Molecular signatures of cortical expansion in the human fetal brain.

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2 Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, µBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, µBrain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3 with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4 Using µBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantified in utero using magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5 and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The µBrain atlas is available from: https://garedaba.github.io/micro-brain/ and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.

Non-negative data-driven mapping of structural connections with application to the neonatal brain.

Mapping connections in the neonatal brain can provide insight into the crucial early stages of neurodevelopment that shape brain organisation and lay the foundations for cognition and behaviour. Diffusion MRI and tractography provide unique opportunities for such explorations, through estimation of white matter bundles and brain connectivity. Atlas-based tractography protocols, i.e. a priori defined sets of masks and logical operations in a template space, have been commonly used in the adult brain to drive such explorations. However, rapid growth and maturation of the brain during early development make it challenging to ensure correspondence and validity of such atlas-based tractography approaches in the developing brain. An alternative can be provided by data-driven methods, which do not depend on predefined regions of interest. Here, we develop a novel data-driven framework to extract white matter bundles and their associated grey matter networks from neonatal tractography data, based on non-negative matrix factorisation that is inherently suited to the non-negative nature of structural connectivity data. We also develop a non-negative dual regression framework to map group-level components to individual subjects. Using in-silico simulations, we evaluate the accuracy of our approach in extracting connectivity components and compare with an alternative data-driven method, independent component analysis. We apply non-negative matrix factorisation to whole-brain connectivity obtained from publicly available datasets from the Developing Human Connectome Project, yielding grey matter components and their corresponding white matter bundles. We assess the validity and interpretability of these components against traditional tractography results and grey matter networks obtained from resting-state fMRI in the same subjects. We subsequently use them to generate a parcellation of the neonatal cortex using data from 323 new-born babies and we assess the robustness and reproducibility of this connectivity-driven parcellation.

Balanced detection for interferometry with a noisy source.

Optical properties of nanostructures depend on size, shape, material, and local environment. These characteristics can be probed interferometrically, given a broadband source. However, broadband supercontinuum sources are intrinsically noisy, limiting the measurement sensitivity. In this article we describe the application of an auto-balancing technique to reduce the noise in a broadband supercontinuum source, thus increasing the signal to noise ratio. We show a noise reduction of 41 dB allowing optical powers as small as 0.01 pW to be interferometrically detected with a 5 ms integration time.

The genotoxic potential of linear alkylbenzene mixtures in a short-term test battery.

Alkylate 215 (A-215), Alkylate 225 (A-225), and Alkylate 230 (A-230) are mixtures of C10-C14 linear alkylbenzenes used as intermediates for the manufacture of detergents. These products were evaluated for genotoxic activity in the Ames bacterial mutagenesis assay (strains TA98, 100, 1535, and 1537), the CHO/HGPRT mammalian cell forward gene mutation assay, and the in vivo rat bone marrow chromosome assay. The Ames and CHO/HGPRT assays were conducted both with and without the addition of Aroclor-induced rat liver S9. The maximum concentrations evaluated were 10 mg/plate (A-215) and 3 mg/plate (A-225 and A-230) for the Ames test, and 1.5 mg/ml (A-215 and A-225) and 2.0 mg/ml (A-230) for the CHO/HGPRT assay. In each case, the highest concentrations produced evidence of either toxicity or insolubility. The highest dose in the bone marrow cytogenetics assay was 12,700 mg/kg, a level which produced significant weight loss. The results of all tests were negative, indicating a lack of genotoxic activity as measured by the battery of tests used.

Reproductive and developmental toxicity studies of a linear alkylbenzene mixture in rats.

Alkylate 215, a mixture of linear decyl- to tridecylbenzenes, is an intermediate in the manufacture of detergent sulfonates. A two-generation reproduction study and a developmental toxicity study were conducted using single daily doses given by gastric intubation in a corn oil vehicle. In the reproduction study, groups of 30 rats/sex/group were given doses of 0, 5, 50, or 500 mg/kg/day. F0 animals received a 10-week premating treatment period and were then mated to produce a single litter; F1 adults were selected from the F1 litters. F1 animals were dosed for 11 weeks before mating to produce a single litter. Adults and weaned pups received a gross postmortem examination. Histopathology studies were conducted on reproductive tissues, tissues with gross lesions, and the pituitary gland taken from each adult in the control and high dose groups. In the developmental toxicity study, groups of 24 mated female rats were given 0, 125, 500, or 2000 mg/kg/day on Days 6 through 15 of gestation. Dams were terminated on gestation Day 20 and fetuses were examined for external, soft tissue, and skeletal defects. Results of the reproduction study were as follows. At 50 mg/kg/day, pup weights were decreased at Day 7 in the F1 litter. At 500 mg/kg/day, decreases were found in the F0 females in premating and early lactation weight gains; in both generations in premating weight gains in males and in weight gains during gestation in females; and in litter size, pup viability at birth, Day 0-4 survival, and pup weights on Days 14 and 21. The NOAEL for reproductive effects was 5 mg/kg/day. The developmental toxicity study found effects on several parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of neuropathological changes in rats after exposure to butyl benzyl phthalate.

