Central human B cell tolerance manifests with a distinctive cell phenotype and is enforced via CXCR4 signaling in hu-mice

Central B cell tolerance, the process restricting the development of many newly generated autoreactive B cells, has been intensely investigated in mouse cells while studies in humans have been hampered by the inability to phenotypically distinguish autoreactive and nonautoreactive immature B cell clones and the difficulty in accessing fresh human bone marrow samples. Using a human immune system mouse model in which all human Igκ+ B cells undergo central tolerance, we discovered that human autoreactive immature B cells exhibit a distinctive phenotype that includes lower activation of ERK and differential expression of CD69, CD81, CXCR4, and other glycoproteins. Human B cells exhibiting these characteristics were observed in fresh human bone marrow tissue biopsy specimens, although differences in marker expression were smaller than in the humanized mouse model. Furthermore, the expression of these markers was slightly altered in autoreactive B cells of humanized mice engrafted with some human immune systems genetically predisposed to autoimmunity. Finally, by treating mice and human immune system mice with a pharmacologic antagonist, we show that signaling by CXCR4 is necessary to prevent both human and mouse autoreactive B cell clones from egressing the bone marrow, indicating that CXCR4 functionally contributes to central B cell tolerance.This work was supported by the NIH (Grants AI124474 and AI131639 to R.P. and Grant AI136534 to R.M.T.). It was also supported in part by NIH National Center for Advancing Translational Sciences Colorado Clinical and Translational Science Awards Grant UL1 TR002535. The contents are the authors’sole responsibility anddo not necessarily represent official NIH views.S

Young People Who Meaningfully Improve Are More Likely to Mutually Agree to End Treatment

Objective: Symptom improvement is often examined as an indicator of a good outcome of accessing mental health services. However, there is little evidence of whether symptom improvement is associated with other indicators of a good outcome, such as a mutual agreement to end treatment. The aim of this study was to examine whether young people accessing mental health services who meaningfully improved were more likely to mutually agree to end treatment. Methods: Multilevel multinomial regression analysis controlling for age, gender, ethnicity, and referral source was conducted on N = 8,995 episodes of care [Female = 5,469, 61%; meanAge = 13.66 (SD = 2.87) years] using anonymised administrative data from young people's mental health services. Results: Compared to young people with no change in mental health difficulties, those showing positive meaningful changes in mental health difficulties were less likely to have case closure due to non-mutual agreement (Odds Ratio or OR = 0.58, 95% Confidence Interval or CI = 0.50-0.61). Similarly, they were less likely to transfer (OR = 0.61, 95% CI = 0.49-0.74) or end treatment for other reasons (OR = 0.59, 95% CI = 0.50-0.70) than by case closure due to mutual agreement. Conclusion: The findings suggest that young people accessing mental health services whose symptoms meaningfully improve are more likely to mutually agree to end treatment, adding to the evidence that symptom improvement may be appropriate to examine as an indicator of a good outcome of accessing mental health services

Predicting mental health improvement and deterioration in a large community sample of 11- to 13-year-olds

Multivariate analysis of psychological dat

It Takes Two to Tango, Part II : Synthesis of A-Ring Functionalised Quinones Containing Two Redox-Active Centres with Antitumour Activities

In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/seleniumcontaining triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of paranaphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango

Is early center-based child care associated with tantrums and unmanageable behavior over time up to school entry?

Background. Existing research suggests that there is a relationship between greater exposure to center-based child care and child behavioral problems though the mechanism for the impact is unclear. However the measure used to document child care has usually been average hours, which may be particularly unreliable in the early months when fewer children are in center care. In addition individual trajectories for behavior difficulties have not been studied. Objective. The purpose of the current study was to examine whether the extent of exposure to center-based child care before two years predicted the trajectory of children’s difficult behavior (i.e., tantrums and unmanageable behavior) from 30 to 51 months controlling for child and maternal characteristics. Method. Data were drawn from UK-based Families, Children and Child Care (FCCC) study (n=1201). Individual growth models were fitted to test the relation between early center-based child care experiences and subsequent difficult behavior. Results. Children with more exposure to center-based care before two had less difficult behavior at 30 months, but more increase over time. Initial levels were predicted by higher difficult temperament and lower verbal ability. Higher difficult temperament and lower family socio-economic status predicted its change over time. Conclusion. Findings suggest that early exposure to center-based care before two years old is a risk factor for subsequent behavior problems especially when children have a longer period of exposure. A possible explanatory process is that child coping strategies to manage frustration are less well developed in a group context, especially when they lag behind in expressive language

