Involvement of Bruton's tyrosine kinase in FcepsilonRI-dependent mast cell degranulation and cytokine production.

We investigated the role of Bruton's tyrosine kinase (Btk) in FcepsilonRI-dependent activation of mouse mast cells, using xid and btk null mutant mice. Unlike B cell development, mast cell development is apparently normal in these btk mutant mice. However, mast cells derived from these mice exhibited significant abnormalities in FcepsilonRI-dependent function. xid mice primed with anti-dinitrophenyl monoclonal IgE antibody exhibited mildly diminished early-phase and severely blunted late-phase anaphylactic reactions in response to antigen challenge in vivo. Consistent with this finding, cultured mast cells derived from the bone marrow cells of xid or btk null mice exhibited mild impairments in degranulation, and more profound defects in the production of several cytokines, upon FcepsilonRI cross-linking. Moreover, the transcriptional activities of these cytokine genes were severely reduced in FcepsilonRI-stimulated btk mutant mast cells. The specificity of these effects of btk mutations was confirmed by the improvement in the ability of btk mutant mast cells to degranulate and to secrete cytokines after the retroviral transfer of wild-type btk cDNA, but not of vector or kinase-dead btk cDNA. Retroviral transfer of Emt (= Itk/Tsk), Btk's closest relative, also partially improved the ability of btk mutant mast cells to secrete mediators. Taken together, these results demonstrate an important role for Btk in the full expression of FcepsilonRI signal transduction in mast cells

Evidence for the classical integrability of the complete AdS(4) x CP(3) superstring

We construct a zero-curvature Lax connection in a sub-sector of the superstring theory on AdS(4) x CP(3) which is not described by the OSp(6|4)/U(3) x SO(1,3) supercoset sigma-model. In this sub-sector worldsheet fermions associated to eight broken supersymmetries of the type IIA background are physical fields. As such, the prescription for the construction of the Lax connection based on the Z_4-automorphism of the isometry superalgebra OSp(6|4) does not do the job. So, to construct the Lax connection we have used an alternative method which nevertheless relies on the isometry of the target superspace and kappa-symmetry of the Green-Schwarz superstring.Comment: 1+26 pages; v2: minor typos corrected, acknowledgements adde

Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity

Background. Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Methodology/Principal findings. Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Conclusions/significance. Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF

Brief evidence-based interventions for universal child health services: a restricted evidence assessment of the literature

Background Universal child health services (UCHS) provide an important pragmatic platform for the delivery of universal and targeted interventions to support families and optimize child health outcomes. We aimed to identify brief, evidence-based interventions for common health and developmental problems that could be potentially implemented in UCHS. Methods A restricted evidence assessment (REA) of electronic databases and grey literature was undertaken covering January 2006 to August 2019. Studies were eligible if (i) outcomes related to one or more of four areas: child social and emotional wellbeing (SEWB), infant sleep, home learning environment or parent mental health, (ii) a comparison group was used, (iii) universal or targeted intervention were delivered in non-tertiary settings, (iv) interventions did not last more than 4 sessions, and (v) children were aged between 2 weeks postpartum and 5 years at baseline. Results Seventeen studies met the eligibility criteria. Of these, three interventions could possibly be implemented at scale within UCHS platforms: (1) a universal child behavioural intervention which did not affect its primary outcome of infant sleep but improved parental mental health, (2) a universal screening programme which improved maternal mental health, and (3) a targeted child behavioural intervention which improved parent-reported infant sleep problems and parental mental health. Key lessons learnt include: (1) Interventions should impart the maximal amount of information within an initial session with future sessions reinforcing key messages, (2) Interventions should see the family as a holistic unit by considering the needs of parents with an emphasis on identification, triage and referral, and (3) Brief interventions may be more acceptable for stigmatized topics, but still entail considerable barriers that deter the most vulnerable. Conclusions Delivery and evaluation of brief evidence-based interventions from a UCHS could lead to improved maternal and child health outcomes through a more responsive and equitable service. We recommend three interventions that meet our criteria of “best bet” interventions

Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway

Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb-induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. These findings also demonstrate a general role for NFAT5 in TLR- and MTb-mediated control of gene expression

Medical Evidence of Human Rights Violations against Non-Arabic-Speaking Civilians in Darfur: A Cross-Sectional Study

Alexander Tsai and colleagues review medical records from the Amel Centre, Sudan, to assess consistency between recorded medical evidence and patient reports of human rights violations by the Government of Sudan and Janjaweed forces

Long-Term Relationships between Synaptic Tenacity, Synaptic Remodeling, and Network Activity

Long term time-lapse imaging reveals that individual synapses undergo significant structural remodeling not only when driven by activity, but also when network activity is absent, raising questions about how reliably individual synapses maintain connections

Prevalence of Torture Survivors Among Foreign-Born Patients Presenting to an Urban Ambulatory Care Practice

BACKGROUND: The prevalence of torture among foreign-born patients presenting to urban medical clinics is not well documented. OBJECTIVE: To determine the prevalence of torture among foreign-born patients presenting to an urban primary care practice. DESIGN: A survey of foreign-born patients. PATIENTS: Foreign-born patients, age ≥ 18, presenting to the Primary Care Clinic at Boston Medical Center. MEASUREMENTS: Self-reported history of torture as defined by the UN, and history of prior disclosure of torture. RESULTS: Of the 308 eligible patients, 88 (29%) declined participation, and 78 (25%) were not included owing to lack of a translator. Participants had a mean age of 47 years (range 19 to 76), were mostly female (82/142, 58%), had been in the United States for an average of 14 years (range 1 month to 53 years), and came from 35 countries. Fully, 11% (16/142, 95 percent confidence interval 7% to 18%) of participants reported a history of torture that was consistent with the UN definition of torture. Thirty-nine percent (9/23) of patients reported that their health care provider asked them about torture. While most patients (15/23, 67%) reported discussing their experience of torture with someone in the United States, 8 of 23 (33%) reported that this survey was their first disclosure to anyone in the United States. CONCLUSION: Among foreign-born patients presenting to an urban primary care center, approximately 1 in 9 met the definition established by the UN Convention Against Torture. As survivors of torture may have significant psychological and physical sequelae, these data underscore the necessity for primary care physicians to screen for a torture history among foreign-born patients

Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria.

Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage