Key stages in mammary gland development: The mammary end bud as a motile organ

In the rodent, epithelial end buds define the tips of elongating mammary ducts. These highly motile structures undergo repeated dichotomous branching as they aggressively advance through fatty stroma and, turning to avoid other ducts, they finally cease growth leaving behind the open, tree-like framework on which secretory alveoli develop during pregnancy. This review identifies the motility of end buds as a unique developmental marker that represents the successful integration of systemic and local mammotrophic influences, and covers relevant advances in ductal growth regulation, extracellular matrix (ECM) remodeling, and cell adhesion in the inner end bud. An unexpected growth-promoting synergy between insulin-like growth factor-1 and progesterone, in which ducts elongate without forming new end buds, is described as well as evidence strongly supporting self-inhibition of ductal elongation by end-bud-secreted transforming growth factor-β acting on stromal targets. The influence of the matrix metalloproteinase ECM-remodeling enzymes, notably matrix metalloproteinase-2, on end bud growth is discussed in the broader context of enzymes that regulate the polysaccharide-rich glycosaminoglycan elements of the ECM. Finally, a critical, motility-enabling role for the cellular architecture of the end bud is identified and the contribution of cadherins, the netrin/neogenin system, and ErbB2 to the structure and motility of end buds is discussed

Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children

Background: Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood. Objective: To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children. Methods: Children at high risk of asthma and other allergic diseases because of parental history were enrolled at birth and followed prospectively. FeNO was measured by an online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated. Results: Reproducible FeNO measurements were obtained in 64% (135/210) of 6-year-old and 93% (180/194) of 8-year-old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at ages 6 and 8 years had increased levels of FeNO compared with those not sensitized (geometric mean; 6 years, 10.9 vs 6.7 parts per billion [ppb], P < .0001; 8 years, 14.6 vs 7.1 ppb, P < .0001). FeNO was higher in children with asthma than in those without asthma at 8 years but not 6 years of age (6 years, 9.2 vs 8.3 ppb, P 5 .48; 8 years, 11.5 vs 9.2 ppb, P 5 .03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallerge

Key stages in mammary gland development: The cues that regulate ductal branching morphogenesis

Part of how the mammary gland fulfills its function of producing and delivering adequate amounts of milk is by forming an extensive tree-like network of branched ducts from a rudimentary epithelial bud. This process, termed branching morphogenesis, begins in fetal development, pauses after birth, resumes in response to estrogens at puberty, and is refined in response to cyclic ovarian stimulation once the margins of the mammary fat pad are met. Thus it is driven by systemic hormonal stimuli that elicit local paracrine interactions between the developing epithelial ducts and their adjacent embryonic mesenchyme or postnatal stroma. This local cellular cross-talk, in turn, orchestrates the tissue remodeling that ultimately produces a mature ductal tree. Although the precise mechanisms are still unclear, our understanding of branching in the mammary gland and elsewhere is rapidly improving. Moreover, many of these mechanisms are hijacked, bypassed, or corrupted during the development and progression of cancer. Thus a clearer understanding of the underlying endocrine and paracrine pathways that regulate mammary branching may shed light on how they contribute to cancer and how their ill effects might be overcome or entirely avoided

Rhinovirus illnesses during infancy predict subsequent childhood wheezing

Background: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/ or allergic diseases in early childhood is not established. Objective: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. Methods: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. Results: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR] 5 2.1), older siblings (OR 5 2.5), allergic sensitization to foods at age 1 year (OR 5 2.0), any moderate to severe respiratory illness without wheezing during infancy (OR 5 3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR 5 3.0), rhinovirus (OR 5 10) and/or non-rhinovirus/RSV pathogens (OR 5 3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR 5 6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR 5 6.6; P < .0001). Conclusion: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature. (J Allergy Clin Immunol 2005;116:571-7.

Domestication Syndrome in Caimito (Chrysophyllum cainito L.): Fruit and Seed Characteristics

Domestication Syndrome in Caimito (Chrysophyllum cainitoL.): Fruit and Seed Characteristics: The process of domestication is understudied and poorly known for many tropical fruit tree crops. The star apple or caimito tree (Chrysophyllum cainito L., Sapotaceae) is cultivated throughout the New World tropics for its edible fruits. We studied this species in central Panama, where it grows wild in tropical moist forests and is also commonly cultivated in backyard gardens. Using fruits collected over two harvest seasons, we tested the hypothesis that cultivated individuals of C. cainito show distinctive fruit and seed characteristics associated with domestication relative to wild types. We found that cultivated fruits were significantly and substantially larger and allocated more to pulp and less to exocarp than wild fruits. The pulp of cultivated fruits was less acidic; also, the pulp had lower concentrations of phenolics and higher concentrations of sugar. The seeds were larger and more numerous and were less defended with phenolics in cultivated than in wild fruits. Discriminant Analysis showed that, among the many significant differences, fruit size and sugar concentration drove the great majority of the variance distinguishing wild from cultivated classes. Variance of pulp phenolics among individuals was significantly higher among wild trees than among cultivated trees, while variance of fruit mass and seed number was significantly higher among cultivated trees. Most traits showed strong correlations between years. Overall, we found a clear signature of a domestication syndrome in the fruits of cultivated caimito in Panama

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier–penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy

Resisting Sleep Pressure:Impact on Resting State Functional Network Connectivity

In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs