Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1.

SummaryBlimp-1 is considered an essential regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. We show here that Rag1−/− mice reconstituted with fetal liver cells homozygous for a DNA-binding-deficient mutant of Prdm1 (the gene encoding Blimp-1) lack a defined plasma-cell compartment, yet show detectable amounts of all immunoglobulin isotypes. In vitro analysis revealed that Blimp-1 is not required for the initiation of antibody secretion but is essential for subsequent high immunoglobulin production. Blimp-1-independent differentiation was blocked at a preplasmablast stage characterized by decreased Pax5 expression and the activation of plasma-cell genes. Analysis of Blimp-1-sufficient differentiation revealed a phase prior to Blimp-1 expression in which several genes normally repressed by Pax5 are re-expressed, suggesting that plasma-cell differentiation is initiated by the inhibition of Pax5 function. Our results indicate that full plasma-cell differentiation but not commitment to the plasma-cell fate requires the expression of functional Blimp-1

Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1.

SummaryBlimp-1 is considered an essential regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. We show here that Rag1−/− mice reconstituted with fetal liver cells homozygous for a DNA-binding-deficient mutant of Prdm1 (the gene encoding Blimp-1) lack a defined plasma-cell compartment, yet show detectable amounts of all immunoglobulin isotypes. In vitro analysis revealed that Blimp-1 is not required for the initiation of antibody secretion but is essential for subsequent high immunoglobulin production. Blimp-1-independent differentiation was blocked at a preplasmablast stage characterized by decreased Pax5 expression and the activation of plasma-cell genes. Analysis of Blimp-1-sufficient differentiation revealed a phase prior to Blimp-1 expression in which several genes normally repressed by Pax5 are re-expressed, suggesting that plasma-cell differentiation is initiated by the inhibition of Pax5 function. Our results indicate that full plasma-cell differentiation but not commitment to the plasma-cell fate requires the expression of functional Blimp-1

Transcriptome and proteome profiling reveals stress-induced expression signatures of imiquimod-treated Tasmanian devil facial tumor disease (DFTD) cells

As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimodactivates tumor regression via stimulation of immune cell infiltration and cytotoxicresponses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells invitro, but a role for these effects in imiquimod-induced tumor regression remainsundefined. We previously demonstrated that cell lines derived from devil facial tumordisease (DFTD), a transmissible cancer threatening the survival of the Tasmaniandevil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis. In thisstudy, the pro-apoptotic effects of imiquimod in DFTD have been investigated usingRNA-sequencing and label-free quantitative proteomics. This analysis revealedthat changes to gene and protein expression in imiquimod treated DFTD cells areconsistent with the onset of oxidative and endoplasmic reticulum stress responses,and subsequent activation of the unfolded protein response, autophagy, cell cyclearrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways,providing a direct mechanism by which this drug may increase tumor susceptibilityto immune cytotoxicity in vivo. Our study has provided the first global analysis ofimiquimod-induced effects in any tumor cell line. These findings have highlightedthe potential of cell stress pathways as therapeutic targets in DFTD, and will allowfor improved mechanistic use of imiquimod as a therapy in both the Tasmanian deviland human cancers

Relations Among Anhedonia, Reinforcement Learning, and Global Functioning in Help-seeking Youth

Dysfunction in the neural circuits underlying salience signaling is implicated in symptoms of psychosis and may predict conversion to a psychotic disorder in youth at clinical high risk (CHR) for psychosis. Additionally, negative symptom severity, including consummatory and anticipatory aspects of anhedonia, may predict functional outcome in individuals with schizophrenia-spectrum disorders. However, it is unclear whether anhedonia is related to the ability to attribute incentive salience to stimuli (through reinforcement learning [RL]) and whether measures of anhedonia and RL predict functional outcome in a younger, help-seeking population. We administered the Salience Attribution Test (SAT) to 33 participants who met criteria for either CHR or a recent-onset psychotic disorder and 29 help-seeking youth with nonpsychotic disorders. In the SAT, participants must identify relevant and irrelevant stimulus dimensions and be sensitive to different reinforcement probabilities for the 2 levels of the relevant dimension ("adaptive salience"). Adaptive salience attribution was positively related to both consummatory pleasure and functioning in the full sample. Analyses also revealed an indirect effect of adaptive salience on the relation between consummatory pleasure and both role (αβ = .22, 95% CI = 0.02, 0.48) and social functioning (αβ = .14, 95% CI = 0.02, 0.30). These findings suggest a distinct pathway to poor global functioning in help-seeking youth, via impaired reward sensitivity and RL

Letter processing and font information during reading: beyond distinctiveness, where vision meets design

Letter identification is a critical front end of the reading process. In general, conceptualizations of the identification process have emphasized arbitrary sets of distinctive features. However, a richer view of letter processing incorporates principles from the field of type design, including an emphasis on uniformities across letters within a font. The importance of uniformities is supported by a small body of research indicating that consistency of font increases letter identification efficiency. We review design concepts and the relevant literature, with the goal of stimulating further thinking about letter processing during reading

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

PURPOSE:The activating mutation AKT1 E17K occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1 E17K-mutant ER+ MBC patients. PATIENTS AND METHODS:Patients with an AKT1 E17K mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A 50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]). CONCLUSIONS:Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1 E17K-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination

Multiple var2csa-Type PfEMP1 Genes Located at Different Chromosomal Loci Occur in Many Plasmodium falciparum Isolates

BACKGROUND:The var2csa gene encodes a Plasmodium falciparum adhesion receptor which binds chondroitin sulfate A (CSA). This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates. In isolates 3D7, FCR3/It4 and HB3, var2csa is transcribed from a sub-telomeric position on the left arm of chromosome 12, but it is not known if this location is conserved in all parasites. Genome sequencing indicates that the var2csa gene is duplicated in HB3, but whether this is true in natural populations is uncertain. METHODOLOGY/PRINCIPAL FINDINGS:To assess global variation in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant women and from the peripheral circulation of other malaria patients. Sequence analysis, gene mapping and copy number quantitation in P.falciparum isolates indicate that there are at least two loci and that both var2csa-like genes can be transcribed. All VAR2CSA DBL2X domains fall into one of two distinct phylogenetic groups possessing one or the other variant of a large (approximately 26 amino acid) dimorphic motif, but whether either motif variant is linked to a specific locus is not known. CONCLUSIONS/SIGNIFICANCE:Two or more related but distinct var2csa-type PfEMP1/var genes exist in many P. falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria