MYD88 L265P mutations identify a prognostic gene expression signature and a pathway for targeted inhibition in CLL.

The L265P somatic mutation in the Myeloid Differentiation Primary Response 88 (MYD88) gene is a recurrent mutation in chronic lymphocytic leukaemia (CLL). This mutation has functional effects in various haematological malignancies but its role in CLL remains to be fully elucidated. Here, we report that MYD88 L265P mutations are associated with mutated immunoglobulin heavy-chain gene (IGHV-M) status and that among IGHV-M patients, the presence of MYD88 L265P is associated with younger age at diagnosis. Using microarray and RNA-Seq gene expression analysis, we further observe that the MYD88 L265P mutation is associated with a distinctive gene expression signature that predicts both failure-free survival and overall survival. This association was validated in an independent cohort of patients. To determine whether MYD88 L265P mutations can be therapeutically exploited in CLL, we treated primary cells with an inhibitor of interleukin 1 receptor-associated kinase 4 (IRAK4), a critical effector of the MYD88 pathway. IRAK4 inhibition decreased downstream nuclear factor-κB signalling and cell viability in CLL cells, indicating the potential of the MYD88 pathway as a therapeutic target in CLL.

Mathematical modelling and evaluation of the different routes of transmission of lumpy skin disease virus.

Lumpy skin disease (LSD) is a severe viral disease of cattle. Circumstantial evidence suggests that the virus is transmitted mechanically by blood-feeding arthropods. We compared the importance of transmission via direct and indirect contact in field conditions by using mathematical tools. We analyzed a dataset collected during the LSD outbreak in 2006 in a large dairy herd, which included ten separated cattle groups. Outbreak dynamics and risk factors for LSD were assessed by a transmission model. Transmission by three contact modes was modelled; indirect contact between the groups within a herd, direct contact or contact via common drinking water within the groups and transmission by contact during milking procedure. Indirect transmission was the only parameter that could solely explain the entire outbreak dynamics and was estimated to have an overall effect that was over 5 times larger than all other possible routes of transmission, combined. The R0 value induced by indirect transmission per the presence of an infectious cow for 1 day in the herd was 15.7, while the R0 induced by direct transmission was 0.36. Sensitivity analysis showed that this result is robust to a wide range of assumptions regarding mean and standard deviation of incubation period and regarding the existence of sub-clinically infected cattle. These results indicate that LSD virus spread within the affected herd could hardly be attributed to direct contact between cattle or contact through the milking procedure. It is therefore concluded that transmission mostly occurs by indirect contact, probably by flying, blood-sucking insects. This has important implications for control of LSD.

Sleep-wake transitions in premature neonates predict early development.

OBJECTIVE: To identify patterns of sleep-wake transitions in the neonatal period that might differentiate premature infants who would show better or worse outcomes in multiple developmental domains across the first 5 years of life. METHODS: Participants were 143 low birth weight premature infants (mean birth weight: 1482 g; mean gestational age [GA]: 31.82 weeks). Sleep states were observed at a GA of 37 weeks in 10-second epochs over 4 consecutive evening hours and were analyzed through mathematical clustering. Neurobehavioral maturation was evaluated with the Neonatal Behavior Assessment Scale at discharge, emotional regulation was assessed during infant-mother and infant-father interactions at 3 and 6 months, cognitive development was measured at 6, 12, and 24 months, and verbal IQ, executive functions, and symbolic competence were tested at 5 years. RESULTS: Three types of state-transition patterns were identified, and no differences in birth weight, GA, or medical risk between the 3 groups were found. Infants whose sleep-state transitions were mainly characterized by shifts between quiet sleep and wakefulness exhibited the best development, including greater neonatal neuromaturation, less negative emotionality, better cognitive development, and better verbal, symbolic, and executive competences at 5 years. In comparison, infants who cycled mainly between states of high arousal, such as active sleep and cry, or between short episodes of active and quiet sleep showed poorer outcomes. CONCLUSIONS: Defining sleep organization on the basis of transitions between states proved useful for identifying risk and resilience indicators in neonatal behavior to predict trajectories of neurobehavioral, emotional, and cognitive growth.

Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees.

MOTIVATION: B cells responding to antigenic stimulation can fine-tune their binding properties through a process of affinity maturation composed of somatic hypermutation, affinity-selection and clonal expansion. The mutation rate of the B cell receptor DNA sequence, and the effect of these mutations on affinity and specificity, are of critical importance for understanding immune and autoimmune processes. Unbiased estimates of these properties are currently lacking due to the short time-scales involved and the small numbers of sequences available. RESULTS: We have developed a bioinformatic method based on a maximum likelihood analysis of phylogenetic lineage trees to estimate the parameters of a B cell clonal expansion model, which includes somatic hypermutation with the possibility of lethal mutations. Lineage trees are created from clonally related B cell receptor DNA sequences. Important links between tree shapes and underlying model parameters are identified using mutual information. Parameters are estimated using a likelihood function based on the joint distribution of several tree shapes, without requiring a priori knowledge of the number of generations in the clone (which is not available for rapidly dividing populations in vivo). A systematic validation on synthetic trees produced by a mutating birth-death process simulation shows that our estimates are precise and robust to several underlying assumptions. These methods are applied to experimental data from autoimmune mice to demonstrate the existence of hypermutating B cells in an unexpected location in the spleen.