Sustainable B12-Dependent Dehalogenation of Organohalides in E. coli.

Microbial bioremediation can provide an environmentally friendly and scalable solution to treat contaminated soil and water. However, microbes have yet to optimize pathways for degrading persistent anthropogenic pollutants, in particular organohalides. In this work, we first expand our repertoire of enzymes useful for bioremediation. By screening a panel of cobalamin (B12)-dependent reductive dehalogenases, we identified previously unreported enzymes that dechlorinate perchloroethene and regioselectively deiodinate the thyroidal disruptor 2,4,6-triiodophenol. One deiodinase, encoded by the animal-associated anaerobe Clostridioides difficile, was demonstrated to dehalogenate the naturally occurring metabolites L-halotyrosines. In cells, several combinations of ferredoxin oxidoreductase and flavodoxin extract and transfer low-potential electrons from pyruvate to drive reductive dehalogenation without artificial reductants and mediators. This work provides new insights into a relatively understudied family of B12-dependent enzymes and sets the stage for engineering synthetic pathways for degrading unnatural small molecule pollutants.

Chronic exposure to nanocellulose altered depression-related behaviors in mice on a western diet: The role of immune modulation and the gut microbiome.

AIMS: To determine if cellulose nanofibrils (CNF) have potential applications as food additives. MATERIALS AND METHODS: Male C57BL/6 mice on a Western diet were exposed to CNF for one month at a dose of 30 mg/kg by gavage. Male NOD mice, a model for type 1 diabetes (T1D), were used in a six-month study. KEY FINDINGS: Sequencing analysis of 16S rRNA genes suggested significant changes in gut microbiome of male C57BL/6 mice exposed to CNF. Analysis of functional metagenomics indicated that many of the functional contents that might be altered following CNF ingestion were associated with lipid and carbohydrate processing. Further studies in NOD mice suggested that there were some decreases in the blood glucose levels during the insulin tolerance test and glucose tolerance test following CNF treatment. However, these small decreases were not considered biologically meaningful as there were no significant changes in either the area under the curve or the first-order rate constant for glucose disappearance. Moreover, serum concentrations of cytokines/chemokines including IL-3, IL-12(p70) and the keratinocyte chemoattractant were increased following chronic exposure to CNF. In addition, behavioral studies suggested that the percentage of immobility time during the tail-suspension test was significantly increased following six months of exposure to CNF in NOD mice, signifying an increase in depression-related behavior. SIGNIFICANCE: Collectively, long-term CNF consumption was associated with changes in the ecology of the gut microbiome, immune homeostasis, and possibly energy metabolism and mental health in male NOD mice on a Western diet.

Intramedullary Nailing with and without the Use of Bone Cement for Impending and Pathologic Fractures of the Humerus in Multiple Myeloma and Metastatic Disease.

Although intramedullary nailing (IMN) is considered the standard of care for the surgical management of most femur metastatic diseases, the optimal treatment of metastatic humeral impending and/or pathologic fractures is still debatable. Moreover, the use of cemented humeral nails has not been thoroughly studied, and only a few small series have compared their results with uncemented nails. The purpose of this study was to compare the (1) survivorship, (2) functional outcomes, and (3) perioperative complications in patients receiving cemented versus uncemented humerus IMN for impending or complete pathologic fractures resulting from metastatic disease or multiple myeloma. We retrospectively reviewed 100 IMNs in 82 patients, of which 53 were cemented and 47 were uncemented. With a mean survival of 10 months (Cemented: 8.3 months vs. Uncemented: 11.6 months, p = 0.34), the mean Musculoskeletal Tumor Society (MSTS) scores increased from 42.4% preoperatively (Cemented: 40.2% vs. Uncemented: 66.7%, p = 0.01) to 89.2% at 3 months postoperatively (Cemented: 89.8% vs. Uncemented: 90.9%, p = 0.72) for the overall group (p < 0.001). Both cohorts yielded comparable complication rates (overall [22.6% vs. 19.1%)], surgical ([11.3% vs. 4.3%], and medical [13.2% vs. 14.9%], all p > 0.05), but estimated blood loss was significantly higher in the cemented group (203 mL vs. 126 mL, p = 0.003). Thus, intramedullary nailing, with and without cement augmentation in select patients, is a relatively safe and effective therapeutic modality for metastatic humeral disease with similar clinical outcomes and acceptable complication rates. While controlling for possible selection bias, larger-scale, higher-level studies are warranted to validate our results.

