The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutation-positive and mutation-negative subtypes, ...timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F- essential thrombocythemia do not commonly progress to become V617F+. Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F+. We also investigated the existence of a “pre-JAK2” phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F+ granulocytes. Our results demonstrate that inherent XCIP variability between granulocytes and T cells produces a systematically biased pattern of results that may be misinterpreted as evidence for an excess of clonally derived granulocytes, an observation that limits the utility of XCIP analysis in this context. Lastly, we studied 4 patients with V617F+ myeloproliferative disorders who subsequently developed acute myeloid leukemia. In 3 patients the leukemic cells were V617F-, suggesting that in these patients the leukemia arose in a V617F- cell.
Dietary bacteriophages potentially can serve as a step to reduce Salmonella contamination of feed through direct lysis of the bacteria. However, poultry producers commonly vaccinate with live ...Salmonella vaccines, which could potentially be lysed by dietary bacteriophages. The objective of this study was to evaluate if dietary bacteriophages impacted the colonization of a live Salmonella vaccine. A total of 210 day-of-hatch Ross male broiler chicks were divided into 3 treatments consisting of 2 replicate per treatment. Each replicate contained 35 birds. T1 was the challenge control, given no Salmonella vaccine, T2 was challenged and given Salmonella vaccine and T3 was challenged, given Salmonella vaccine as well as dietary bacteriophage. Salmonella vaccine was administered day of hatch. On d 3, four birds/pen were sampled for Salmonella vaccine colonization of ceca and liver/spleen. The remaining birds were challenged with 5 × 107 CFU of nalidixic acid- resistant Salmonella enteritidis (S.E.). On d 28, ten birds/replicate were sampled via cloaca swabs to culture for S.E. On d 42, the trial was terminated, birds were weighed, and performance was calculated. In addition, 15 birds/replicate were sampled for cecal cultures of S.E.
On d 3, T1 had 0% vaccine strain isolated, and significantly lower (P = 0.009) cecal prevalence compared with T2 (75%) and T3 (38%) being intermediate. T1 (0%) had significantly lower liver/spleen vaccine strain prevalence (P = 0.002) compared with T3 (88%) and T2 (63%) being intermediate. No significant differences (P > 0.05) were observed among treatments in Salmonella prevalence in d 28 cloacal swabs. No significant differences (P > 0.05) were observed in d 42 cecal Salmonella prevalence between all treatments. No significant differences in bird weight were observed between treatments d 0 to 42 (P > 0.05). However, T2 and T3 had lower mortality and adjusted feed conversion ratio (FCR; P < 0.05) compared with T1. Therefore, the dietary bacteriophage did not interfere with colonization or protection afforded by the live Salmonella vaccine.
Anthropogenic climate change is predicted to severely impact the global hydrological cycle
, particularly in tropical regions where agriculture-based economies depend on monsoon rainfall
. In the ...Horn of Africa, more frequent drought conditions in recent decades
contrast with climate models projecting precipitation to increase with rising temperature
. Here we use organic geochemical climate-proxy data from the sediment record of Lake Chala (Kenya and Tanzania) to probe the stability of the link between hydroclimate and temperature over approximately the past 75,000 years, hence encompassing a sufficiently wide range of temperatures to test the 'dry gets drier, wet gets wetter' paradigm
of anthropogenic climate change in the time domain. We show that the positive relationship between effective moisture and temperature in easternmost Africa during the cooler last glacial period shifted to negative around the onset of the Holocene 11,700 years ago, when the atmospheric carbon dioxide concentration exceeded 250 parts per million and mean annual temperature approached modern-day values. Thus, at that time, the budget between monsoonal precipitation and continental evaporation
crossed a tipping point such that the positive influence of temperature on evaporation became greater than its positive influence on precipitation. Our results imply that under continued anthropogenic warming, the Horn of Africa will probably experience further drying, and they highlight the need for improved simulation of both dynamic and thermodynamic processes in the tropical hydrological cycle.
Pseudomonas aeruginosa clinical isolates demonstrating difficult-to-treat resistance (DTR) and multidrug-resistant (MDR) phenotypes were evaluated by broth microdilution. Susceptibility was lower for ...all antimicrobials versus DTR relative to MDR isolates. Ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-relebactam susceptibility was 35.9%, 64.5%, and 47.0% for DTR isolates and 60.5%, 80.6%, and 71.5% for MDR isolates.
Continuous spike and wave of sleep with encephalopathy (CSWS) is a rare and severe developmental electroclinical epileptic encephalopathy characterized by seizures, abundant sleep activated ...interictal epileptiform discharges, and cognitive regression or deceleration of expected cognitive growth. The cause of the cognitive symptoms is unknown, and efforts to link epileptiform activity to cognitive function have been unrevealing. Converging lines of evidence implicate thalamocortical circuits in these disorders. Sleep spindles are generated and propagated by the same thalamocortical circuits that can generate spikes and, in healthy sleep, support memory consolidation. As such, sleep spindle deficits may provide a physiologically relevant mechanistic biomarker for cognitive dysfunction in epileptic encephalopathies.
