR of 4.56 (95% CI 2.15-9.69), NLR of 0.26 (95% CI 0.17-0.39), and DOR of 19.62 (95% CI 6.45-59.68). The area under the summary receiver operating characteristics curve was 0.82. Conclusion: Female pelvic ultrasonography may serve as a complementary tool to the GnRH stimulation test in differentiating PP from PT. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232427, ID: CRD42021232427.

TAD fusion score: discovery and ranking the contribution of deletions to genome structure.

Deletions that fuse two adjacent topologically associating domains (TADs) can cause severe developmental disorders. We provide a formal method to quantify deletions based on their potential disruption of the three-dimensional genome structure, denoted as the TAD fusion score. Furthermore, we show that deletions that cause TAD fusion are rare and under negative selection in the general population. Finally, we show that our method correctly gives higher scores to deletions reported to cause various disorders, including developmental disorders and cancer, in comparison to the deletions reported in the 1000 Genomes Project. The TAD fusion score tool is publicly available at https://github.com/HormozdiariLab/TAD-fusion-score .

A Perspective on the Development of TGF-ß Inhibitors for Cancer Treatment.

Transforming growth factor (TGF)-ß is a secreted multifunctional cytokine that signals via plasma membrane TGF-ß type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-ß signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-ß can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-ß in cancer cells are blocked, TGF-ß signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-ß signaling in cancer and summarize the clinical status of TGF-ß signaling inhibitors that interfere with TGFï€­ß bioavailability, TGF-ßreceptor interaction, or TGF-ß receptor kinase function. Moreover, we will discuss targeting of TGF-ß signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs.

Combinatorial Approach for Complex Disorder Prediction: Case Study of Neurodevelopmental Disorders.

Early prediction of complex disorders (e.g., autism and other neurodevelopmental disorders) is one of the fundamental goals of precision medicine and personalized genomics. An early prediction of complex disorders can improve the prognosis, increase the effectiveness of interventions and treatments, and enhance the life quality of affected patients. Considering the genetic heritability of neurodevelopmental disorders, we are proposing a novel framework for utilizing rare coding variation for early prediction of these disorders in subset of affected samples. We provide a combinatorial framework for addressing this problem, denoted as Odin (Oracle for DIsorder predictioN), to make a prediction for a small, yet significant, subset of affected cases while having very low false positive rate (FPR) prediction for unaffected samples. Odin also takes advantage of the available functional information (e.g., pairwise coexpression of genes during brain development) to increase the prediction power beyond genes with recurrent variants. Application of our method accurately recovers an additional 8% of autism cases without any severe variant in known recurrent mutated genes with a <1% FPR. Furthermore, Odin predicted a set of 391 genes that severe variants in these genes can cause autism or other developmental delay disorders. Approaches such as the one presented in this paper are needed to translate the biomedical discoveries into actionable items by clinicians. Odin is publicly available at https://github.com/HormozdiariLab/Odin.

Social behavior deficits in the Fmr1 mutant mouse.

Mice exhibiting deficits in social behavior may provide valuable models for autistic-like behavioral problems. We tested social interactions in male mice from three inbred strains: C57BL/6J (B6), BALB/cJ (C) and DBA/2J (D2). All three strains showed gradual habituation of the number of social interactions with an ovariectomized female over four subsequent 2min sessions, returning to initial levels when presented with another stimulus mouse. Next, we studied males with a knockout mutation in the Fmr1 gene on a B6 background. KO animals showed strongly reduced levels of social interaction, which were about similar as those of habituated controls. This social behavior deficit suggests that Fmr1 KO mice could possibly be used as models for autistic behaviors.

A Parts Database with Consensus Parameter Estimation for Synthetic Circuit Design.

Mathematical modeling and numerical simulation are crucial to support design decisions in synthetic biology. Accurate estimation of parameter values is key, as direct experimental measurements are difficult and time-consuming. Insufficient data, incompatible measurements, and specialized models that lack universal parameters make this task challenging. Here, we have created a database (PAMDB) that integrates data from 135 publications that contain 118 circuits and 165 genetic parts of the bacterium Escherichia coli. We used a succinct, universal model formulation to describe the part behavior in each circuit. We introduce a constrained consensus inference method that was used to infer the value of the model parameters and evaluated its performance through cross-validation in a benchmark of 23 circuits. We discuss these results and summarize the challenges in data integration and parameter inference. This work provides a resource and a methodology that can be used as a point of reference for synthetic circuit modeling.

Two Histone Variants TH2A and TH2B Enhance Human Induced Pluripotent Stem Cell Generation.

There are two major methods of reprogramming: generation of induced pluripotent stem cells (iPSCs) by overexpressing embryonic stem cell-specific transcription factors (OCT4, SOX2, KLF4, and c-MYC) and somatic cell nuclear transfer by oocyte-specific factors. Previously, we reported oocyte-enriched histone variants TH2A, TH2B, and the histone chaperone nucleoplasmin (NPM2) enhance the reprogramming by OSKM in mice by inducing open chromatin structure. In this study, we showed that human TH2A, TH2B, and NPM2 enhance the OSKM-induced reprogramming of adult and neonatal human dermal fibroblasts and umbilical vein endothelial cells. Pluripotency of iPSCs generated by coexpressing OSKM, TH2A, TH2B, and NPM2 was shown by in vitro and in vivo differentiation assays. These iPSCs gave rise to highly differentiated teratomas compared to iPSCs induced by OSKM alone. Genome-wide analysis suggests a possibility that TH2A, TH2B, and NPM2 might regulate genes that are involved in naïve stem cell stage. Thus, TH2A, TH2B, and NPM2 enhance reprogramming of human somatic cells and improve the quality of human iPSCs.

Fast and Accurate Circuit Design Automation through Hierarchical Model Switching.

In computer-aided biological design, the trifecta of characterized part libraries, accurate models and optimal design parameters is crucial for producing reliable designs. As the number of parts and model complexity increase, however, it becomes exponentially more difficult for any optimization method to search the solution space, hence creating a trade-off that hampers efficient design. To address this issue, we present a hierarchical computer-aided design architecture that uses a two-step approach for biological design. First, a simple model of low computational complexity is used to predict circuit behavior and assess candidate circuit branches through branch-and-bound methods. Then, a complex, nonlinear circuit model is used for a fine-grained search of the reduced solution space, thus achieving more accurate results. Evaluation with a benchmark of 11 circuits and a library of 102 experimental designs with known characterization parameters demonstrates a speed-up of 3 orders of magnitude when compared to other design methods that provide optimality guarantees.