International Guidelines for the Diagnosis and Management of Hyperinsulinism.

Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in 'developed' countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Discovery of the Azaserine Biosynthetic Pathway Uncovers a Biological Route for α-Diazoester Production.

Azaserine is a bacterial metabolite containing a biologically unusual and synthetically enabling α-diazoester functional group. Herein, we report the discovery of the azaserine (aza) biosynthetic gene cluster from Glycomyces harbinensis. Discovery of related gene clusters reveals previously unappreciated azaserine producers, and heterologous expression of the aza gene cluster confirms its role in azaserine assembly. Notably, this gene cluster encodes homologues of hydrazonoacetic acid (HYAA)-producing enzymes, implicating HYAA in α-diazoester biosynthesis. Isotope feeding and biochemical experiments support this hypothesis. These discoveries indicate that a 2-electron oxidation of a hydrazonoacetyl intermediate is required for α-diazoester formation, constituting a distinct logic for diazo biosynthesis. Uncovering this biological route for α-diazoester synthesis now enables the production of a highly versatile carbene precursor in cells, facilitating approaches for engineering complete carbene-mediated biosynthetic transformations in vivo.

Six weeks effect of different nanocellulose on blood lipid level and small intestinal morphology in mice.

AIMS: Cellulose nanofibrils (CNF, or NFC), cellulose nanocrystals (CNC, or NCC), and Tempo (2,2,6,6-tetramethylpiperidine-1-oxyl radical) oxidized CNF (Tempo-CNF) were compared for the short-term effect on mice fed with a high-fat and high-sugar (Western diet, WD) to investigate their effect when combined with a sub-optimal diet. SCOPE: Thirty C57B/C female mice (10 weeks old; 5-6 mice/group) were given water, cellulose, or three types of nanocellulose once daily in a dose of 30 mg/kg body weight by oral gavage. After six weeks, weight changes, fecal output, glucose homeostasis, and gut permeability showed no significant among groups. Serum analysis including triglycerides, cholesterol and total bile acids and small intestinal morphology including villus length, villus width, crypt depth, goblet cell count and goblet cell density were no difference for all groups. Only CNC group had higher excretion of bile acids in the feces. CONCLUSIONS: These results suggest that current treated dose using three types of nanocellulose had no detrimental effects on blood lipid level and small intestinal morphology.

Subacute exposure to dechlorane 602 dysregulates gene expression and immunity in the gut of mice.

Dechlorane 602 (Dec 602) has biomagnification potential. Our previous studies suggested that exposure to Dec 602 for 7 days induced colonic inflammation even after 7 days of recovery. To shed some light on the underlying mechanisms, disturbances of gut immunity and gene expression were further studied. Adult C57BL/6 mice were administered orally with Dec 602 for 7 days, then allowed to recover for another 7 days. Colonic type 3 innate lymphoid cells (ILC3s) in lamina propria lymphocytes (LPLs) and lymphocytes in mesenteric lymph nodes (MLNs) were examined by flow cytometry. Expressions of genes in the gut were determined by RNA-Seq. It was found that Dec 602 exposure up-regulated the percentage of CD4+ T cells in MLNs. The mean fluorescent intensity (MFI) of interleukin (IL)- 22 in LPLs was decreased, while the MFI of IL-17a as well as the percentage of IL-17a+ ILC3s in LPLs were increased after exposure to Dec 602. Genes involved in the formation of blood vessels and epithelial-mesenchymal transition were up-regulated by Dec 602. Ingenuity pathway analysis of differentially expressed genes predicted that exposure to Dec 602 resulted in the activation of liver X receptor/retinoid X receptor (LXR/RXR) and suppression of muscle contractility. Our results, on one hand, verified that the toxic effects of Dec 602 on gut immunity could last for at least 14 days, and on the other hand, these results predicted other adverse effects of Dec 602, such as muscle dysfunction. Overall, our studies provided insights for the further investigation of Dec 602 and other emerging environmental pollutants.