Butyl benzyl phthalate (BBP; Santicizer 160 Plasticizer) was fed to 3 groups of 10 male and 10 female Charles River CD rats for 6 wk at target doses of 500, 1500, and 3000 mg/kg/d. Control groups of 6 males and 6 females received untreated diets for the same period. Body weight gains were decreased at the 1500 and 3000 mg/kg/d levels. Hindlimb stiffness was noted at the 3000 mg/kg/d level and was more prevalent in males. Stiffness was apparently reversed after withdrawal from BBP exposure for 2 d. Microscopic examination of central and peripheral nervous system tissues did not reveal any compound-related pathological changes. Thus, there were no morphological changes in the nervous system that could be related to the apparently reversible hindlimb stiffness.

Interactions between the adenovirus type 2 DNA polymerase and the DNA binding domain of nuclear factor I.

The adenovirus origin of DNA replication is located within the terminal 51 bp of the viral genome and contains three recognizable domains: the minimal origin or "core" and binding sites for the cellular transcription factors NFI (CTF) and NFIII (oct-1, OTF-I). In vivo assays with a series of plasmids containing insertions between the "core" and NFI binding site revealed that a strict spatial arrangement of the NFI binding site relative to the "core" was required for efficient DNA replication. To determine if this strict positional constraint was a result of interactions between genome-bound proteins, we used the DNA-binding domain of NFI immobilized on Sepharose as an affinity matrix to examine binding of the adenovirus DNA polymerase and preterminal protein. Extracts from insect cells infected with baculoviruses expressing the polymerase or preterminal protein were passed over the NFI affinity matrix and bound proteins were eluted. Whereas preterminal protein passed through the column, the DNA polymerase was specifically retained. When extracts containing both preterminal protein and polymerase were passed over the NFI column, both proteins were retained because of the formation of DNA polymerase-preterminal protein heterodimers. Thus, interactions between the DNA binding domain of NFI and the DNA polymerase may serve to direct the DNA polymerase-preterminal protein heterodimer into a preinitiation complex that assembles at the adenovirus origin of DNA replication.

Metabolic and peroxisome proliferation studies with di(2-ethylhexyl)phthalate in rats and monkeys.

Male Fischer 344 rats and cynomolgus monkeys were treated with various doses of di(2-ethylhexyl)phthalate (DEHP) for at least 21 days. There was metabolic, biochemical, and morphological evidence for peroxisomal proliferation in rats that consumed diets containing 1000 ppm DEHP and above. These diets were estimated to provide average daily doses of about 100 mg/kg of DEHP. In contrast, peroxisomal proliferation was not observed in monkeys that received up to 500 mg/kg/day of DEHP by gavage. The results of this study suggest that rats do not provide a good model for predicting the results of DEHP exposure on peroxisomal proliferation in higher primates.

A review of the subchronic toxicity of butyl benzyl phthalate.

This review compares the subchronic toxicity of butyl benzyl phthalate (BBP) across several species. Data from the published literature as well as previously unpublished studies sponsored by Monsanto are presented. BBP-induced toxicity occurs only at relatively high levels of exposure and is dependent on the species, age and strain of test animals used. These factors should be considered in extrapolating findings from animal toxicology studies to humans when assessing the safety of BBP.

Stabilization of translationally active mRNA by prokaryotic REP sequences.

The REP sequence is a highly conserved inverted repeat that is present in about 25% of all E. coli transcription units. We show that the REP sequence can stabilize upstream RNA, independently of any other sequences, by protection from 3'-5' exonuclease attack. The REP sequence is frequently responsible for the differential stability of different segments of mRNA within an operon. We demonstrate that REP-stabilized mRNA can be translated in vivo and that cloning the REP sequence downstream of a gene can increase protein synthesis. This provides direct evidence that alterations in mRNA stability can play a role in determining bacterial gene expression. The implications of these findings for the mechanisms of mRNA degradation and for the role of RNA stability in the regulation of gene expression are discussed.

Teratogenicity studies of alkylaryl phosphate ester plasticizers in rats.

Santicizer 141 plasticizer (2-ethylhexyldiphenyl phosphate) and Santicizer 148 plasticizer (isodecyldiphenyl phosphate) were tested for teratogenic activity in Charles River COBS CD rats. Groups of 25 mated females were given 0, 300, 1000, or 3000 mg/kg/day by gavage on Days 6 through 15 (Santicizer 141) or 6 through 19 (Santicizer 148) of gestation. Mean maternal body weight gains were slightly and severely reduced at the mid- and high-dose levels of Santicizer 141, respectively. Body weights were not affected by treatment with Santicizer 148. Most malformations found in groups treated with either plasticizer occurred as single incidences and have been observed in historical controls. Thus, no teratogenic response was observed in rats after treatment with either of these two alkylaryl phosphates during the period of organogenesis.

Repetitive extragenic palindromic sequences: a major component of the bacterial genome.

We describe a remarkably conserved nucleotide sequence, the many copies of which may occupy up to 1% of the genomes of E. coli and S. typhimurium. This sequence, the REP (repetitive extragenic palindromic) sequence, is about 35 nucleotides long, includes an inverted repeat, and can occur singly or in multiple adjacent copies. A possible role for the REP sequences in regulation of gene expression has been thoroughly investigated. While the REP sequences do not appear to modulate differential gene expression within an operon, they can affect the expression of both upstream and downstream genes to a small extent, probably by affecting the rate of mRNA degradation. Possible roles for the REP sequence in mRNA degradation, chromosome structure, and recombination are discussed.

Leiomyosarcoma of the cheek: a case report.

Oral leiomyosarcomata have been reported on only 15 occasions in the world literature. An additional case of leiomyosarcoma of the cheek in an 88-year-old male is reported. The relevant features of leiomyosarcomata are reviewed and discussed.