Perinatal germ cell development and differentiation in the male marmoset (Callithrix jacchus):similarities with the human and differences from the rat

STUDY QUESTION: Is perinatal germ cell (GC) differentiation in the marmoset similar to that in the human? SUMMARY ANSWER: In a process comparable with the human, marmoset GC differentiate rapidly after birth, losing OCT4 expression after 5–7 weeks of age during mini-puberty. WHAT IS KNOWN ALREADY: Most of our understanding about perinatal GC development derives from rodents, in which all gonocytes (undifferentiated GC) co-ordinately lose expression of the pluripotency factor OCT4 and stop proliferating in late gestation. Then after birth these differentiated GC migrate to the basal lamina and resume proliferation prior to the onset of spermatogenesis. In humans, fetal GC differentiation occurs gradually and asynchronously and OCT4(+) GC persist into perinatal life. Failure to switch off OCT4 in GC perinatally can lead to development of carcinoma in situ (CIS), the precursor of testicular germ cell cancer (TGCC), for which there is no animal model. Marmosets show similarities to the human, but systematic evaluation of perinatal GC development in this species is lacking. Similarity, especially for loss of OCT4 expression, would support use of the marmoset as a model for the human and for studying CIS origins. STUDY DESIGN, SIZE AND DURATION: Testis tissues were obtained from marmosets (n = 4–10 per age) at 12–17 weeks' gestation and post-natal weeks 0.5, 2.5, 5–7, 14 and 22 weeks, humans at 15–18 weeks' gestation (n = 5) and 4–5 weeks of age (n = 4) and rats at embryonic day 21.5 (e21.5) (n = 3) and post-natal days 4, 6 and 8 (n = 4 each). PARTICIPANTS/MATERIALS, SETTING AND METHODS: Testis sections from fetal and post-natal marmosets, humans and rats were collected and immunostained for OCT4 and VASA to identify undifferentiated and differentiated GC, respectively, and for Ki67, to identify proliferating GC. Stereological quantification of GC numbers, differentiation (% OCT4(+) GC) and proliferation were performed in perinatal marmosets and humans. Quantification of GC position within seminiferous cords was performed in marmosets, humans and rats. MAIN RESULTS AND ROLE OF CHANCE: The total GC number increased 17-fold from birth to 22 post-natal weeks in marmosets; OCT4(+) and VASA(+) GC proliferated equally in late gestation and early post-natal life. The percentage of OCT4(+) GC fell from 54% in late fetal life to <0.5% at 2.5 weeks of age and none were detected after 5–7 weeks in marmosets. In humans, the percentage of OCT4(+) GC also declined markedly during the equivalent period. In marmosets, GC had begun migrating to the base of seminiferous cords at ∼22 weeks of age, after the loss of GC OCT4 expression. LIMITATIONS, REASONS FOR CAUTION: There is considerable individual variation between marmosets. Although GC development in marmosets and humans was similar, there are differences with respect to proliferation during fetal life. The number of human samples was limited. WIDER IMPLICATIONS OF THE FINDINGS: The similarities in testicular GC differentiation between marmosets and humans during the perinatal period, and their differences from rodents, suggest that the marmoset may be a useful model for studying the origins of CIS, with relevance for the study of TGCC. STUDY FUNDING/COMPETING INTERESTS: This work was supported by Grant G33253 from the Medical Research Council, UK. No external funding was sought and there are no competing interests

A possible dominant white gene in Jersey cattle

A white heifer ("Snow") was born in 1991 from coloured registered Jersey parents. She produced six calves sired by coloured Jersey bulls: three white bull calves, two white heifer calves, and one coloured bull calf. One of the white bull calves was mated with 40 Hereford × Friesian yearling heifers (white face, predominantly black body with some white patches). The 38 resulting calves included 16 white and 22 coloured calves. Twelve of the 16 white calves were heifers and four were bulls. Red or black spotting was recorded on some white calves. The results are consistent with an autosomal dominant mutant causing the white phenotype. The mutation appears to have arisen spontaneously in Snow, then passing to her white progeny and white grand-progeny. The white individuals varied from entirely white in a few cases, to most having some residual small areas of red or black pigmentation in patterns not typical of other reported white spotting patterns of cattle

