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The notochord functions primarily as a supporting tissue to maintain the anteroposterior axis of primitive chordates, a function that is replaced entirely by the vertebral column in many vertebrates. The notochord still appears during vertebrate embryogenesis and plays a crucial role in the developmental pattern formation of surrounding structures, such as the somites and neural tube, providing the basis for the vertebrate body plan. The indispensable role of the notochord has often been referred to as the developmental burden and used to explain the evolutionary conservation of notochord; however, the existence of this burden has not been successfully exemplified so far. Since the adaptive value of target tissues appears to result in the evolutionary conservation of upstream structures through the developmental burden, we performed comparative gene expression profiling of the notochord, somites, and neural tube during the mid-embryonic stages in turtles and chicken to measure their evolutionary conservation. When compared with the somites and neural tube, overall gene expression profiles in the notochord showed significantly lower or merely comparable levels of conservation. However, genes involved in inductive signalings, such as the sonic hedgehog (Shh) cascade and the formation of functional primary cilia, showed relatively higher levels of conservation in all the three structures analyzed. Collectively, these results suggest that shh signals are critical as the inductive source and receiving structures, possibly constituting the inter-dependencies of developmental burden.

In this study, we considered the role of home care support clinics for patients who wanted to go back to their homes from a hospice, duringa pre-discharge conference. The subjects of our study were 8 patients, of which 7 of them had cancer. Two patients died after the conference. These patients were discharged from the hospice three days after the conference and caregivers from the home care support clinics visited their homes 24 hours after their discharge. The clinic has a role to fulfill in terms of medical treatment and support, based on their life style and power of caregiving. We considered an advancedmeetingwith family or caregiver benefits in the conference. Further, the clinic has a role of establishinga relationship with each multi-disciplinary care unit and cooperate with them as soon as possible when needed.

Silene latifolia is a dioecious flowering plant with sex chromosomes in the family Caryophyllaceae. Development of a gynoecium and stamens are suppressed in the male and female flowers of S. latifolia, respectively. Microbotryum lychnidis-dioicae promotes stamen development when it infects the female flower. If suppression of the stamen and gynoecium development is regulated by the same mechanism, suppression of gynoecium and stamen development is released simultaneously with the infection by M. lychnidis-dioicae. To assess this hypothesis, an asexual mutant without a gynoecium or stamen was infected with M. lychnidis-dioicae. A filament of the stamen in the infected asexual mutant was elongated at stages 11 and 12 of flower bud development as well as in the male, but the gynoecium did not form. Instead of the gynoecium, a filamentous structure was suppressed as in the male flower. Developmental suppression of the stamen was released by M. lychnidis-dioicae, but that of gynoecium development was not released. M. lychnidis-dioicae would have a function similar to stamen-promoting factor (SPF), since the elongation of the stamen that is not observed in the healthy asexual mutant was observed after stage 8 of flower bud development. An infection experiment also revealed that a deletion on the Y chromosome of the asexual mutant eliminated genes for maturation of tapetal cells because the tapetal cells did not mature in the asexual mutant infected with M. lychnidis-dioicae.

Silene latifoliais a dioecious flowering plant with sex chromosomes in the family Caryophyllaceae. Development of a gynoecium and stamens are suppressed in the male and female flowers ofS. latifolia, respectively.Microbtryum lychnidis-dioicaepromotes stamen development when it infects the female flower. If suppression of the stamen and gynoecium development is regulated by the same mechanism, suppression of gynoecium and stamen development is released simultaneously with the infection byM. lychnidis-dioicae. To assess this hypothesis, an asexual mutant, without gynoecium or stamen, was infected withM. lychnidis-dioicae. A filament of the stamen in the infected asexual mutant was elongated at stages 11 and 12 of the flower bud development as well as the male, but the gynoecium did not form. Instead of the gynoecium, a filamentous structure was suppressed as in the male flower. Developmental suppression of the stamen was released byM. lychnidis-dioicae, but that of gynoecium development was not released. It is thought, therefore, that the suppression of gynoecium development was not released by the infection ofM. lychnidis-dioicae. M. lychnidis-dioicaewould have a function similar to SPF since the elongation of the stamen that is not observed in the healthy asexual mutant was observed after stage 8 of flower bud development. Such an infection experiment also that the Y chromosome of the asexual mutant has genes related to the differentiation of archesporial cells, but none related to maturation of the tapetal cells.

