Mechanism of tumor-suppressive cell competition in flies.

Oncogenic mutations often trigger antitumor cellular response such as induction of apoptosis or cellular senescence. Studies in the last decade have identified the presence of the third guardian against mutation-induced tumorigenesis, namely "cell competition." Cell competition is a context-dependent cell elimination whereby cells with higher fitness eliminate neighboring cells with lower fitness by inducing cell death. While oncogene-induced apoptosis or oncogene-induced senescence acts as a cell-autonomous tumor suppressor, cell competition protects the tissue from tumorigenesis via cell-cell communication. For instance, in Drosophila epithelium, oncogenic cells with cell polarity mutations overproliferate and develop into tumors on their own but are eliminated from the tissue when surrounded by wild-type cells. Genetic studies in flies have unraveled that such tumor-suppressive cell competition is regulated by at least three mechanisms: direct cell-cell interaction between polarity-deficient cells and wild-type cells, secreted factors from epithelial cells, and systemic factors from distant organs. Molecular manipulation of tumor-suppressive cell competition could provide a novel therapeutic strategy against human cancers.

Characteristics of socially high-risk pregnant women and children's outcomes.

BACKGROUND: The number of reports of child abuse and neglect in Japan has increased each year. A causal relationship between socially high-risk pregnant women and child abuse is strongly suggested. This study aims to investigate the characteristics of socially high-risk pregnant women and their children's outcomes, to help prevent child abuse. METHODS: In total, 2,342 births were retrospectively analyzed from medical records. We extracted the frequency, factors, and circumstances of socially high-risk pregnant women, and the presence of social interventions for their children. RESULTS: There were 538 (23%) socially high-risk pregnant women out of 2,342 cases investigated. Related factors (with duplication) were: economic problems (258 cases, 48%), mental disorders (139 cases, 26%), teenage pregnancies (112 cases, 21%), multiple pregnancies (90 cases, 17%), and pregnancy conflict (73 cases, 14%). Sixty-four (12%) expectant mothers received their first health examination in late pregnancy or were not receiving pregnancy health examinations. An analysis of births showed neonatal intensive care unit hospitalization in 40% of the children born to socially high-risk pregnant women. The hospital Child Abuse Prevention Committee intervened in 71 cases, and child consultation centers intervened in 55 cases. Twenty-two children entered social care facilities and four children died of unknown causes. CONCLUSIONS: Socially high-risk pregnant women had various social and individual problems, and received multidisciplinary interventions for child rearing support. Antenatal assessment and multidisciplinary early intervention for socially high-risk pregnant women are necessary to prevent child abuse.

Musashi mediates translational repression of the Drosophila hypoxia inducible factor.

Adaptation to hypoxia depends on a conserved α/ß heterodimeric transcription factor called Hypoxia Inducible Factor (HIF), whose α-subunit is regulated by oxygen through different concurrent mechanisms. In this study, we have identified the RNA binding protein dMusashi, as a negative regulator of the fly HIF homologue Sima. Genetic interaction assays suggested that dMusashi participates of the HIF pathway, and molecular studies carried out in Drosophila cell cultures showed that dMusashi recognizes a Musashi Binding Element in the 3' UTR of the HIFα transcript, thereby mediating its translational repression in normoxia. In hypoxic conditions dMusashi is downregulated, lifting HIFα repression and contributing to trigger HIF-dependent gene expression. Analysis performed in mouse brains revealed that murine Msi1 protein physically interacts with HIF-1α transcript, suggesting that the regulation of HIF by Msi might be conserved in mammalian systems. Thus, Musashi is a novel regulator of HIF that inhibits responses to hypoxia specifically when oxygen is available.

Recovery and reproduction of an Antarctic tardigrade retrieved from a moss sample frozen for over 30 years.

Long-term survival has been one of the most studied of the extraordinary physiological characteristics of cryptobiosis in micrometazoans such as nematodes, tardigrades and rotifers. In the available studies of long-term survival of micrometazoans, instances of survival have been the primary observation, and recovery conditions of animals or subsequent reproduction are generally not reported. We therefore documented recovery conditions and reproduction immediately following revival of tardigrades retrieved from a frozen moss sample collected in Antarctica in 1983 and stored at -20 °C for 30.5 years. We recorded recovery of two individuals and development of a separate egg of the Antarctic tardigrade, Acutuncus antarcticus, providing the longest records of survival for tardigrades as animals or eggs. One of the two resuscitated individuals and the hatchling successfully reproduced repeatedly after their recovery from long-term cryptobiosis. This considerable extension of the known length of long-term survival of tardigrades recorded in our study is interpreted as being associated with the minimum oxidative damage likely to have resulted from storage under stable frozen conditions. The long recovery times of the revived tardigrades observed is suggestive of the requirement for repair of damage accrued over 30 years of cryptobiosis. Further more detailed studies will improve understanding of mechanisms and conditions underlying the long-term survival of cryptobiotic organisms.