Exposure to dechlorane 602 induces perturbation of gut immunity and microbiota in female mice.

The homeostasis of gut immunity and microbiota are associated with the health of the gut. Dechlorane 602 (Dec 602) with food web magnification potential has been detected in daily food. People who were orally exposed to Dec 602 may encounter increased risk of health problems in the gut. In order to reveal the influence of short-term exposure of Dec 602 on gut immunity and microbiota, adult female C57BL/6 mice were administered orally with Dec 602 (low/high doses: 1.0/10.0 µg/kg body weight per day) for 7 days. Lymphocytes were examined by flow cytometry. Gut microbiota was measured by 16S rRNA gene sequencing. Results showed that fecal IgA was upregulated after exposure to the high dose of Dec 602, suggesting that there might be inflammation in the gut. Then, changes of immune cells in mesenteric lymph nodes and colonic lamina propria were examined. We found that exposure to the high dose of Dec 602 decreased the percentages of the anti-inflammatory T regulatory cells in mesenteric lymph nodes. In colonic lamina propria, the production of gut protective cytokine interleukin-22 by CD4+ T cells was decreased, and a decreased trend of interleukin-22 production was also observed in type 3 innate lymphoid cells in the high dose group. Furthermore, an altered microbiota composition toward inflammation in the gut was observed after exposure to Dec 602. Additionally, the altered microbiota correlated with changes of immune parameters, suggesting that there were interactions between influenced microbiota and immune parameters after exposure to Dec 602. Taken together, short-term exposure to Dec 602 induced gut immunity and microbiota perturbations, and this might be the mechanisms for Dec 602 to elicit inflammation in the gut.

Subacute effects of the chlorinated flame retardant dechlorane 602 on intestinal microenvironment in mice.

BACKGROUND: Chlorinated flame retardant Dechlorane 602 (Dec 602) has been detected in daily food, indicating that it may pose a risk to intestinal health. The intestinal microenvironment plays an important role in intestinal health. Intestinal microbiota and metabolites are two important factors for maintaining the microenvironment. However, little is known about the effects of Dec 602 on intestinal microbiota and metabolites. OBJECTIVES: We aimed to probe the effects of Dec 602 on the intestine by revealing the changes that Dec 602 caused to the intestinal microbiota and metabolites. METHODS: Adult female C57BL/6 mice were exposed to Dec 602 (low/high doses: 1.0/10.0 µg/kg body weight per day) orally for 7 consecutive days, and sacrificed after 7 days of recovery. The composition of colonic microbiota was measured by 16S rRNA gene sequencing, and the colonic metabolites were determined by LC-ESI-MS/MS. Finally, the effects of Dec 602 on the colon were validated by histopathological analysis. RESULTS: The intestinal microbiota composition was altered toward a pro-inflammatory status after exposure to Dec 602. Dec 602 exposure also up-regulated oxidative metabolites (glutathione disulfide, taurine and retinoic acid) and pro-inflammatory metabolites (prostaglandin E2). On the other hand, antioxidative metabolites (s-adenosylmethionine and 11-cis-retinol) and anti-inflammatory metabolites (alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid) were down-regulated after exposure to Dec 602. Infiltration of lymphocytes in the colonic lamina propria was observed in the mice treated with Dec 602 for 7 days, and it was not recovered after another 7 days without further treatment. CONCLUSION: Dec 602 interfered with the colonic microbiota and metabolome, and exhibited inflammatory features. Histopathological studies confirmed that Dec 602 exposure did induce colonic inflammation.