Background Major depressive disorder (MDD) is a heterogeneous condition. Identifying the brain responses to antidepressant treatment is of particular interest as these may represent potential neural networks related to treatment response, forming one aspect of the biological markers of MDD. Near-infrared spectroscopy (NIRS) is suitable for repeated measurements with short intervals because of its noninvasiveness, and can provide detailed time courses of functional alterations in prefrontal regions. Methods We conducted a 12-week longitudinal study to explore prefrontal hemodynamic changes at 4-week intervals following sertraline treatment in 11 medication-naive participants with MDD using 52-channel NIRS. Results While all participants achieved remission after treatment, intra-class correlation coefficient of oxygenated hemoglobin [oxy-Hb] values throughout the 12-week observation was moderate at the spatially and temporally contiguous cluster located in the left inferior frontal and temporal gyri. There was a significant negative correlation between mean [oxy-Hb] values in the significant cluster at 4 weeks and changes in Hamilton Rating Scale for Depression total score from 4 to 8 weeks (r = −0.73, P = 0.011) and from 4 to 12 weeks (r = −0.63, P = 0.039). Limitations Without healthy controls for comparison, we were unable to fully evaluate whether improvement of [oxy-Hb] activations after treatment in MDD reached normal levels or not. Conclusion Our NIRS findings of detailed prefrontal hemodynamic alterations over short interval observations such as 4 weeks may have revealed potential trait marker for MDD and biological maker for predicting clinical response to sertraline treatment in MDD.

Background The Japanese version of the Rapid Dementia Screening Test (RDST-J) and the clock-drawing test (CDT) are both brief psychometric screening tools used to detect the severity of Alzheimer's disease. It remains unclear, however, which is more effective when screening for mild Alzheimer's disease. Methods We administered the RDST-J and CDT to 250 patients with very mild to severe Alzheimer's disease and to 49 healthy volunteers. Patients with a Mini-Mental State Examination score of 12–26 had Clinical Dementia Rating (CDR) scores from 0.5 to 3. Patients were divided into four groups according to CDR score. We performed one-way factorial anova between the four groups and control subjects based on the CDT and RDST-J scores. Results Data analysis revealed that RDST-J could distinguish patients with CDR 0.5 from the controls, but CDT could not. Furthermore, the sensitivity of a RDST-J score ≥8 was 57.1%, with a specificity of 81.0%, and the sensitivity of a RDST-J score ≥9 was 79.6%, with a specificity of 55.1% for discriminating CDR 0.5 from controls. Conclusions RDST-J is a more effective tool than CDT for distinguishing CDR 0.5 from controls.

We would like to thank Ferlazzo and Foray (1) for their very important comments and suggestions. We will keep in mind that “scientists should take particular care to justify their methodology and moderate their conclusions.” One concern of Ferlazzo and Foray (1) is that our control experiment entailed exposure to the ground radiation of Japan, rather than to a high natural radiation background (NRB), such as Ramsar. As the authors suggest, it would have been a good idea to expose our control sample to both Ramsar and Japan. When the control radiation level increases from 0.5 mSv/y (Japan) to 70 mSv/y (Ramsar) the difference between space and ground … [↵][1]1To whom correspondence may be addressed. Email: sayakaw{at}yamanashi.ac.jp or twakayama{at}yamanashi.ac.jp. [1]: #xref-corresp-1-1