Conserved metabolic energy production pathways govern Eiger/TNF-induced nonapoptotic cell death.

Caspase-independent cell death is known to be important in physiological and pathological conditions, but its molecular regulation is not well-understood. Eiger is the sole fly ortholog of TNF. The ectopic expression of Eiger in the developing eye primordium caused JNK-dependent but caspase-independent cell death. To understand the molecular basis of this Eiger-induced nonapoptotic cell death, we performed a large-scale genetic screen in Drosophila for suppressors of the Eiger-induced cell death phenotype. We found that molecules that regulate metabolic energy production are central to this form of cell death: it was dramatically suppressed by decreased levels of molecules that regulate cytosolic glycolysis, mitochondrial ß-oxidation of fatty acids, the tricarboxylic acid cycle, and the electron transport chain. Importantly, reducing the expression of energy production-related genes did not affect the cell death triggered by proapoptotic genes, such as reaper, hid, or debcl, indicating that the energy production-related genes have a specific role in Eiger-induced nonapoptotic cell death. We also found that energy production-related genes regulate the Eiger-induced cell death downstream of JNK. In addition, Eiger induced the production of reactive oxygen species in a manner dependent on energy production-related genes. Furthermore, we showed that this cell death machinery is involved in Eiger's physiological function, because decreasing the energy production-related genes suppressed Eiger-dependent tumor suppression, an intrinsic mechanism for removing tumorigenic mutant clones from epithelia by inducing cell death. This result suggests a link between sensitivity to cell death and metabolic activity in cancer.

[Perioperative management of two patients with renal malignant tumor involving the vena cava].

Two patients underwent resection of renal malignant tumors involving vena cava. Such tumors occasionally extend to the inferior vena cava with tumor thrombus and invasion to the lymph nodes and adjacent organs. Perioperative management of patients with these tumors is difficult because of the risk of pulmonary embolism and massive bleeding, and requires appropriate cooperation among the surgical team. In case 1, a 56-year-old man, renal cell carcinoma with tumor thrombus had extended into the intrahepatic vena cava. It was resected after isolating the liver from vena cava and incising the cross-clamped inferior vena cava without extracorporeal circulation or blood transfusion. A prosthetic graft replaced the inferior vena cava. In case 2, a 64-year-old woman, renal pelvis cancer adhered to the inferior vena cava and the mesentery with enlarged lymph nodes. It was separated from the inferior vena cava and removed with the ascending colon. The patient received a blood transfusion of approximately 2,000ml. Cardiomyopathy associated with a left ventricular outflow tract pressure gradient of 100mmHg required perioperative management. After surgery, both patients underwent controlled ventilation in the intensive care unit. After recovery, they were discharged without complications. We discuss perioperative management, with regard to the level of the tumor extension and perioperative complications.

Tumor suppressor CYLD regulates JNK-induced cell death in Drosophila.

CYLD encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of CYLD in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila CYLD (dCYLD) mutant and transgenic flies expressing wild-type and mutant dCYLD proteins. Here we show that dCYLD is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, dCYLD regulates TNF-induced JNK activation and cell death through dTRAF2, which acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that dCYLD plays a critical role in modulating TNF-JNK-mediated cell death.

Measurement of solar UV radiation in Antarctica with collagen sheets.