Global Registries in Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies and children. There are many areas of need for HI research. Some of the most critical needs include describing the natural history of the disease, research leading to new and better treatments, and identifying and managing hypoglycemia before it is prolonged and causes brain damage or death. Patient-reported data provides a basis for understanding the day-to-day experience of living with HI. Commonly identified goals of registries include performing natural history studies, establishing a network for future product and treatment studies, and supporting patients and families to offer more successful and coordinated care. Congenital Hyperinsulinism International (CHI) created the HI Global Registry (HIGR) in October 2018 as the first global patient-powered hyperinsulinism registry. The registry consists of thirteen surveys made up of questions about the patient's experience with HI over their lifetime. An international team of HI experts, including family members of children with HI, advocates, clinicians, and researchers, developed the survey questions. HIGR is managed by CHI and advised by internationally recognized HI patient advocates and experts. This paper aims to characterize HI through the experience of individuals who live with it. This paper includes descriptive statistics on the birthing experience, hospitalizations, medication management, feeding challenges, experiences with glucose monitoring devices, and the overall disease burden to provide insights into the current data in HIGR and demonstrate the potential areas of future research. As of January 2022, 344 respondents from 37 countries consented to participate in HIGR. Parents or guardians of individuals living with HI represented 83.9% of the respondents, 15.3% were individuals living with HI. Data from HIGR has already provided insight into access challenges, patients' and caregivers' quality of life, and to inform clinical trial research programs. Data is also available to researchers seeking to study the pathophysiology of HI retrospectively or to design prospective trials related to improving HI patient outcomes. Understanding the natural history of the disease can also guide standards of care. The data generated through HIGR provides an opportunity to improve the lives of all those affected by HI.

Congenital Hyperinsulinism International: A Community Focused on Improving the Lives of People Living With Congenital Hyperinsulinism.

Congenital hyperinsulinism (HI) is a rare disease affecting newborns. HI causes severe hypoglycemia due to the overproduction of insulin. The signs and symptoms of hypoglycemia in HI babies is often not discovered until brain damage has already occurred. Prolonged hypoglycemia from HI can even lead to death. Disease management is often complex with a high burden on caregivers. Treatment options are extremely limited and often require long hospital stays to devise. Cascading from suboptimal treatments and diagnostic practices are a host of other problems and challenges that many with HI and their families experience including continued fear of hypoglycemia and feeding problems. The aim of this paper is (1) to describe the current challenges of living with HI including diagnosis and disease management told from the perspective of people who live with the condition (2), to provide family stories of life with HI, and (3) to share how a rare disease patient organization, Congenital Hyperinsulinism International (CHI) is working to improve the lives of HI patients and their families. CHI is a United States based nonprofit organization with a global focus. The paper communicates the programs the patient advocacy organization has put into place to support HI families through its virtual and in-person gatherings. The organization also helps individuals access diagnostics, medical experts, and treatments. CHI also raises awareness of HI to improve patient outcomes with information about HI and prolonged hypoglycemia in twenty-three languages. CHI drives innovation for new and better treatments by funding research pilot grants, conducting research through the HI Global Registry, and providing patient experience expertise to researchers developing new treatments. The organization is also the sponsor of the CHI Collaborative Research Network which brings medical and scientific experts together for the development of a patient-focused prioritized research agenda.

High-Content Screening and Computational Prediction Reveal Viral Genes That Suppress the Innate Immune Response.