If humans ever start to live permanently in space, assisted reproductive technology using preserved spermatozoa will be important for producing offspring; however, radiation on the International Space Station (ISS) is more than 100 times stronger than that on Earth, and irradiation causes DNA damage in cells and gametes. Here we examined the effect of space radiation on freeze-dried mouse spermatozoa held on the ISS for 9 mo at –95 °C, with launch and recovery at room temperature. DNA damage to the spermatozoa and male pronuclei was slightly increased, but the fertilization and birth rates were similar to those of controls. Next-generation sequencing showed only minor genomic differences between offspring derived from space-preserved spermatozoa and controls, and all offspring grew to adulthood and had normal fertility. Thus, we demonstrate that although space radiation can damage sperm DNA, it does not affect the production of viable offspring after at least 9 mo of storage on the ISS.

The relationship between reaction time and both state and trait personality variables was investigated in 37 participants after 30 h of sleep deprivation. Regression analyses suggested that endorsement of greater Novelty Seeking, anger/hostility, and depression/dejection, and less confusion, was associated with greater reaction time declines on one Multi-Attribute Task Battery index after sleep deprivation. Further, greater Novelty Seeking and depression/dejection, and less vigor/activity, was associated with greater reaction time declines after sleep deprivation on another Multi-Attribute Task Battery index. Additional correlational analyses indicated that better reaction times were associated with greater Novelty Seeking and lower anger/hostility prior to sleep deprivation, and less confusion/bewilderment following sleep deprivation. Findings suggest that both state and trait personality variables are associated with reaction time performance following sleep deprivation.

The objectives of this longitudinal study were to assess children's caries risk and mean number of decayed teeth and determine their life style factors that influence their caries activity. A total of 283 children were selected based on the following criteria: they had 1.5, 2.5, and 3.5-year-old oral examinations, participated in Cariostat microbial sampling and the mother of a child filled out the questionnaires. Caries experiences of children were 2.1% for the 1.5-year-old, 8.1% for the 2.5-year-old, and 14.8% for 3.5-year-old period, respectively. Caries risk at the 1.5-year-old period showed significant differences ( P P

Specification of germ cell fate is fundamental in development. With a highly representative single-cell microarray and rigorous quantitative PCR analysis, we defined the genome-wide transcription dynamics that create primordial germ cells (PGCs) from the epiblast, a process that exclusively segregates them from their somatic neighbors. We also analyzed the effect of the loss of Blimp1, a key transcriptional regulator, on these dynamics. Our analysis revealed that PGC specification involves complex, yet highly ordered regulation of a large number of genes, proceeding under the strong influence of mesoderm induction but specifically avoiding developmental programs such as the epithelial–mesenchymal transition, Hox cluster activation, cell cycle progression, and DNA methyltransferase machinery. Remarkably, Blimp1 is essential for repressing nearly all the genes normally down-regulated in PGCs relative to their somatic neighbors. In contrast, it is dispensable for the activation of approximately half of the genes up-regulated in PGCs, uncovering the Blimp1-independent events for PGC specification. Notably, however, highly PGC-specific genes exhibited distinct correlations to Blimp1 in wild-type embryos, and these correlations faithfully predicted their expression impairments in Blimp1 mutants. Moreover, their expression overlaps within single cells were severely damaged without Blimp1, demonstrating that Blimp1 exerts positive influence on their concerted activation. Thus, Blimp1 is not a single initiator but a dominant coordinator of the transcriptional program for the establishment of the germ cell fate in mice.