We describe the longitudinal course of a child with CSWS with initial cognitive regression followed by dramatic cognitive improvement after treatment. Using validated automated detection algorithms, we analyzed electroencephalograms for epileptiform discharges and sleep spindles alongside contemporaneous neuropsychological evaluations over the course of the patient's disease. We found that sleep spindles increased dramatically with high-dose diazepam treatment, corresponding with marked improvements in cognitive performance. We also found that the sleep spindle rate was anticorrelated to spike rate, consistent with a competitively shared underlying thalamocortical circuitry.
Epileptic encephalopathies are challenging electroclinical syndromes characterized by combined seizures and a deceleration or regression in cognitive skills over childhood. This report identifies thalamocortical circuit dysfunction in a case of epileptic encephalopathy and motivates future investigations of sleep spindles as a biomarker of cognitive function and a potential therapeutic target in this challenging disease.
Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. ...Here, we show increased axon initial segment length in CA1 of the Fmr1−/y mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1−/y neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1−/y mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons.
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•Fmr1−/y neurons in CA1 are hyperexcitable, with longer axon initial segments•Pyramidal cells respond more strongly to prolonged depolarization in Fmr1−/y mice•Temporoammonic input to CA1 is reduced in the Fmr1−/y mouse•Cellular hyperexcitability equalizes neuron firing to reduced temporoammonic input
Neuronal hyperexcitability may underlie many features of fragile X syndrome. Booker et al. show that in hippocampal area CA1, pyramidal neurons are hyperexcitable, with longer axon initial segments. This hyperexcitability helps neurons to overcome a strong reduction in synaptic input from the entorhinal cortex, thus homeostatically regulating local network outputs.
MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling ...approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data.
We recruited patients with primary glioblastoma undergoing image-guided biopsies and preoperative imaging, including contrast-enhanced MR imaging, dynamic susceptibility contrast MR imaging, and diffusion tensor imaging. We calculated relative cerebral blood volume from DSC-MR imaging and mean diffusivity and fractional anisotropy from DTI. Following image coregistration, we assessed tumor cell density for each biopsy and identified corresponding localized MR imaging measurements. We then explored a range of univariate and multivariate predictive models of tumor cell density based on MR imaging measurements in a generalized one-model-fits-all approach. We then implemented both univariate and multivariate individualized transfer learning predictive models, which harness the available population-level data but allow individual variability in their predictions. Finally, we compared Pearson correlation coefficients and mean absolute error between the individualized transfer learning and generalized one-model-fits-all models.
Tumor cell density significantly correlated with relative CBV (
= 0.33,
< .001), and T1-weighted postcontrast (
= 0.36,
< .001) on univariate analysis after correcting for multiple comparisons. With single-variable modeling (using relative CBV), transfer learning increased predictive performance (
= 0.53, mean absolute error = 15.19%) compared with one-model-fits-all (
= 0.27, mean absolute error = 17.79%). With multivariate modeling, transfer learning further improved performance (
= 0.88, mean absolute error = 5.66%) compared with one-model-fits-all (
= 0.39, mean absolute error = 16.55%).
Transfer learning significantly improves predictive modeling performance for quantifying tumor cell density in glioblastoma.
By linking iterative learning and knowledge generation with power-sharing, adaptive co-management (ACM) provides a potential solution to resolving complex social-ecological problems. In this paper we ...evaluate ACM as a mechanism for resolving conservation conflict using a case study in Scotland, where seal and salmon fishery stakeholders have opposing and entrenched objectives. ACM emerged in 2002, successfully resolving this long-standing conflict. Applying evaluation approaches from the literature, in 2011 we interviewed stakeholders to characterise the evolution of ACM, and factors associated with its success over 10 years. In common with other ACM cases, triggers for the process were shifts in slow variables controlling the system (seal and salmon abundance, public perceptions of seal shooting), and exogenous shocks (changes in legal mandates, a seal disease outbreak). Also typical of ACM, three phases of evolution were evident: emerging local leadership preparing the system for change, a policy window of opportunity, and stakeholder partnerships building the resilience of the system. Parameters maintaining ACM were legal mechanisms and structures, legal power held by government, and the willingness of all stakeholders to reach a compromise and experiment with an alternative governance approach. Results highlighted the critical role of government power and support in resolving conservation conflict, which may constrain the extent of local stakeholder-driven ACM. The evaluation also demonstrated how, following perceived success, the trajectory of ACM has shifted to a ‘stakeholder apathy’ phase, with declining leadership, knowledge exchange, stakeholder engagement, and system resilience. We discuss remedial actions required to revive the process, and the importance of long term government resourcing and alternative financing schemes for successful conflict resolution. Based on the results we present a generic indicator framework and participatory method for the longitudinal evaluation of ACM applied to conservation conflict resolution.
•Adaptive co-management has emerged from conflict between seal and salmon interests.•Theoretical evaluation frameworks were tested using a participatory method.•Resource crises, legislation and opposition to seal shooting triggered the process.•Government legal power and long term resourcing is critical to conflict mitigation.•An integrated indicator framework is presented for future evaluation of conflict.
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