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single-virus or -gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human virus genes. We found that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-κB and interferon regulatory factor 3 (IRF3). We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins. IMPORTANCE Infectious diseases caused by viral pathogens exacerbate health care and economic burdens. Numerous viral biomolecules suppress the human innate immune system, enabling viruses to evade an immune response from the host. Despite our current understanding of viral replications and immune evasion, new viral proteins, including those encoded by uncultivated viruses or emerging viruses, are being unearthed at a rapid pace from large-scale sequencing and surveillance projects. The use of medium- and high-throughput functional assays to characterize immunosuppressive functions of viral proteins can advance our understanding of viral replication and possibly treatment of infections. In this study, we assembled a large viral-gene library from diverse viral families and developed a high-content assay to test for inhibition of innate immunity pathways. Our work expands the tools that can rapidly link sequence and protein function, representing a practical step toward early-stage evaluation of emerging and understudied viruses.

HIF-1alpha/VEGF pathway mediates 1,3,6,8-tetrabromo-9 H-carbazole-induced angiogenesis: a potential vascular toxicity of an emerging contaminant.

The dioxin-like substances polyhalogenated carbazoles (PHCZs) may trigger the aryl hydrocarbon receptor (AhR) signaling pathway. Although the crosstalk between AhR and the hypoxia inducible factor-1 (HIF-1) pathways is generally believed to occur, the exact mechanisms of the HIF-1 pathway in PHCZ toxicity have not been determined. We aimed to elucidate the effect of PHCZs on the HIF-1 pathway and its involvement in the regulation of target genes of HIF-1. Herein, we employed human HepG2 cells transiently transfected with a hypoxia response element (HRE) luciferase reporter to identify PHCZs that could influence HIF-1 pathway. We found that exposure to one of the four selected PHCZs, specifically 1,3,6,8-tetrabromo-9 H-carbazole (1368-BCZ), induced a significant enhancement of the activity of HRE activity. In silico data supported 1368-BCZ-induced HIF-1α activity preferentially. Moreover, 1368-BCZ significantly upregulated the expression of HIF-1 target genes, including endothelial growth factor (VEGF) and erythropoietin. Importantly, the stimulated secretion of VEGF by 1368-BCZ promoted the angiogenesis in human umbilical vein endothelial cells. Therefore, the present experimental and computational studies provide new and direct evidence of 1368-BCZ - HIF-1 interaction, which sheds light on the HIF-mediated cardiovascular toxicity and allows a knowledge-based risk assessment of emerging pollutants.

Developmental toxicity of bisphenol S in Caenorhabditis elegans and NODEF mice.

The growing concern surrounding bisphenol A (BPA) has led to increased industrial production and application of its analog bisphenol S (BPS). The goals of this study were: (1) To examine the generational effects in the nematode C. elegans for up to three generations following developmental exposure to BPS (0.1, 1.0, 5.0 and 10.0 µM), and (2) To examine the neurotoxicity and metabolic toxicity in NODEF mouse offspring exposed to BPS (3 µg/kg BW) in utero throughout gestation once/day via oral pipette. First, worms were exposed to BPS developmentally for a single period of 48 hours and then propagated for 2 additional generations. Exposure to 0.1 and 1.0 µM BPS decreased lifespan and the number of progeny with an ability to recover in subsequent generations. In contrast, worms exposed to 5.0 or 10.0 µM BPS exhibited a continuous effect in the second generation, e.g., decreased lifespan and reduced number of progeny. Only worms exposed to 10.0 µM BPS continued to have a significant long-term effect (e.g., decreased lifespan) through the third generation. In addition, worms developmentally exposed to BPS at 5.0 µM and 10.0 µM also showed decreases in body bends. In contrast, worms exposed to 0.1 µM BPS exhibited a significant increase in head thrashes. When the multigenerational effects were examined by exposing worms to BPS for 48 hours developmentally at each generation for three generations, an accumulative effect was observed in worms treated with 0.1 or 1.0 µM BPS for two generations, but not for three generations, suggesting a threshold existed. Worms exposed to either 5.0 or 10.0 µM BPS demonstrated accumulative effects through two and three generations. When the developmental effects of BPS were studied in NODEF mice, offspring exposed gestationally exhibited behavioral deficits at 12, but not at 3, weeks of age. Specifically, female offspring had decreases in working and short-term memories while male offspring showed increases in hyperactivity and anxiety-like behaviors. In summary, this study demonstrates the sex-related effects of BPS in NODEF mouse offspring exposed in utero, along with the generational effects observed in C. elegans.