Repetitive transcranial magnetic stimulation (rTMS) is an experimental technology that involves a powerful magnetic pulse applied to the scalp, which is sufficient to cause neuronal depolarization. Transcranial magnetic stimulation has been used in treatment studies for psychiatric disorders, primarily unipolar depression, and as a tool to map brain function. Although thousands of rTMS sessions have been given with few side effects, rTMS can produce serious adverse effects such as an unintended seizure. Safety guidelines for frequency, duration, and intensity of rTMS have aided in the prevention of such adverse side effects. However, the total dose (number of stimuli) able to be delivered safely to human subjects within a day or within a week has not been established. For example, previous rTMS studies as a treatment for depression consisted of delivering 800 to 3,000 magnetic pulses per day, with 8000 to 30,000 magnetic pulses over 2 to 3 weeks. This study examined whether high doses of rTMS within a day or over a week would produce significant side effects. As part of a study to examine rTMS effects in sleep deprivation, we exposed healthy men to 12,960 magnetic pulses a day for up to 3 days in 1 week. This equals 38,880 magnetic pulses over 1 week, which is likely one of the largest exposures of TMS to date. Despite this intense treatment regimen, we failed to produce significant side effects. Doses of up to 12,960 pulses per day appear safe and tolerable in healthy young men.

The aim of this study was to assess risk behaviors and its association with caries activity and dental caries in Japanese children. The subjects were 392 young Japanese children who underwent dental health check-up at 18, 30 and 42 months of age. Oral examinations, Cariostat tests and dental health questionnaires were carried out at each time. The caries prevalence of children was 1.5% at 18 months, 9.9% at 30 months and 28.1% at 42 months. Caries activity based on the Cariostat scores of children was correlated with caries status (caries-free/carious) at 42 months. In children with caries during each examination period at 42 months, eating snacks while playing was ranked as the most important behavioral risk ( P P P P P P P

STUDY OBJECTIVE: To examine whether differences in patterns of brain activation under baseline conditions relate to the differences in sleep-deprivation vulnerability. DESIGN: Using blood oxygenation level dependent (BOLD) functional magnetic resonance imaging, we scanned 33 healthy young men while they performed the Sternberg working memory task following a normal night of sleep and again following 30 hours of sleep deprivation. From this initial group, based on their Sternberg working memory task performance, we found 10 subjects resilient to sleep deprivation (sleep deprivation-resilient group) and then selected 10 age- and education-matched subjects vulnerable to sleep deprivation (sleep deprivation-vulnerable group). SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: Data from 10 young men (mean age 27.8 +/- 1.7 years) in the sleep deprivation-resilient group and 10 young men (mean age 28.2 +/- 1.9 years) in the sleep deprivation-vulnerable group were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We compared functional magnetic resonance imaging BOLD signal at rested baseline and sleep deprivation states in the 2 groups. As hypothesized, following sleep deprivation, both groups showed significant decreases in global brain activation compared to their rested group baseline. At rested baseline and in the sleep-deprivation state, the sleep deprivation-resilient group had significantly more brain activation than did the sleep deprivation-vulnerable group. There were also differences in functional circuits within and between groups in response to sleep deprivation. CONCLUSIONS: These preliminary data suggest that patterns of brain activation during the Sternberg working memory task at the rested baseline and the sleep-deprivation state, differ across individuals as a function of their sleep-deprivation vulnerability. Language: en

In contrast to the effects seen in younger adults, depressed elderly subjects have shown more modest antidepressant responses to transcranial magnetic stimulation (TMS). We theorized that higher stimulation intensities in older depressed subjects with prefrontal atrophy might be needed to stimulate underlying cortex. In an open design with patients on stable baseline medications, we treated 18 treatment-resistant elderly depressed subjects (mean age 61.2 +/- 7.3) with 15 rTMS sessions over 3 weeks. We adjusted the delivered TMS intensity to account for MRI measured prefrontal atrophy. The skull to prefrontal cortex distance increased with age, whereas the skull to motor cortex distance did not. All subjects tolerated the higher doses well. The average intensity used was 114% of motor threshold (MT) with a range from 103-141% MT. There was an average 35% decline over the 3 weeks in HRSD scores. After 3 weeks of treatment, 27% (5/18) met response criteria (> 50% improvement), with four of these five also meeting criteria for remission (exit Hamilton Depression Score < 8). These initial pilot findings support the need for blinded studies using prefrontal TMS in an elderly population, testing whether TMS, delivered at stimulation intensities calculated to overcome atrophy, is more effective than TMS without adjusting for atrophy.