Hydrogen/silicon complexes in silicon from computational searches

Defects in crystalline silicon consisting of a silicon self-interstitial atom and one, two, three, or four hydrogen atoms are studied within density-functional theory (DFT). We search for low-energy defects by starting from an ensemble of structures in which the atomic positions in the defect region have been randomized. We then relax each structure to a minimum in the energy. We find a new defect consisting of a self-interstitial and one hydrogen atom (denoted by {I,H}) which has a higher symmetry and a lower energy than previously reported structures. We recover the {I,H_2} defect found in previous studies and confirm that it is the most stable such defect. Our best {I,H_3} defect has a slightly different structure and lower energy than the one previously reported, and our lowest energy {I,H_4} defect is different to those of previous studies.Comment: 7 pages, 8 figure

Discovery of a z=4.93, X-ray selected quasar by the Chandra Multiwavelength Project (ChamP)

We present X-ray and optical observations of CXOMP J213945.0-234655, a high redshift (z=4.93) quasar discovered through the Chandra Multiwavelength Project (ChaMP). This object is the most distant X-ray selected quasar published, with an X-ray luminosity of L(X)=5.9x10^44 erg/s (measured in the 0.3-2.5 keV band and corrected for Galactic absorption). CXOMP J213945.0-234655 is a g' dropout object (>26.2), with r'=22.87 and i'=21.36. The rest-frame X-ray to optical flux ratio is similar to quasars at lower redshifts and slightly X-ray bright relative to z>4 optically-selected quasars observed with Chandra. The ChaMP is beginning to acquire significant numbers of high redshift quasars to investigate the unobscured X-ray luminosity function out to z~5.Comment: Published in ApJ Letters; 4 pages; 3 figures; http://hea-www.harvard.edu/CHAMP

Rapid dissemination of Francisella tularensis and the effect of route of infection

<p>Abstract</p> <p>Background</p> <p><it>Francisella tularensis </it>subsp. <it>tularensis </it>is classified as a Category A bioweapon that is capable of establishing a lethal infection in humans upon inhalation of very few organisms. However, the virulence mechanisms of this organism are not well characterized. <it>Francisella tularensis </it>subsp. <it>novicida</it>, which is an equally virulent subspecies in mice, was used in concert with a microPET scanner to better understand its temporal dissemination in vivo upon intranasal infection and how such dissemination compares with other routes of infection. Adult mice were inoculated intranasally with <it>F. tularensis </it>subsp. <it>novicida </it>radiolabeled with ⁶⁴Cu and imaged by microPET at 0.25, 2 and 20 hours post-infection.</p> <p>Results</p> <p>⁶⁴Cu labeled <it>F. tularensis </it>subsp. <it>novicida </it>administered intranasally or intratracheally were visualized in the respiratory tract and stomach at 0.25 hours post infection. By 20 hours, there was significant tropism to the lung compared with other tissues. In contrast, the images of radiolabeled <it>F. tularensis </it>subsp. <it>novicida </it>when administered intragastrically, intradermally, intraperitoneally and intravenouslly were more generally limited to the gastrointestinal system, site of inoculation, liver and spleen respectively. MicroPET images correlated with the biodistribution of isotope and bacterial burdens in analyzed tissues.</p> <p>Conclusion</p> <p>Our findings suggest that Francisella has a differential tissue tropism depending on the route of entry and that the virulence of Francisella by the pulmonary route is associated with a rapid bacteremia and an early preferential tropism to the lung. In addition, the use of the microPET device allowed us to identify the cecum as a novel site of colonization of <it>Francisella tularensis </it>subsp. <it>novicida </it>in mice.</p

