TLR2-Dependent Induction of IL-10 and Foxp3+CD25+CD4+ Regulatory T Cells Prevents Effective Anti-Tumor Immunity Induced by Pam2 Lipopeptides In Vivo

16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2) lipopeptides act as toll-like receptor (TLR)2/6 ligands and activate natural killer (NK) cells and dendritic cells (DCs) to produce inflammatory cytokines and cytotoxic NK activity in vitro. However, in this study, we found that systemic injection of Pam2 lipopeptides was not effective for the suppression of NK-sensitive B16 melanomas in vivo. When we investigated the immune suppressive mechanisms, systemic injection of Pam2 lipopeptides induced IL-10 in a TLR2-dependent manner. The Pam2 lipopeptides increased the frequencies of Foxp3+CD4+ regulatory T (T reg) cells in a TLR2- and IL-10- dependent manner. The T reg cells from Pam2-lipopeptide injected mice maintained suppressor activity. Pam2 lipopeptides, plus the depletion of T reg with an anti-CD25 monoclonal antibody, improved tumor growth compared with Pam2 lipopeptides alone. In conclusion, our data suggested that systemic treatment of Pam2 lipopeptides promoted IL-10 production and T reg function, which suppressed the effective induction of anti-tumor immunity in vivo. It is necessary to develop an adjuvant that does not promote IL-10 and T reg function in vivo for the future establishment of an anti-cancer vaccine

Repeated Starvation Leads Fat Accumulation in Caenorhabditis elegans

Our aim is to define the effect of repeated-starvation on organism using nematode Caenorhabditis elegans. Adult worms were exposed to two cycles of 6 hr starvation-18 hr feeding protocol, and fat content in worms was analyzed by Nile Red staining and biochemical quantification. The expression of genes involved in fat synthesis (pod-2, fasn-1, mboa-2, sbp-1) and fat degradation (hosl-1, lipl-4, cpt-1, cpt-2, B03003.3, F53a2.7) was also analyzed by quantitative RT-PCR. Both Nile Red staining and biochemical quantification showed that fat content in worms that experienced repeated-starvation increased. There was no obvious change in the expression of genes involved in fat synthesis, but those of genes involved in fat degradation tended to decrease, which is consistent with the increment of fat in worms experienced repeated-starvation. The lifespan, fecundity and mobility of worms that experienced repeated-starvation did not show remarkable differences compared to those of the fed worms. However, the pharyngeal pumping increased upon experiencing starvation, indicating amount of food intake increased by starvation. Our results indicate that repeated-starvation caused metabolic and nutritional effect in worms. It is often mentioned that repeating weight loss leads to weight regain, sometimes referred as “weight rebound”, and our data may also provide a molecular basis of weight regain

The Peptide Sequence of Diacyl Lipopeptides Determines Dendritic Cell TLR2-Mediated NK Activation

Natural killer (NK) cells are lymphocyte effectors that are activated to control certain microbial infections and tumors. Many NK-activating and regulating receptors are involved in regulating NK cell function. In addition, activation of naïve NK cells is fundamentally triggered by cytokines or myeloid dendritic cells (mDC) in various modes. In this study, we synthesized 16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2Cys) lipopeptides with sequences designed from lipoproteins of Staphylococcus aureus, and assessed their functional properties using mouse (C57BL/6) bone marrow-derived DC (BMDC) and NK cells. NK cell activation was evaluated by three criteria: IFN-γ production, up-regulation of NK activation markers and cytokines, and NK target (B16D8 cell) cytotoxicity. The diacylated lipopeptides acted as TLR2 ligands, inducing up-regulation of CD25/CD69/CD86, IL-6, and IL-12p40, which represent maturation of BMDC. Strikingly, the Pam2Cys lipopeptides induced mouse NK cell activation based on these criteria. Cell-cell contact by Pam2Cys peptide-stimulated BMDC and NK cells rather than soluble mediators released by stimulated BMDC induced activation of NK cells. For most lipopeptides, the BMDC TLR2/MyD88 pathway was responsible for driving NK activation, while some slightly induced direct activation of NK cells via the TLR2/MyD88 pathway in NK cells. The potential for NK activation was critically regulated by the peptide primary sequence. Hydrophobic or proline-containing sequences proximal to the N-terminal lipid moiety interfered with the ability of lipopeptides to induce BMDC-mediated NK activation. This mode of NK activation is distinctly different from that induced by polyI:C, which is closely associated with type I IFN-inducing pathways of BMDC. These results imply that the MyD88 pathway of BMDC governs an alternative NK-activating pathway in which the peptide sequence of TLR2-agonistic lipopeptides critically affects the potential for NK activation