Collagen sheets were used in a unique evaluation method to examine skin damage caused by ultraviolet (UV) light of short wavelength during a season of the Antarctic ozone hole. The collagen sheets were exposed outdoors for 25 and 50 d, in the spring when the ozone hole was formed and in the ozone-hole-free autumn. Extracts from the exposed collagen sheets were analyzed for total protein and terminal amino acid concentrations as an index of collagen fragmentation. The results show that the amount of extractable collagen and terminal amino acid concentration in the spring exposure were approximately double and five times higher, respectively, when compared with those in the autumn exposure. During the ozone hole occurrence, the terminal amino acid concentration of the extracted collagen was about five times higher when exposure lasted 50 d from mid-September to the end of October compared to when exposure lasted 25 d from mid-September to early October. This result could be attributed to a limited amount of short-wavelength UV radiation reaching the ground surface as a result of the low height of the sun in September, when the ozone hole occurred. In fact, UV radiation measurements taken at Syowa Station indicate that short-wavelength UV radiation in the range 290-295 nm was not detected until approximately 1-2 months after the beginning of the ozone hole occurrence.

Estimated Gestational Age From Infant's Foot Length in Japanese.

Aim In developed countries including Japan, gestational age (GA) is predicted by the last menstrual period (LMP) and/or fetal ultrasound. In some developing countries, GA is predicted by infant's foot length (FL). Pregnant women who did not have pregnancy check-up is not infrequent in Japan, therefore there are sometimes opportunities to estimate the GA from infants after the delivery. The aim of this study is to determine the estimated GA formula from infant's FL in Japanese. Methods This study was a prospective cohort study. Infants between May 2021 and August 2021 at Iizuka Hospital and Tagawa Hospital or transferred from other hospitals within 24 hours of birth were collected. GA was determined using LMP and/or fetal ultrasound. The infant's FL was measured with a digital caliper within 24 hours of birth. The relationship between FL and GA was analyzed by simple regression analysis to determine the coefficient of determination (R2). The infant's FL of males and females, infant's FL of preterm and term, and infant's FL of low birth weight and appropriate weight infants were performed by the t-test as independent samples. A statistically significant difference was p < 0.05. Statistical analysis was performed using JMP Pro 16 (SAS Institute Japan Co., Ltd., Minato-ku, Tokyo). Results Ninety of the 135 infants were enrolled. The average GA was 38.2 ± 1.8 weeks, the average infant's FL was 7.230 ± 0.411 centimeter (cm), and the range of the infant's FL was 5.385 to 8.089 cm. The estimated GA formula, GA = 18.49 + 0.27 x infant's FL (R2 = 0.39), was determined. Conclusions We determined the estimated GA formula from the infant's FL. There are some limitations and care should be taken in the use.

Levothyroxine replacement therapy and refractory hypotension out of transitional period in preterm infants.

BACKGROUND: Recent studies suggest that refractory hypotension from causes other than septicaemia or cardiac failure is common in extremely preterm infants even out of the transitional period. Marked response to low-dose cortisol suggests underlying adrenal insufficiency, although the exact mechanism remains unknown. METHODS: To investigate potential triggers for and related short-term outcomes of early-onset (

Capicua regulates cell proliferation downstream of the receptor tyrosine kinase/ras signaling pathway.

Signaling via the receptor tyrosine kinase (RTK)/Ras pathway promotes tissue growth during organismal development and is increased in many cancers [1]. It is still not understood precisely how this pathway promotes cell growth (mass accumulation). In addition, the RTK/Ras pathway also functions in cell survival, cell-fate specification, terminal differentiation, and progression through mitosis [2-7]. An important question is how the same canonical pathway can elicit strikingly different responses in different cell types. Here, we show that the HMG-box protein Capicua (Cic) restricts cell growth in Drosophila imaginal discs, and its levels are, in turn, downregulated by Ras signaling. Moreover, unlike normal cells, the growth of cic mutant cells is undiminished in the complete absence of a Ras signal. In addition to a general role in growth regulation, the importance of cic in regulating cell-fate determination downstream of Ras appears to vary from tissue to tissue. In the developing eye, the analysis of cic mutants shows that the functions of Ras in regulating growth and cell-fate determination are separable. Thus, the DNA-binding protein Cic is a key downstream component in the pathway by which Ras regulates growth in imaginal discs.

Production of biological soil crusts in the early stage of primary succession on a high Arctic glacier foreland.

