Maternal diet-induced obesity during pregnancy alters lipid supply to mouse E18.5 fetuses and changes the cardiac tissue lipidome in a sex-dependent manner

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in late gestation E18.5 fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female fetal heart lipidomes are more sensitive to maternal obesity than males; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.

The Unshakable Kingdom: The Life and Ministry of Paul Berron (1887–1970)

Paul Berron was a singular missionary, a missionary ‘in between’ cultures and nations. He lived and worked not only between his European roots and the field of mission he organised in Syria and Lebanon, but also between two European countries, France and Germany, then involved in a harsh conflict. His experience as an Alsatian and his Christian commitment enabled him to sympathise with the fate of the Armenian survivors of the genocide of 1915. He maintained close links with Christians in the Netherlands, Switzerland, and other nations, involving them in the work of the emerging Action Chrétienne en Orient. To him, mission was not only a work in distant countries, but began at home, especially among newcomers to Europe. In his writings he reflected on nationalism, culture, providence and the church, developing a unique and early expression of ecumenical missiology.

Adrenalectomy improves glycemic responses in congenic obese LA/Ntul//-cp RATS

To determine the effects of adrenalectomy on typical insulin-mediated glycemic responses in male obese rats, groups (n=6 -12 rats/phenotype) of normally reared congenic lean and obese animals were fed a Purina chow diet from 6 to 9 weeks of age, and the Chow diet plus a highly palatable cafeteria diet from 9 to 12 weeks of age. The congenic LA/Ntul//-cp rat strain is noted for its longevity and early expression of the obese trait but remains non-diabetic throughout much if not all of its normal lifespan. Subgroups of obese animals were subjected to bilateral adrenalectomy (ADX) at 6 weeks of age to remove glucocorticoid contributions to glycemic parameters. Measures of weight gain (WG )and of glucose tolerance (OGT) were obtained in the three treatment groups at 6, 9 and 12 weeks of age. WG on ADX-obese rats was similar to that of their lean littermates at 6 and 9 weeks of age on the chow diet but increased to twice that observed in their lean littermates from 9 to 12 weeks of age. OGT responses after 30 to 60 minutes and the area under the OGT curve were impaired but not diabetic in obese animals at all ages compared to lean littermates and returned toward those of normally lean rats after ADX. The Insulin to glucose ratio (I:G) was also consistent with insulin resistance in obese but not in ADX-obese or lean rats at 12 weeks of age. In conclusion, ADX resulted in normalization of OGT and glycemic parameters in the obese phenotype at 9 and 12 weeks of age. These results are consistent with normalization of typical insulin-mediated components of glycemic parameters and glucose uptake in peripheral tissues following adrenalectomy of congenic obese rats. The results further suggest that the counterregulatory effects of insulin and glucocorticoid hormones may be contributory to the impaired glycemic responses in the obese phenotype of the LA/N//-cp (corpulent) rat and are consistent with a receptor-mediated element in the development of insulin resistance and glucose uptake in peripheral tissues commonly associated with the early development of obesity in this strain.

Preclinical efficacy, safety, and immunogenicity of PHH-1V, a second-generation COVID-19 vaccine candidate based on a novel recombinant RBD fusion heterodimer of SARS-CoV-2.

Since the genetic sequence of SARS-CoV-2 became available in January 2020, new vaccines have been developed at an unprecedented speed. The current vaccines have been directly associated with a decline in new infection rates, prevention of severe disease and an outstanding decrease in mortality rates. However, the pandemic is still far from being over. New Variants of Concern (VoCs) are continuously evolving. Thus, it is essential to develop accessible second-generation COVID-19 vaccines against known and future VoCs to mitigate the current pandemic. Here, we provide preclinical data showing the immunogenicity, efficacy, and safety results in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine candidate (PHH-1V) which consists of a novel RBD fusion heterodimer containing the B.1.1.7 (alpha) and B.1.351 (beta) variants of SARS-CoV-2, formulated with an oil-based adjuvant equivalent to MF59C.1. BALB/c and K18-hACE2 mice were immunized with different doses of recombinant RBD fusion heterodimer, following a two-dose prime-and-boost schedule. Upon 20 μg RBD fusion heterodimer/dose immunization, BALB/c mice produced RBD-binding antibodies with neutralising activity against the alpha, beta, gamma, and delta variants. Furthermore, vaccination elicited robust activation of CD4+ and CD8+ T cells with early expression of Th1 cytokines upon in vitro restimulation, along with a good tolerability profile. Importantly, vaccination with 10 μg or 20 μg RBD fusion heterodimer/dose conferred 100% efficacy preventing mortality and bodyweight loss upon SARS-CoV-2 challenge in K18-hACE2 mice. These findings demonstrate the feasibility of this novel recombinant vaccine strategy, allowing the inclusion of up to 2 different RBD proteins in the same vaccine. Most importantly, this new platform is easy to adapt to future VoCs and has a good stability profile, thus ensuring its global distribution.