ANÁLISE DA DISTRIBUIÇÃO ESPACIAL DAS URGÊNCIAS ODONTOLÓGICAS E SUA RELAÇÃO COM O SISTEMA ÚNICO DE SAÚDE

The study aims to analyze the profile of emergency service patients in dentistry (SUO-FOB) and the spatial analysis of their households concerning the network of Primary Health Care and emergency in dentistry of the Brazilian Health System (SUS), this prospective cohort. The data were collected from February 2017 to August 2018 in the SUO-FOB and e-SUS, municipality of Bauru, São Paulo, Brazil. From 4,121 patients, 78.60% were between 20 and 64 years old, 81% presented pain as the main complaint, and the location of their households showed a spatial pattern of higher intensity of concentration in the outskirts of the city. This study evidence that the SUO-FOB contributes to oral health care in the municipality, especially in areas where it needs improvement. The university emergency services can help support the health care network when demanded.Objetivou-se analisar o perfil dos pacientes de um serviço de extensão de urgência em odontologia (SUO-FOB) e sua distribuição espacial por local de residência, relacionando-os à rede de Atenção Primária à Saúde e serviços de urgência odontológica do Sistema Único de Saúde (SUS), em uma coorte prospectiva. Os dados foram coletados de fevereiro de 2017 a agosto de 2018 no SUO-FOB e e-SUS no município de Bauru, São Paulo, Brasil. Dos 4.121 pacientes, 78,60% possuíam entre 20 a 64 anos, 81% apresentaram sintomatologia dolorosa como queixa principal, e a localização de suas residências apresentou um padrão espacial de maior intensidade de concentração nos arredores da cidade. Evidenciou-se que o SUO-FOB contribui com a atenção à saúde bucal do município, especialmente em áreas onde a atenção primária à saúde precisa ser aprimorada e que os serviços de urgência universitários podem compor a rede de atenção à saúde de suas localidades

O raciocínio geográfico e as chaves de leitura da Covid-19 no território brasileiro

RESUMO Para compreender como a Covid-19 se distribui pelo espaço brasileiro, os geógrafos utilizam-se do raciocínio geográfico apoiados em técnicas de mapeamento e representações espaciais. Nesse sentido, propomos aqui uma série de procedimentos para compreender a doença no espaço, primeiramente com a exploração e descrição dos dados, a análise espacial e a síntese por meio da modelização gráfica, partindo em seguida para a comunicação cartográfica. Como efeito, esperamos que esse caminho teórico e metodológico possa balizar a criação de uma imagem de mundo capaz de responder a demandas mais urgentes postas pela pandemia, ao mesmo tempo criar reflexões sobre como a produção do espaço atual cria vulnerabilidades nesta globalização perversa

A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis.

Funder: Japan Foundation for Applied Enzymology; doi: https://doi.org/10.13039/100008695Funder: Pancreas Research Foundation of Japan Collaborative Research Project Program of the Medical Institute of Bioregulation, Kyushu University, Japan Joint Research Program of the Institute for Molecular and Cellular Regulation, Gunma University, Japan Grant for Joint Research Project of the Research Institute for Microbial Diseases Osaka UniversityFunder: European Research Council (ERC (639050) and the Interpark Bio-Convergence Center Grant Program.Frequent mutation of the tumour suppressor RNF43 is observed in many cancers, particularly colon malignancies. RNF43, an E3 ubiquitin ligase, negatively regulates Wnt signalling by inducing degradation of the Wnt receptor Frizzled. In this study, we discover that RNF43 activity requires phosphorylation at a triplet of conserved serines. This phospho-regulation of RNF43 is required for zebrafish development and growth of mouse intestinal organoids. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing the inhibitory function of RNF43 in Wnt signalling while maintaining its inhibitory function in p53 signalling. Our data suggest that RNF43 mutations cooperate with KRAS mutations to promote multi-step tumorigenesis via the Wnt-Ras-p53 axis in human colon cancers. Lastly, phosphomimetic substitutions of the serine trio restored the tumour suppressive activity of extracellular oncogenic mutants. Therefore, harnessing phospho-regulation of RNF43 might be a potential therapeutic strategy for tumours with RNF43 mutations

