Animal and plant microbiomes encompass diverse microbial communities that colonize every accessible host tissue. These microbiomes enhance host functions, contributing to host health and fitness. A ...novel approach to improve animal and plant fitness is to artificially select upon microbiomes, thus engineering evolved microbiomes with specific effects on host fitness. We call this engineering approach host-mediated microbiome selection, because this method selects upon microbial communities indirectly through the host and leverages host traits that evolved to influence microbiomes. In essence, host phenotypes are used as probes to gauge and manipulate those microbiome functions that impact host fitness. To facilitate research on host-mediated microbiome engineering, we explain and compare the principal methods to impose artificial selection on microbiomes; discuss advantages and potential challenges of each method; offer a skeptical appraisal of each method in light of these potential challenges; and outline experimental strategies to optimize microbiome engineering. Finally, we develop a predictive framework for microbiome engineering that organizes research around principles of artificial selection, quantitative genetics, and microbial community-ecology.
Mutualisms are of fundamental importance in all ecosystems but their very existence poses a series of challenging evolutionary questions. Recently, the application of molecular analyses combined with ...theoretical advances have transformed our understanding of many specific systems, thereby contributing to the possibility of a more general understanding of the factors that influence mutualisms.
Analysis of high‐resolution data offers greater opportunity to understand the nature of data variability, behaviours, trends and to detect small changes. Climate studies often require complete time ...series data which, in the presence of missing data, means imputation must be undertaken. Research on the imputation of high‐resolution temporal climate time series data is still at an early phase. In this study, multiple approaches to the imputation of missing values were evaluated, including a structural time series model with Kalman smoothing, an autoregressive integrated moving average (ARIMA) model with Kalman smoothing and multiple linear regression. The methods were applied to complete subsets of data from 12 month time series of hourly temperature, humidity and wind speed data from four locations along the coast of Western Australia. Assuming that observations were missing at random, artificial gaps of missing observations were studied using a five‐fold cross‐validation methodology with the proportion of missing data set to 10%. The techniques were compared using the pooled mean absolute error, root mean square error and symmetric mean absolute percentage error. The multiple linear regression model was generally the best model based on the pooled performance indicators, followed by the ARIMA with Kalman smoothing. However, the low error values obtained from each of the approaches suggested that the models competed closely and imputed highly plausible values. To some extent, the performance of the models varied among locations. It can be concluded that the modelling approaches studied have demonstrated suitability in imputing missing data in hourly temperature, humidity and wind speed data and are therefore recommended for application in other fields where high‐resolution data with missing values are common.
Multiple linear regression with modified error assumptions and univariate time series models by state‐space methods impute highly plausible values for missing observations in high‐resolution temporal temperature, humidity and wind speed time series data.
Aims : To standardize the histopathological assessment of synovial membrane specimens in order to contribute to the diagnostics of rheumatic and non‐rheumatic joint diseases.
Methods and results : ...Three features of chronic synovitis (enlargement of lining cell layer, cellular density of synovial stroma, leukocytic infiltrate) were semiquantitatively evaluated (from 0, absent to 3, strong) and each feature was graded separately. The sum provided the synovitis score, which was interpreted as follows: 0–1, no synovitis; 2–4, low‐grade synovitis; 5–9, high‐grade synovitis. Five hundred and fifty‐nine synovectomy specimens were graded by two independent observers. Clinical diagnoses were osteoarthrosis (n = 212), post‐traumatic arthritis (n = 21), rheumatoid arthritis (n = 246), psoriatic arthritis (n = 22), reactive arthritis (n = 9), as well as controls (n = 49) from autopsies of patients without joint damage. Median synovitis scores when correlated with clinical diagnoses were: controls 1.0, osteoarthritis 2.0, post‐traumatic arthritis 2.0, psoriatic arthritis 3.5, reactive arthritis 5.0 and rheumatoid arthritis 5.0. The scores differed significantly between most disease groups, especially between degenerative and rheumatic diseases. A high‐grade synovitis was strongly associated with rheumatic joint diseases (P < 0.001, sensitivity 61.7%, specificity 96.1%). The correlation between the two observers was high (r = 0.941).
Conclusion : The proposed synovitis score is based on well‐defined, reproducible histopathological criteria and may contribute to diagnosis in rheumatic and non‐rheumatic joint diseases.
The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is crucial for normal development of granulocytes. Various mechanisms have been identified how CEBPA function is dysregulated in ...patients with acute myeloid leukemia (AML). In particular, dominant-negative mutations located either at the N- or the C terminus of the CEBPA gene are observed in roughly 10% of AML patients, either in the combination on separate alleles or as sole mutation. Clinically significant complexity exists among AML with CEBPA mutations, and patients with double CEBPA mutations seem to have a more favorable course of the disease than patients with a single mutation. In addition, myeloid precursor cells of healthy carriers with a single germ-line CEBPA mutation evolve to overt AML by acquiring a second sporadic CEBPA mutation. This review summarizes recent reports on dysregulation of CEBPA function at various levels in human AML and therapeutic concepts targeting correction of CEBPA activity. The currently available data are persuasive evidence that impaired CEBPA function contributes directly to the development of AML, whereas restoring CEBPA function represents a promising target for novel therapeutic strategies in AML.