Dietary advanced glycation end-products elicit toxicological effects by disrupting gut microbiome and immune homeostasis.

The aging immune system is characterized by a low-grade chronic systemic inflammatory state ("inflammaging") marked by elevated serum levels of inflammatory molecules such as interleukin (IL)-6 and C-reactive protein (CRP). These inflammatory markers were also reported to be strong predictors for the development/severity of Type 2 diabetes, obesity, and COVID-19. The levels of these markers have been positively associated with those of advanced glycation end-products (AGEs) generated via non-enzymatic glycation and oxidation of proteins and lipids during normal aging and metabolism. Based on the above observations, it is clinically important to elucidate how dietary AGEs modulate inflammation and might thus increase the risk for aging-exacerbated diseases. The present narrative review discusses the potential pro-inflammatory properties of dietary AGEs with a focus on the inflammatory mediators CRP, IL-6 and ferritin, and their relations to aging in general and Type 2 diabetes in particular. In addition, underlying mechanisms - including those related to gut microbiota and the receptors for AGEs, and the roles AGEs might play in affecting physiologies of the healthy elderly, obese individuals, and diabetics are discussed in regard to any greater susceptibility to COVID-19.

Navigating the U.S. health insurance landscape for children with rare diseases: a qualitative study of parents' experiences.

BACKGROUND: Parents of children with rare diseases often face uncertainty about diagnosis, treatment, and costs associated with healthcare for their child. Health insurance status impacts each of these areas, but no U.S. study has explored parents' perceptions of the health insurance impacts on their child's care. This study aimed to qualitatively explore how these parents navigate the complex health insurance system for their children and their experiences in doing so. METHODS: Semi-structured interviews were conducted with parents of children with metachromatic leukodystrophy (MLD) and spinal muscular atrophy (SMA), chosen for specific disease characteristics and orphan drug status. Participants were recruited via e-mail through patient advocacy organizations between September and December 2018. Interviews were conducted via Skype, were recorded, and professionally transcribed. Modified grounded theory was utilized as a methodology to analyze transcripts in an iterative process to determine themes and sub-themes based on participant described experiences. RESULTS: Major themes and subthemes that emerged across the 15 interviews included: (1) difficulties obtaining secondary insurance based on state eligibility criteria; (2) difficulty accessing needed healthcare services; and (3) need for repeated interactions with insurance representatives. The absence of clearly documented or widely recognized clinical guidelines exacerbated the difficulty accessing care identified as necessary by their healthcare team, such as therapy and equipment. An explanatory model for parent's experiences was developed from the themes and subthemes. The model includes the cyclical nature of interacting with insurance for redundant reauthorizations and the outside support and financial assistance that is often necessary to address their child's healthcare needs. CONCLUSIONS: With complex health conditions, small setbacks can become costly and disruptive to the health of the child and the life of the family. This study suggests that patients with rare diseases may benefit from time limits for processing coverage decisions, increasing transparency in the claims and preauthorization processes, and more expansive authorizations for on-going needs. Additional studies are needed to understand the full scope of barriers and to inform policies that can facilitate better access for families living with rare diseases.

Theranostic cells: emerging clinical applications of synthetic biology.