ジショウ コウイ ト シンリ トクセイ トノ カンレン ニ ツイテ ノ ヨビ ケンキュウ

近年、教育界において自傷行為が数多く報告されている。自傷行為については、わからないことが多く、予防支援のためには、心理的要因を検討することが望まれる。そこで、本研究では、自傷行為と心理特性との関連を予備的に検討する。関東地方A高校2年生1クラスの39名に対し、2010年11月に無記名自記式質問紙調査を実施した。調査項目は(1)属性(性別)(2)学校について(学校満足度)・家庭について(居心地・愛着)(3)故意に健康を害する行為(経験・念慮)の有無(4)自傷行為(経験・念慮)の有無( 5)心理的要因に関する尺度(5項目)であった。結果は、次のとおりである。(1)喫煙(経験1人・念慮3人)、飲酒(経験18人・念慮3人)、ダイエット(経験4人・念慮6人)、過食嘔吐(経験8人・念慮3人)、過量服薬(経験0人・念慮2人)であった。(2)自傷行為有(経験4人・念慮3人)、無32人であった。(3)特性不安、抑うつ、自己否定感の各尺度値が基準値を超え、特性不安尺度、抑うつ尺度、自己否定感尺度間に強い正の相関がみられた。(4)自傷行為(経験・念慮)と心理特性尺度との相関については「抑うつ」「自己否定感」において有意、「特性不安」において有意傾向であった。(5)自傷行為(経験・念慮)有無2群における心理特性については、有群が無群に比して「抑うつ」「自己否定感」において有意に、「特性不安」において有意傾向で課題が見られた。これらのことから、次のことが考えられる。心理的課題を抱える生徒は複数の心理的問題を同時に抱え、学校生活の大変さがうかがわれた。健康を害する行為や自傷行為の一定数は、そのことに関連している可能性が推察される。特に、自傷行為(経験・念慮)については、統計学的に心理的課題との関連が推測され、対象者の一部が、自傷行為という行為を通して、心理的課題に独自に対応しているのではないかと考えられる。自傷行為予防支援に向けての本格的調査が必要である。In recent years, there have been numerous reports of individuals committing acts of nonsuicidal self-injury in educational circles. Much is still unknown about non-suicidal self-injury and it is vital that we examine psychological factors for the prevention support of such behavior. To this end, this research provides a preliminary investigation of the relationship between nonsuicidal self-injury and psychological characteristics. In November 2010, an unsigned selfadministered questionnaire was conducted on 39 Class 1, 2nd Year, A High School students. The questionnaire items included criteria relating to:(1) gender;(2) school(degree of satisfaction) and home(comfort level and attachment);(3) deliberate acts to harm health(actual experiences and entertaining thoughts of such behavior);(4) non-suicidal self-injury(actual experiences and entertaining thoughts of such behavior); and(5) psychological factors. The result is as follows(1) Smoking(past experience 1, entertained thoughts 3); Drinking(past experience 18, entertained thoughts 3); Dieting(past experience 4, entertained thoughts 6); Bulimic behavior(past experience 8, entertained thoughts 3); and Drug overdoses(past experience 0, entertained thoughts 2). 2) Non-suicidal self-injury: 4 people had past experiences, 3 people had entertained such thoughts, with 32 having no such thoughts. 3) Scale values for trait anxiety, depression, and feeling of selfdenial were all above the normal range and a strong positive correlation was observed amongst trait anxiety criterion, depression criterion, and feeling of self-denial criterion(4) The correlation between self-injurious behavior and psychological characteristics was significant for "depression" and "feeling of self-denial." It was found to be marginally significant for "trait anxiety."(5) There was a significant difference in the scale values of "depression" and " feelings of self-denial" between the two groups that " had" and " did not have" experience of self-injurious behavior(experience and entertained thoughts of). There was a marginally significant difference with the scale of "trait anxiety." From these things, consideration is as follows. Students with psychological issues appeared to have multiple psychological problems simultaneously, which shed light on the difficulties of school life. One can surmise that there is a possibility that actions designed to harm one\u27s health and non-suicidal self-injury were related to psychological issues. In particular, non-suicidal selfinjury was assumed to be statistically related to psychological issues. Some of the subjects were thought to be coping in their own way with psychological issues by committing non-suicidal selfinjury. It is necessary to conduct a full-scale investigation for the prevention support of self-injurious behavior

Mechanism of Cancer Cell Death Induced by Depletion of an Essential Replication Regulator

Background: Depletion of replication factors often causes cell death in cancer cells. Depletion of Cdc7, a kinase essential for initiation of DNA replication, induces cancer cell death regardless of its p53 status, but the precise pathways of cell death induction have not been characterized. Methodology/Principal Findings: We have used the recently-developed cell cycle indicator, Fucci, to precisely characterize the cell death process induced by Cdc7 depletion. We have also generated and utilized similar fluorescent cell cycle indicators using fusion with other cell cycle regulators to analyze modes of cell death in live cells in both p53-positive and-negative backgrounds. We show that distinct cell-cycle responses are induced in p53-positive and-negative cells by Cdc7 depletion. p53-negative cells predominantly arrest temporally in G2-phase, accumulating CyclinB1 and other mitotic regulators. Prolonged arrest at G2-phase and abrupt entry into aberrant M-phase in the presence of accumulated CyclinB1 are followed by cell death at the post-mitotic state. Abrogation of cytoplasmic CyclinB1 accumulation partially decreases cell death. The ATR-MK2 pathway is responsible for sequestration of CyclinB1 with 14-3-3s protein. In contrast, p53-positive cancer cells do not accumulate CyclinB1, but appear to die mostly through entry into aberrant S-phase after Cdc7 depletion. The combination of Cdc7 inhibition with known anti-cancer agents significantly stimulates cell death effects in cancer cells in a genotype-dependent manner, providing a strategic basis for future combination therapies

Characteristic of face shapes and body image depicted in Japanese comics （manga）

The present study investigated the stereotypes of the ideal male and female face shapes depicted in Japanese comics （manga） and their influence on body image. General trends of face shapes in male and female figures （n=1381） were analyzed in manga published during 2006-2008. In manga for female readers, both males and females have a thinner cheek-jaw silhouette, while in manga for male readers, they have a natural cheek-jaw silhouette. Moreover, compared with females’ face shapes of males depicted in all the manga categories have more variation of face shape. Interestingly, males in manga stories for adult female readers are depicted with the highest frequency of thin cheek-jaw silhouette. The meaning of the thinner cheek-jaw silhouette in manga is discussed