Transcranial magnetic stimulation (TMS) is unique among the current brain stimulation techniques because it is relatively non-invasive. TMS markedly differs from vagus nerve stimulation, deep brain stimulation and magnetic seizure therapy, all of which require either an implanted prosthesis or general anesthesia, or both. Since its rebirth in its modern form in 1985, TMS has already shown potential usefulness in at least three important domains—as a basic neuroscience research instrument, as a potential clinical diagnostic tool, and as a therapy for several different neuropsychiatric conditions. The TMS scientific literature has now expanded beyond what a single summary article can adequately cover. This review highlights several new developments in combining TMS with functional brain imaging, using TMS as a psychiatric therapy, potentially using TMS to enhance performance, and finally recent advances in the core technology of TMS. TMS' ability to non-invasively and focally stimulate the brain of an awake human is proving to be a most important development for neuroscience in general, and neuropsychiatry in particular.

The advances in understanding the functional and structural anatomy of bipolar affective disorder (BPAD) outlined in the rest of this volume provide the background and rationale for attempting to manipulate these regions as potential antidepressant and anti-manic therapies. The idea of using circuit and device based approaches to regulating mood follows in the tradition of electroconvulsive therapy (ECT). In marked contrast to ECT, however, these new stimulation techniques represent an important new paradigm shift, with treatments that neither produce seizures nor require general anesthesia. The new techniques are safer, with fewer side effects, and are more focal than ECT in their entry into the brain. Transcranial magnetic stimulation (TMS) produces direct cortical brain stimulation by creating a powerful transient magnetic field. Five published randomized controlled trials suggest it has clinically significant acute antidepressant effects. One controlled study suggests that it may have antimanic effects as well. Vagus nerve stimulation (VNS) involves direct electrical stimulation of the vagus nerve in the neck, with propagation of the signal to the brainstem. One controlled and one open study in epilepsy patients with depression found antidepressant effects of VNS. An open study of VNS in treatment resistant unipolar and bipolar depression found acute antidepressant effects. These two device-based approaches to stimulating the brain offer promise as potential acute and even long-term treatments. Imaging studies suggest that TMS likely causes changes in mood regulating regions by stimulating limbic regions from the cortex down, while VNS influences this same circuit from the brainstem up. These two approaches are not yet approved by the Food and Drug Administration (FDA) for use in the US, although pivotal trials geared for eventual FDA approval are underway. Finally, the research determining whether and how these devices work to influence mood also promises to help unravel the pathophysiology of BPAD.

In a previous study, we succeeded in improving the spatial working memory (WM) performance in healthy young persons by applying transcranial magnetic stimulation (TMS) to the parietal cortex and simultaneously measuring the oxygenated hemoglobin (oxy-Hb) level using near-infrared spectroscopy (NIRS). Since an improvement in WM was observed when TMS was applied to the right parietal cortex, the oxy-Hb distribution seemed to support a model of hemispheric asymmetry (HA). In the present study, we used the same study design to evaluate healthy elderly persons and investigated the effect of TMS on WM performance in the elderly, comparing the results with those previously obtained from young persons. The application of TMS did not affect WM performance (both reaction time and accuracy) of 38 elderly participants (mean age = 72.5 years old). To investigate the reason for this result, we conducted a three-way ANOVA examining oxy-Hb in both young and elderly participants. For the right parietal TMS site in the elderly, TMS significantly decreased the oxy-Hb level during WM performance; this result was the opposite of that observed in young participants. An additional three-way ANOVA was conducted for each of the 52 channels, and a P value distribution map was created. The P value maps for the young participants showed a clearly localized TMS effect for both the WM and control task, whereas the P map for the elderly participants showed less significant channels and localization. Further analysis following the time course revealed that right-side parietal TMS had almost no effect on the frontal cortex in the elderly participants. This result can most likely be explained by age-related differences in HA arising from the over-recruitment of oxy-Hb, differentiation in the parietal cortex, and age-related alterations of the frontal-parietal networks.