Synthetic biology seeks to redesign biological systems to perform novel functions in a predictable manner. Recent advances in bacterial and mammalian cell engineering include the development of cells that function in biological samples or within the body as minimally invasive diagnostics or theranostics for the real-time regulation of complex diseased states. Ex vivo and in vivo cell-based biosensors and therapeutics have been developed to target a wide range of diseases including cancer, microbiome dysbiosis and autoimmune and metabolic diseases. While probiotic therapies have advanced to clinical trials, chimeric antigen receptor (CAR) T cell therapies have received regulatory approval, exemplifying the clinical potential of cellular therapies. This Review discusses preclinical and clinical applications of bacterial and mammalian sensing and drug delivery platforms as well as the underlying biological designs that could enable new classes of cell diagnostics and therapeutics. Additionally, we describe challenges that must be overcome for more rapid and safer clinical use of engineered systems.

Behavioral changes and hyperglycemia in NODEF mice following bisphenol S exposure are affected by diets.

Bisphenol S (BPS), an analogue of the controversial bisphenol A (BPA) that is found in epoxy resins and plastics, is a potential endocrine-disrupting chemical that can mimic endogenous hormone signaling. However, little is known about the behavioral or immunologic effects of BPS. The purpose of this study was to examine the impact of diets in BPS-treated mice in relation to hyperglycemia, development of type 1 diabetes, immunomodulation, and behavioral changes. Adult male and female nonobese diabetic excluded flora (NODEF) mice were exposed to environmentally relevant doses of BPS (VH, 30, or 300 µg/kg BW) and fed either a soy-based diet, a phytoestrogen-free diet, or a Western diet. NODEF male mice fed a soy-based diet exhibited a decreased curiosity/desire to explore, and possibly increased anxiety-like behavior and decreased short-term memory when exposed to BPS (300 µg/kg BW). In addition, these mice had significant increases in non-fasting blood glucose levels along with increased insulin sensitivity, impaired glucose tolerance, resistance to fasting and proinflammation. Although BPS had little effect on the glucose parameters in NODEF male mice fed a Western diet, there were decreases in %CD24+CD5+ and %B220+CD40L-cell populations and increases in distance traveled during the novel object test, suggesting hyperactivity. NODEF females fed a phytoestrogen-free diet exhibited slight decreases in time spent immobile during the tail suspension test in both the 30 and 300 µg/kg BW dose groups along with increases in %CD4+CD8+ and %Mac3+CD45R+ cell populations, signifying increased hyperactivity and anxiety-like behavior. In conclusion, BPS-exposed NODEF mice exhibited sex and diet-related changes in hyperglycemia, behaviors and immune endpoints.

Modulation of folliculogenesis in adult laying chickens by bisphenol A and bisphenol S: Perspectives on ovarian morphology and gene expression.

Both bisphenol A (BPA) and its analog bisphenol S (BPS) are industrial chemicals that have been used to make certain plastic products applied in chicken farms, including food and water containers. They are endocrine disrupting chemicals (EDCs) with xenoestrogenic activities and affect reproductive success in many ways. It was hypothesized that BPA and BPS could adversely affect the folliculogenesis in chickens due to their disruption of the estrogen responses, using either genomic or non-genomic mechanisms. This study investigated the deleterious effects of BPA and BPS on the ovaries when adult layer chickens were orally treated with these EDCs at 50 µg/kg body weight, the reference dose for chronic oral exposure of BPA established by the U.S. EPA. The chickens in both BPA and BPS-treated groups showed a decreased number of the preovulatory follicles. BPA-treated chickens showed a significant decrease in the diameter of F1. Additionally, both BPA and BPS treatments increased the infiltrations of lymphocytes and plasma cells in ovaries. Moreover, it was found that the ovaries of BPS-treated chickens weighed the most among the groups. RNA sequencing and subsequent pathway enrichment analysis of differentially expressed genes revealed that both BPA- and BPS-treatment groups showed significant changes in gene expression and pathways related to reproduction, immune function and carcinogenesis. Taken together, both BPA and BPS are potentially carcinogenic and have deleterious effects on the fertility of laying chickens by inducing inflammation, suggesting that BPS may not be a safe replacement for BPA.