The transcription factor CCAAT/enhancer binding protein-alpha (CEBPA) is crucial for normal myeloid differentiation. Mutations in the CEBPA gene are found in subsets of patients with acute myeloid ...leukemia (AML). Recently, three families were reported in whom several family members had germline CEBPA mutations and subsequently developed AML. Whereas familial AML is considered a rare event, the frequency of CEBPA germline mutations in AML is not known.
In this study, we screened 187 consecutive AML patients for CEBPA mutations at diagnosis. We detected 18 patients (9.6%) with CEBPA mutations. We then analyzed remission samples and constitutive DNA from these patients.
We found that two (11.1%) of 18 AML patients with CEBPA mutations carried a germline N-terminal frameshift CEBPA mutation. Interestingly, additional members in the families of both of these patients have been affected by AML, and the germline CEBPA mutations were also observed in these patients. Additional somatic mutations in AML patients with germline CEBPA mutations in the two families comprised in-frame C-terminal CEBPA mutations in two patients, two nonsilent CEBPA point mutations in one patient, and monosomy 7 in one patient.
This study shows, for the first time to our knowledge, that germline CEBPA mutations are frequently observed among AML patients with CEBPA mutations. Including the families with germline CEBPA mutations reported previously, additional somatic CEBPA mutations represent a frequent second event in AML with germline CEBPA mutations. Our data strongly indicate that germline CEBPA mutations predispose to AML and that additional somatic CEBPA mutations contribute to the development of the disease.
Prognosis for
-ITD positive acute myeloid leukemia with high allelic ratio (>0.5) is poor, particularly in relapse, refractory to or unfit for intensive treatment, thus highlighting an unmet need for ...novel therapeutic approaches. The combined use of compounds targeting both the mutated FLT3 receptor and cellular p53 inhibitors might be a promising treatment option for this poor risk leukemia subset. We therefore assessed MDM2 and FLT3 inhibitors as well as cytotoxic compounds used for conventional induction treatment as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. Acute myeloid leukemia cells represented all major morphologic and molecular subtypes with normal karyotype, including
-ITD (>0.5) and FLT3 wild type,
mutant and
wild type, as well as TP53 mutant and
wild type cell lines. Acute myeloid leukemia cells with mutated or deleted
were resistant to MDM2- and
-inhibitors.
-ITD positive
wild type acute myeloid leukemia cells were significantly more susceptible to FLT3-inhibitors than
-ITD negative
wild type cells. The presence of a
mutation reduced the susceptibility of
wild type acute myeloid leukemia cells to the MDM2 inhibitor NVP-HDM201. Moreover, the combined use of MDM2- and
-inhibitors was superior to single agent treatment, and the combination of midostaurin and NVP-HDM201 was as specific and effective against
-ITD positive TP53 wild type cells as the combination of midostaurin with conventional induction therapy. In summary, the combined use of the MDM2 inhibitor NVP-HDM201 and the
inhibitor midostaurin was a most effective and specific treatment to target
and
wild type acute myeloid leukemia cells with high allelic
-ITD ratio. These data suggest that the combined use of NVP-HDM201 and midostaurin might be a promising treatment option particularly in
-ITD positive acute myeloid leukemia relapsed or refractory to conventional therapy.
CCAAT/enhancer binding protein alpha (CEBPA) mutations in AML are associated with favourable prognosis and are divided into N- and C-terminal mutations. The majority of AML patients have both types ...of mutations. We assessed the prognostic significance of single (n=7) and double (n=12) CEBPA mutations among 224 AML patients. Double CEBPA mutations conferred a decisively favourable overall (P=0.006) and disease-free survival (P=0.013). However, clinical outcome of patients with single CEBPA mutations was not different from CEBPA wild-type patients. In a multivariable analysis, only double -- but not single -- CEBPA mutations were identified as independent prognostic factors. These findings indicate heterogeneity within AML patients with CEBPA mutations.
Background
Diagnostic tests in patients with Hymenoptera venom allergy are frequently positive to venoms of both honey bee and wasp (Vespula). Component‐resolved analysis with recombinant ...species‐specific major allergens (rSSMA) may help to distinguish true double sensitization from crossreactivity.
Methods
Included were 121 patients with systemic allergic reactions to Hymenoptera stings, 76 with double positivity of serum‐specific IgE (sIgE) to both venoms, 45 with single positivity to bee or wasp venom, and 32 controls without history of systemic reactions to Hymenoptera stings and no sIgE to whole venoms. In venom‐allergic patients and controls, sIgE to rSSMA Api m 1 of bee venom and to Ves v 1 and Ves v 5 of wasp venom were tested by ImmunoCAP.
Results
Only 47% of 76 patients with double positivity to whole venoms reacted also to rSSMA of both species. Specificity of sIgE to the 3 rSSMA was very high, with no sIgE to rSSMA of the other species in single‐positive venom‐allergic patients and only one control with low sIgE to Ves v 1. All wasp‐allergic single‐positive patients had sIgE to Ves v 5 and/or Ves v 1, and 78.3% of single‐positive bee venom–allergic patients had sIgE to Api m 1.
Conclusion
Specificity of sIgE to rSSMA of both species is excellent. Sensitivity of sIgE to rSSMA was optimal for wasp venom. Sensitivity of bee venom Api m 1 could be increased by adding rSSMA of other important bee venom allergens.
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