Mechanisms of suppression of pistil primordia in male flowers and of stamen primordia in female flowers differ in diclinous plants. In this study, we investigated how cell death and cell cycle arrest are related to flower organ formation in Silene latifolia. Using in situ hybridization and a TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay, we detected both cell cycle arrest and cell death in suppressed stamens of female flowers and suppressed pistils of male flowers in S. latifolia. In female flowers infected with Microbotryum lychnidis-dioicae, developmental suppression of stamens is released, and cell cycle arrest and cell death do not occur. Smut spores are formed in S. latifolia anthers infected with M. lychnidis-dioicae, followed by cell death in the endothelium, middle layer, tapetal cells and pollen mother cells. Cell death is difficult to detect using a fluorescein isothiocyanate-labeled TUNEL assay due to strong autofluorescence in the anther. We therefore combined a TUNEL assay in an infrared region with transmission electron microscopy to detect cell death in anthers. We show that following infection by M. lychnidis-dioicae, a TUNEL signal was not detected in the endothelium, middle layer or pollen mother cells, and cell death with outflow of cell contents, including the nucleoplast, was observed in tapetal cells.

Fish gelatin (FG) extracted from sea bream scales was reacted with glycidyl methacrylate (GMA), and the product (FG-GMA) was used for photopolymerization using a radical photoinitiator in the presence or absence of imogolite nanofibers in the aqueous solution. The synthesis of FG-GMA was confirmed by 1H NMR spectroscopy, and photopolymerization of FG-GMA was achieved successfully by irradiation with ultraviolet (UV) light for 3 min to yield translucent composite hydrogels. The concentration of FG-GMA varied from 10% to 30% without imogolite, and that of imogolite varied from 0% to 2.0%. A microtomed gel sample was observed with a transmission electron microscope (TEM), and imogolite nanofibers were found to be dispersed finely in the gelatin matrix. Scanning electron microscope (SEM) observation of the lyophilized gel revealed that it had a porous morphology. Mechanical properties of hydrogels were measured by compression tests using a mechanical tester, and viscoelastic properties were measured using a rheometer. The mechanical strength and storage modulus of the hydrogel increased with an increase of imogolite.

The present study investigated whether transcranial magnetic stimulation (TMS) to the parietal cortex improves the performance of healthy persons in a spatial working memory (WM) task. The effect of TMS on the frontal cortex was examined by measuring oxygenated hemoglobin (oxy-Hb) with near-infrared spectroscopy. Fifty-two healthy persons received either 100% resting motor threshold TMS at 5 Hz (real TMS) or sham TMS while engaged in a spatial WM task or a control visuospatial attention task. TMS was applied to either the left or the right parietal cortex during the delay period of the task. Reaction times improved in the spatial WM task, but not in the control task, with real TMS, whereas sham TMS had no effect. This improvement was only observed when TMS was applied to the right parietal cortex. Application of real TMS to the right parietal cortex also significantly increased frontal oxy-Hb levels during the WM task, but reduced oxy-Hb during the control task. These results suggest that TMS to the right parietal cortex may selectively facilitate spatial WM. Hemispheric asymmetry and the frontoparietal network theory may explain the observed effect of right parietal TMS on spatial WM.

SummarySpecification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Here we demonstrate that germ cell fate in the epiblast is a direct consequence of Bmp4 signaling from the extraembryonic ectoderm (ExE), which is antagonized by the anterior visceral endoderm (AVE). Strikingly, Bmp8b from the ExE restricts AVE development, thereby contributing to Bmp4 signaling. Furthermore, Wnt3 in the epiblast ensures its responsiveness to Bmp4. Serum-free, defined cultures revealed that, in response to Bmp4, competent epiblast cells uniformly expressed key transcriptional regulators Blimp1 and Prdm14 and acquired germ-cell properties, including genome-wide epigenetic reprogramming, in an orderly fashion. Notably, the induced cells contributed to both spermatogenesis and fertility of offspring. By identifying a signaling principle in germ cell specification, our study establishes a robust strategy for reconstituting the mammalian germ cell lineage in vitro.