Usual choline and betaine dietary intake and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study

<p>Abstract</p> <p>Background</p> <p>Low dietary intake of the essential nutrient choline and its metabolite betaine may increase atherogenesis both through effects on homocysteine methylation pathways as well as through choline's antioxidants properties. Nutrient values for many common foods for choline and betaine have recently become available in the U.S. nutrient composition database. Our objective was to assess the association of dietary intake of choline and betaine with incident coronary heart disease (CHD), adjusting for dietary intake measurement error.</p> <p>Methods</p> <p>We conducted a prospective investigation of the relation between usual intake of choline and betaine with the risk of CHD in 14,430 middle-aged men and women of the biethnic Atherosclerosis Risk in Communities study. A semi-quantitative food frequency questionnaire was used to assess nutrient intake. Proportional hazard regression models were used to calculate the risk of incident CHD. A regression calibration method was used to adjust for measurement error.</p> <p>Results</p> <p>During an average 14 years of follow-up (1987–2002), 1,072 incident CHD events were documented. Compared with the lowest quartile of intake, incident CHD risk was slightly and non-significantly higher in the highest quartile of choline and choline plus betaine, HR = 1.22 (0.91, 1.64) and HR = 1.14 (0.85, 1.53), controlling for age, sex, education, total energy intake, dietary intakes of folate, methionine and vitamin B₆. No association was found between dietary choline intake and incident CHD when correcting for measurement error.</p> <p>Conclusion</p> <p>Higher intakes of choline and betaine were not protective for incident CHD. Similar investigations in other populations are of interest.</p

COMPLEXIDADE RACIAL: mitos e realidades em duas freguesias de Salvador em 1775

A partir da análise minuciosa dos dados do Censo de 1775 sobre duas freguesias de Salvador (São Pedro e Penha), são colocados em questão cinco mitos dominantes sobre a escravidão no imaginário nacional: (1) o domínio total do trabalho escravo na sociedade; (2) uma sociedade formada apenas por senhores e escravos; (3) uma sociedade constituída, por um lado, por um segmento de dominantes e exploradores e, por outro, por dominados e explorados; (4) uma sociedade urbana segregada; (5) uma sociedade patriarcal, em que as mulheres eram submissas e economicamente subordinadas. Os resultados do censo, portanto, levantam novas questões para o entendimento da complexidade do nosso passado, o que ajuda a entender a manutenção das extremas desigualdades atuais, além de evidenciar a existência de diferenciações espaciais na cidade. PALAVRAS-CHAVE: escravos, libertos, agregados, freguesias, Salvador.RACIAL COMPLEXITY: myth and reality in two Salvador freguesias in 1775 Pedro de Almeida Vasconcelos The meticulous analysis of data from the Census of 1775 on two freguesias of Salvador (São Pedro and Penha), bring doubt to five dominant myths on slavery in the national imaginary: (1) the exclusivity of slave work in the society; (2) a society just formed by slave owners and slaves; (3) a society where, on one side, live a segment of dominant exploiters and, on the other, dominated explored people; (4) a segregated urban society; (5) a patriarchal society, in which women were submissive and economically subordinates. The results of the census, therefore, bring new subjects to understanding the complexity of our past, what helps to understand the maintenance of the extreme current inequalities, besides showing the existence of space differentiations in the city. KEYWORDS: slaves, freed men, agregados, freguesias, Salvador.COMPLEXITÉ RACIALE: mythes et réalités dans deux paroisses de Salvador en 1775 Pedro de Almeida Vasconcelos A partir de l’analyse minutieuse des données du recensement de 1775 concernant deux paroisses de Salvador (São Pedro et Penha) sont remis en question cinq mythes dominants à propos de l’esclavage dans l’imaginaire national: (1) l’exclusivité du travail esclave dans la société; (2) une société formée uniquement de seigneurs et d’esclaves; (3) une société constituée d’une part par un segment de dominants et d’exploiteurs et d’autre part de dominés et d’exploités; (4) une société urbaine ségréguée; (5) une société patriarcale où les femmes étaient soumises et subordonnées économiquement. Les résultats de ce recensement soulèvent donc de nouvelles questions pour la compréhension de la complexité de notre passé, ceci permet de comprendre le maintien d’extrêmes inégalités actuelles et de mettre aussi en évidence l’existence de différenciations spatiales dans la ville. MOTS-CLÉS: esclaves, personnes libres, domestiques, paroisses, Salvador. Publicação Online do Caderno CRH: http://www.cadernocrh.ufba.b