*We examined the photosynthetic characteristics and net primary production of biological soil crusts to evaluate their contribution to the carbon cycle in the High Arctic glacier foreland. *Biological soil crust samples were collected from a deglaciated area in Ny-Alesund, Svalbard, Norway. Net photosynthetic rates (Pn) and dark respiration rates (R) of biological soil crusts were determined using CO(2) gas exchange rates. We examined the effects of moisture conditions, temperature and photon flux density on Pn and R, and estimated the net primary production by a model based on the relationships between abiotic factors and Pn and R. *The maximum Pn value occurred at 50% of the maximum water-holding capacity. Pn decreased with increasing temperature and dropped below zero at high temperatures (c. > 13 degrees C). The estimated net primary production of the biological soil crust was greater than the net primary production of other vegetation when based on ground surface area, during the early stage of primary succession. Model simulation showed that the net primary production of the biological soil crust decreased with increasing temperature. *These results suggest that biological soil crust productivity plays an important role in the carbon cycle during the early stage of succession of the High Arctic glacier foreland, and is susceptible to temperature increases from global warming.

Seasonal shift in factors controlling net ecosystem production in a high Arctic terrestrial ecosystem.

We examined factors controlling temporal changes in net ecosystem production (NEP) in a high Arctic polar semi-desert ecosystem in the snow-free season. We examined the relationships between NEP and biotic and abiotic factors in a dominant plant community (Salix polaris-moss) in the Norwegian high Arctic. Just after snowmelt in early July, the ecosystem released CO(2) into the atmosphere. A few days after snowmelt, however, the ecosystem became a CO(2) sink as the leaves of S. polaris developed. Diurnal changes in NEP mirrored changes in light incidence (photosynthetic photon flux density, PPFD) in summer. NEP was significantly correlated with PPFD when S. polaris had fully developed leaves, i.e., high photosynthetic activity. In autumn, NEP values decreased as S. polaris underwent senescence. During this time, CO(2) was sometimes released into the atmosphere. In wet conditions, moss made a larger contribution to NEP. In fact, the water content of the moss regulated NEP during autumn. Our results indicate that the main factors controlling NEP in summer are coverage and growth of S. polaris, PPFD, and precipitation. In autumn, the main factor controlling NEP is moss water content.

Brain-type natriuretic peptide at birth reflects foetal maturation and antenatal stress.

AIM: Antenatal stress, maturation and other foetal conditions affect the postnatal cardiovascular function. Atrial- (ANP) and brain-type natriuretic peptide (BNP) play important roles in regulating extracellular fluid volume and blood pressure, which may surrogate the foetal cardiovascular condition. The aim of this study was to investigate the dependence of serum ANP and BNP at birth on antenatal variables in high-risk infants. METHODS: Plasma ANP and BNP levels in the umbilical cord blood were compared with antenatal clinical information in 280 infants. RESULTS: High levels of ANP and BNP were associated with multiple pregnancy, antenatal magnesium sulphate and foetal distress. Caesarean section (CS) was paradoxically associated with low ANP and high BNP; low ANP was related with CS before labour whereas high BNP was related with CS after the commencement of labour. High BNP levels further correlated with younger gestational age and intrauteral growth restriction. With regard to short-term postnatal variables, high BNP levels were associated with low Apgar scores and respiratory failure whereas high ANP only correlated with the latter. CONCLUSION: High natriuretic peptide levels were associated with prematurity at birth, uteral contraction and antenatal stress: cord blood ANP and BNP may be a useful surrogate marker for hidden antenatal stress.

Degradation of Extracellular Matrix by Matrix Metalloproteinase 2 Is Essential for the Establishment of the Blood-Brain Barrier in Drosophila.

The blood-brain barrier (BBB) is an essential system that isolates the central nervous system from the internal environment. Increasing evidence has begun to reveal the molecules that are required for BBB integrity. However, how these components are regulated remains unclear. Here we report that a matrix metalloproteinase, Mmp2, is essential for the establishment of the BBB in Drosophila. In the absence of mmp2, the BBB becomes leaky, which allows the tracer to penetrate the brain. Moreover, the expression pattern of a junctional component, Neuroglian, is altered. We also find that the regulation of the amounts of particular extracellular matrix components is critical for BBB establishment. Furthermore, the process of mesenchymal-epithelial transition of BBB-forming cells is perturbed in the absence of Mmp2. These data indicate that the presence of Mmp(s), which is typically considered to be a risk factor for BBB degradation, is essential for BBB integrity in Drosophila.

[Study on intermediate products in chloroform formation from L-tyrosine treated with sodium hypochlorite].