The ability to monitor the development of a given cell lineage in a non-invasive manner by fluorescent markers bothin vivoandin vitroprovides a great advantage for the analysis of the lineage of interest. To date, a number of transgenic or knock-in mouse strains, in which developing germ cells are marked with fluorescent reporters, have been generated. We here describe a novel double transgenic reporter mouse strain that expresses membrane-targeted Venus (mVenus), a brighter variant of yellow fluorescent protein (YFP), under the control ofPrdm1(Blimp1) regulatory elements and enhanced cyan fluorescent protein (ECFP) under the control ofDppa3(Stella/Pgc7). The double transgenic strain unambiguously markedPrdm1expression in the lineage-restricted precursors of primordial germ cells (PGCs) in the proximal epiblast at embryonic day (E) 6.25 and specifically illuminatedPrdm1- andDppa3-positive migrating PGCs after E8.5. The double transgenic reporter also precisely recapitulated dynamic embryonic expression ofPrdm1outside the germ cell lineage. Moreover, we derived ES cells that bore both transgenes. These cells made a robust contribution both to the germ and somatic cell lineages in chimeras with accuratePrdm1-mVenus andDppa3-ECFP expression. The transgenic strain and the ES cells will serve as valuable experimental materials not only for analyzing the origin and properties of the germ cell lineagein vivo, but also for establishing a culture system to efficiently induce proper germ cells with temporally coordinatedPrdm1andDppa3expressionin vitro.

Mitinori Saitou and colleagues report that Prdm14, which encodes a transcription factor expressed exclusively in the germ cell lineage, is essential for re-acquisition of pluripotency and epigenetic reprogramming of primordial germ cells. Specification of germ cell fate is fundamental in development and heredity. Recent evidence indicates that in mice, specification of primordial germ cells (PGCs), the common source of both oocytes and spermatozoa, occurs through the integration of three key events: repression of the somatic program1, reacquisition of potential pluripotency2,3 and ensuing genome-wide epigenetic reprogramming4,5. Here we provide genetic evidence that Prdm14, a PR domain–containing transcriptional regulator with exclusive expression in the germ cell lineage and pluripotent cell lines, is critical in two of these events, the reacquisition of potential pluripotency and successful epigenetic reprogramming. In Prdm14 mutants, the failure of these two events manifests even in the presence of Prdm1 (also known as Blimp1), a key transcriptional regulator for PGC specification6,7. Our combined evidence demonstrates that Prdm14 defines a previously unknown genetic pathway, initiating independently from Prdm1, for ensuring the launching of the mammalian germ cell lineage.

Generally, transportation of preimplantation embryos without freezing requires incubators that can maintain an optimal culture environment with a suitable gas phase, temperature, and humidity. Such incubators are expensive to transport. We reported previously that normal offspring were obtained when the gas phase and temperature could be maintained during transportation. However, that system used plastic dishes for embryo culture and is unsuitable for long-distance transport of live embryos. Here, we developed a simple low-cost embryo transportation system. Instead of plastic dishes, several types of microtubes—usually used for molecular analysis—were tested for embryo culture. When they were washed and attached to a gas-permeable film, the rate of embryo development from the 1-cell to blastocyst stage was more than 90%. The quality of these blastocysts and the rate of full-term development after embryo transfer to recipient female mice were similar to those of a dish-cultured control group. Next, we developed a small warm box powered by a battery instead of mains power, which could maintain an optimal temperature for embryo development during transport. When 1-cell embryos derived from BDF1, C57BL/6, C3H/He and ICR mouse strains were transported by a parcel-delivery service over 3 days using microtubes and the box, they developed to blastocysts with rates similar to controls. After the embryos had been transferred into recipient female mice, healthy offspring were obtained without any losses except for the C3H/He strain. Thus, transport of mouse embryos is possible using this very simple method, which might prove useful in the field of reproductive medicine.