Comparison of the Distinct, Host-Specific Response of Three Solanaceae Hosts Induced by Phytophthora infestans

Three Solanaceae hosts (TSHs), S. tuberosum, N. benthamiana and S. lycopersicum, represent the three major phylogenetic clades of Solanaceae plants infected by Phytophthora infestans, which causes late blight, one of the most devastating diseases seriously affecting crop production. However, details regarding how different Solanaceae hosts respond to P. infestans are lacking. Here, we conducted RNA-seq to analyze the transcriptomic data from the TSHs at 12 and 24 h post P. infestans inoculation to capture early expression effects. Macroscopic and microscopic observations showed faster infection processes in S. tuberosum than in N. benthamiana and S. lycopersicum under the same conditions. Analysis of the number of genes and their level of expression indicated that distinct response models were adopted by the TSHs in response to P. infestans. The host-specific infection process led to overlapping but distinct in GO terms and KEGG pathways enriched for differentially expressed genes; many were tightly linked to the immune response in the TSHs. S. tuberosum showed the fastest response and strongest accumulation of reactive oxygen species compared with N. benthamiana and S. lycopersicum, which also had similarities and differences in hormone regulation. Collectively, our study provides an important reference for a better understanding of late blight response mechanisms of different Solanaceae host interactions.

Early expression of requisite developmental growth hormone imprinted cytochromes P450 and dependent transcription factors

The sexually dimorphic expression of cytochromes P450 (CYP) drug metabolizing enzymes has been reported in all species examined. These sex differences are initially expressed during puberty and are solely regulated by sex differences in the circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoforms are permanent and immutable, suggesting that adult CYP expression requires imprinting. Since the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats while others also received a concurrent physiologic replacement of rat GH. Rats were subsequently challenged, peripubertally, with either a masculine-like episodic GH regimen or the GH vehicle alone. The results demonstrate that episodic GH regulation of male-specific CYP2C11 and CYP3A2, as well as female-predominant CYP2C6, are dependent on developmental GH imprinting. Moreover, the induction and/or activation of major components in the signal transduction pathway regulating the expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. Since there are additional adult metabolic functions also regulated by GH, pediatric drug therapy that is known to disrupt GH secretion could unintentionally impair adult health.

Introduction

This chapter introduces the African American intellectual and theologian Howard Thurman and the physical embodiment of his thought: the Church for the Fellowship of All Peoples. The Fellowship Church, which Thurman cofounded in San Francisco in 1944, was the nation’s first interracial, intercultural, and interfaith church. Amid the growing nationalism of the World War II era and the heightened suspicion of racial and cultural “others,” it successfully established a pluralistic community based on the idea “that if people can come together in worship, over time would emerge a unity that would be stronger than socially imposed barriers.” Rooted in the belief that social change was inextricably connected to internal, psychological transformation and the personal realization of the human community, it was an early expression of Christian nonviolent activism within the long civil rights movement. The Introduction locates the Fellowship Church within its historical context and argues that, rather than being “56 years ahead of his time” as the SF Gate reported in 2010, the Fellowship Church was actually right on time—a distinct product of its historical moment and a provocative expression of midcentury liberal American thought.

The Fellowship Church

The Fellowship Church explores the evolution of the American religious Left through a case study of the African American intellectual and theologian Howard Thurman, and the physical embodiment of his thought, the Church for the Fellowship of All Peoples. The Fellowship Church, which Thurman cofounded in San Francisco in 1944, was the nation’s first interracial, intercultural, and interfaith church. Amid the growing nationalism of the World War II era and the heightened suspicion of racial and cultural “others,” the Fellowship Church successfully established a pluralistic community based on the idea “that if people can come together in worship, over time would emerge a unity that would be stronger than socially imposed barriers.” Rooted in the belief that social change was inextricably connected to internal, psychological transformation and the personal realization of the human community, it was an early expression of Christian nonviolent activism within the long civil rights movement. The Fellowship Church was a product of evolving twentieth-century ideas and a reflection of the shifting midcentury American public consciousness. This book explores a broad scope of modern historical themes, including the philosophy of pragmatism; mysticism and Christian liberalism; racism and imperialism; cosmopolitanism and pluralism; war and pacifism; and nonviolence. It not only expands our understanding of twentieth-century American intellectual history and the origins of the civil rights movement, it offers and exciting look into underexplored methods of democracy-building that can inform contemporary social movements.

Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies.

Expression of KNUCKLES in the Stem Cell Domain Is Required for Its Function in the Control of Floral Meristem Activity in Arabidopsis

In the model plant Arabidopsis thaliana, the zinc-finger transcription factor KNUCKLES (KNU) plays an important role in the termination of floral meristem activity, a process that is crucial for preventing the overgrowth of flowers. The KNU gene is activated in floral meristems by the floral organ identity factor AGAMOUS (AG), and it has been shown that both AG and KNU act in floral meristem control by directly repressing the stem cell regulator WUSCHEL (WUS), which leads to a loss of stem cell activity. When we re-examined the expression pattern of KNU in floral meristems, we found that KNU is expressed throughout the center of floral meristems, which includes, but is considerably broader than the WUS expression domain. We therefore hypothesized that KNU may have additional functions in the control of floral meristem activity. To test this, we employed a gene perturbation approach and knocked down KNU activity at different times and in different domains of the floral meristem. In these experiments we found that early expression in the stem cell domain, which is characterized by the expression of the key meristem regulatory gene CLAVATA3 (CLV3), is crucial for the establishment of KNU expression. The results of additional genetic and molecular analyses suggest that KNU represses floral meristem activity to a large extent by acting on CLV3. Thus, KNU might need to suppress the expression of several meristem regulators to terminate floral meristem activity efficiently.