Possible intermediates in the formation of chloroform during by the sodium hypochlorite (NaClO) treatment of L-tyrosine were investigated using HPLC and LC/MS. One product showed the same MS characteristics as the substance formed by the NaClO treatment of 4-hydroxybenzyl cyanide (4-HBC), and it was suggested to be m-chloro-4-hydroxybenzyl cyanide (m-C-4-HBC). Since m-C-4-HBC is not commercially available it was synthesized by treating 4-HBC with NaClO, and purified by extraction with ethyl acetate, followed by HPLC on preparative isolation columns, using a column switching method. The product was confirmed to be 3-chloro-4-hydroxybenzyl cyanide (3-C-4-HBC), by means of NMR spectral analysis. When L-tyrosine or 4-HBC was treated with NaClO, 3-C-4-HBC and CHCl3 were generated. When 3-C-4-HBC was treated with NaClO, CHCl3 was generated. Judging from these results, 3-C-4-HBC was confirmed to be an intermediate in the formation of CHCl3 from L-tyrosine. Thus, the reaction pathway of CHCl3 formation from L-tyrosine treated with NaClO is concluded to be: L-tyrosine-->4-HBC-->3-C-4-HBC-->CHCl3.

State dependence of climatic instability over the past 720,000 years from Antarctic ice cores and climate modeling.

Climatic variabilities on millennial and longer time scales with a bipolar seesaw pattern have been documented in paleoclimatic records, but their frequencies, relationships with mean climatic state, and mechanisms remain unclear. Understanding the processes and sensitivities that underlie these changes will underpin better understanding of the climate system and projections of its future change. We investigate the long-term characteristics of climatic variability using a new ice-core record from Dome Fuji, East Antarctica, combined with an existing long record from the Dome C ice core. Antarctic warming events over the past 720,000 years are most frequent when the Antarctic temperature is slightly below average on orbital time scales, equivalent to an intermediate climate during glacial periods, whereas interglacial and fully glaciated climates are unfavourable for a millennial-scale bipolar seesaw. Numerical experiments using a fully coupled atmosphere-ocean general circulation model with freshwater hosing in the northern North Atlantic showed that climate becomes most unstable in intermediate glacial conditions associated with large changes in sea ice and the Atlantic Meridional Overturning Circulation. Model sensitivity experiments suggest that the prerequisite for the most frequent climate instability with bipolar seesaw pattern during the late Pleistocene era is associated with reduced atmospheric CO2 concentration via global cooling and sea ice formation in the North Atlantic, in addition to extended Northern Hemisphere ice sheets.

Gain-of-function screen identifies a role of the Sec61alpha translocon in Drosophila postmitotic neurotoxicity.

To elucidate the intrinsic mechanisms of neurotoxicity induction, including those underlying neural cell death and neurodegeneration, we developed a gain-of-function screen for gene products causing neural cell loss. To identify novel genes with a cell-death-related function in neurons, we screened 4,964 Drosophila GS lines, in which one or two genes from much of the Drosophila genome can be overexpressed. Approximately 0.68% of the GS lines produced phenotypes involving a loss of postmitotic neurons. Of these, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61alpha (DSec61alpha), an endoplasmic reticulum protein with protein translocation activity. Ectopic expression of DSec61alpha caused neural cell death accompanied by the accumulation of ubiquitinated proteins, which was mediated by DSec61alpha's translocon activity. This supported our previous observation that the DSec61alpha translocon contributes to expanded polyglutamine-mediated neuronal toxicity, which is also associated with ubiquitinated protein accumulation. These data suggest that the translocon may be a novel component of neural cell death and degeneration pathways. Our approach can be used to identify potential neurotoxic factors within the whole genome, which will increase our understanding of the molecular mechanisms of various types of cell death, including those associated with human neurodegenerative diseases.

Relationships of Drosophila melanogaster RECQ5/QE to cell-cycle progression and DNA damage.

Members of the RecQ family of DNA helicases are involved in the cellular response to DNA damage and are regulated in the cell-cycle. However, little is known about RecQ5, one of these members. The level of RECQ5/QE, Drosophila melanogaster RecQ5, was increased after the exposure of cultured cells to methyl-methanesulfonate. Transgenic flies that overexpressed RECQ5/QE in their developing eye primordia showed mild roughening of the ommatidial lattice. DNA-damaging agents and the mei-41 mutation enhanced the phenotype caused by RECQ5/QE overexpression. Overexpression of RECQ5/QE perturbed the progression of the cell-cycle in response to DNA damage in the eye imaginal discs. These results suggest that RECQ5/QE interacts with components of the cell-cycle during its progression in response to DNA damage.