Recent research has used functional magnetic resonance imaging (fMRI) to examine brain regions related to specific subcomponent cognitive processes of verbal working memory, which include initial encoding of material, maintenance of the information over a brief delay interval, and later retrieval of the information. The present study examined each of these subcomponents in 14 healthy adults using a Sternberg verbal working memory task and fMRI. Group analysis revealed several brain regions active during all subcomponent processes, which included dorsolateral and ventrolateral prefrontal, parietal, hippocampal, and premotor cortex. Several other brain regions showed activation limited to specific subcomponent processes.

Study Objective: To investigate the cerebral hemodynamic response to verbal working memory following sleep deprivation. Design: Subjects were scheduled for 3 functional magnetic resonance imaging scanning visits: an initial screening day (screening state), after a normal night of sleep (rested state), and after 30 hours of sleep deprivation (sleep-deprivation state). Subjects performed the Sternberg working memory task alternated with a control task during an approximate 13-minute functional magnetic resonance imaging scan. Setting: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. Patients or Participants: Results from 33 men (mean age, 28.6 ± 6.6 years) were included in the final analyses. Interventions: None. Measurements and Results: Subjects performed the same Sternberg working memory task at the 3 states within the magnetic resonance imaging scanner. Neuroimaging data revealed that, in the screening and rested states, the brain regions activated by the Sternberg working memory task were found in the left dorsolateral prefrontal cortex, Broca's area, supplementary motor area, right ventrolateral prefrontal cortex, and the bilateral posterior parietal cortexes. After 30 hours of sleep deprivation, the activations in these brain regions significantly decreased, especially in the bilateral posterior parietal cortices. Task performance also decreased. A repeated-measures analysis of variance revealed that subjects at the screening and rested states had similar activation patterns, with each having significantly more activation than during the sleep-deprivation state. Conclusions: These results suggest that human sleep-deprivation deficits are not caused solely or even predominantly by prefrontal cortex dysfunction and that the parietal cortex, in particular, and other brain regions involved in verbal working memory exhibit significant sleep-deprivation vulnerability.

In 1985, Barker et al. built a transcranial magnetic stimulation (TMS) device with enough power to stimulate dorsal roots in the spine. They quickly realized that this machine could likely also noninvasively stimulate the superficial cortex in humans. They waited a while before using their device over a human head, fearing that the TMS pulse might magnetically "erase the hard-drive" of the human brain. Almost 10 years later, in 1994, an editorial in this journal concerned whether TMS might evolve into a potential antidepressant treatment. In the intervening years, there has been an explosion of basic and clinical research with and about TMS. Studies are now uncovering the mechanisms by which TMS affects the brain. It does not "erase the hard-drive" of the brain, and it has many demonstrated research and clinical uses. This article reviews the major recent advances with this interesting noninvasive technique for stimulating the brain, critically reviewing the data on whether TMS has anticonvulsant effects or modulates cortical-limbic loops.

Advances in understanding the functional and structural anatomy of depression outlined in this issue set the stage for attempting to manipulate implicated brain regions as potential antidepressant therapies. On the one hand, these circuit- and device-based approaches to treating depression are not new. Electroconvulsive therapy (ECT) dates back to the beginning of modern biologic psychiatry with the discovery and rapid increase of first chemical (around 1910), and then later ECT. On the other hand, this area represents an important paradigm shift with treatments that are radical and different. A dizzying array of diverse technologies now allows researchers to stimulate the brain in undreamed of ways. However, the approaches described in this article are still considered experimental and are not approved for use in the United States by the Food and Drug Administration (FDA), except ECT, which predates the FDA. These device-based approaches to brain stimulation offer promise as potential acute and even longterm treatments. Additionally, the research determining whether and how these devices work to influence mood promises to help unravel the neurophysiology of mood regulation. These novel treatments are thus the translational tools to bridge from advances in brain imaging, into new treatments for depressed patients.