Attenuated Response of Aged Mice to Respiratory Francisella novicida Is Characterized by Reduced Cell Death and Absence of Subsequent Hypercytokinemia

Pneumonia and pulmonary infections are major causes of mortality among the growing elderly population. Age associated attenuations of various immune parameters, involved with both innate and adaptive responses are collectively known as immune senescence. These changes are likely to be involved with differences in host susceptibility to disease between young and aged individuals.The objective of this study was to assess potential age related differences in the pulmonary host response in mice to the Gram-negative respiratory pathogen, Francisella novicida. We intranasally infected mice with F. novicida and compared various immune and pathological parameters of the pulmonary host response in both young and aged mice.We observed that 20% of aged mice were able to survive an intranasal challenge with F. novicida while all of their younger cohorts died consistently within 4 to 6 days post infection. Further experiments revealed that all of the aged mice tested were initially able to control bacterial replication in the lungs as well as at distal sites of replication compared with young mice. In addition, the small cohort of aged survivors did not progress to a severe sepsis syndrome with hypercytokinemia, as did all of the young adult mice. Finally, a lack of widespread cell death in potential aged survivors coupled with a difference in cell types recruited to sites of infection within the lung confirmed an altered host response to Francisella in aged mice

Characterization of large tilt-angle flexoelectro-optic switching in chiral nematic liquid crystal devices

The “flexoelastic ratio”, which is the ratio of the effective flexoelectric coefficient to the elasticcoefficients, is commonly used to characterize the electro-optic behavior of chiral nematic liquid crystal(LC) devices that exhibit flexoelectro-optic switching. In the uniform lying helix configuration, thiselectro-optic effect is manifested as a rapid (~100 s) rotation of the macroscopic optic axis when anelectric field is applied perpendicular to the helix axis of the chiral nematic LC and is attractive for bothintensity and phase modulation devices. There has been renewed interest in this electro-effect as newLC materials and mixtures have been developed that exhibit large tilt angles, , of the optic axis ( ≥45°) whilst maintaining a fast response time. In this Letter, we consider the relevance of the flexoelasticratio when characterizing the performance of the devices and find that an alternative ratio is required tocharacterize materials that can switch by = ±45° when the pitch is constrained. We show that for largetilt angles of the optic axis the values for the new and conventional flexoelastic ratios measurablydiverge. In addition, a simple way of determining this new characteristic ratio is presented that involvesdetermining the electric field amplitude at the point the transmission levels are the same for bothpositive and negative electric field polarities

Comparison of single-channel EEG, actigraphy, and sleep diary in cognitively normal and mildly impaired older adults

STUDY OBJECTIVES: Multiple methods for monitoring sleep-wake activity have identified sleep disturbances as risk factors for Alzheimer disease (AD). In order to identify the level of agreement between different methods, we compared sleep parameters derived from single-channel EEG (scEEG), actigraphy, and sleep diaries in cognitively normal and mildly impaired older adults. METHODS: Two hundred ninety-three participants were monitored at home for up to six nights with scEEG, actigraphy, and sleep diaries. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO) were calculated using each of these methods. In 109 of the 293 participants, the ratio of cerebrospinal fluid concentrations of phosphorylated tau (p-tau) and amyloid-β-42 (Aβ42) was used as a biomarker for AD pathology. RESULTS: Agreement was highest for TST across instruments, especially in cognitively normal older adults. Overall, scEEG and actigraphy appeared to have greater agreement for multiple sleep parameters than for scEEG and diary or actigraphy and diary. Levels of agreement between scEEG and actigraphy overall decreased in mildly impaired participants and those with biomarker evidence of AD pathology, especially for measurements of TST. CONCLUSIONS: Caution should be exercised when comparing scEEG and actigraphy in individuals with mild cognitive impairment or with AD pathology. Sleep diaries may capture different aspects of sleep compared to scEEG and actigraphy. Additional studies comparing different methods of measuring sleep-wake activity in older adults are necessary to allow for comparison between studies using different methods

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be amore limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching