A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer.

Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC

The combined effect of branch position, temperature, and VPD on gas exchange and water-use efficiency of Norway spruce

The impact of climate change on the physiological processes of Norway spruce in Central Europe is a significant concern. The increased temperature and evaporative demand associated with climate change may negatively affect its photosynthesis and carbon-water balance. This study tests the combined effect of branch position, temperature (T) and water vapour pressure deficit (VPD) on net photosynthetic rate (P$_N$), water vapour stomatal conductance (g$_s$), and intrinsic water-use efficiency (WUE$_i$) of Norway spruce. More than 11 000 gas-exchange measurements during the summer of 2018 revealed that branch position significantly affects gas exchange and WUE$_i$ of juvenile Norway spruce trees. Northern branches showed on average 21% increased P$_N$, 35% higher g$_s$, and 8% lower WUE$_i$ compared to the southern branches (across T and VPD conditions). The P$_N$ and g$_s$ differences between the branches were temperature- and VPD-dependent. We observed the negative impact of raising temperature on gas exchange and WUE$_i$ for both treatments, with a 40°C threshold causing a rapid decline in WUE$_i$. Variability of the southern branches\u27 WUE$_i$ at 42°C was abruptly increased due to the decoupling of P$_N$ and g$_s$ (low P$_N$, high g$_s$). Surprisingly, raising VPD showed no significant impact on WUE$_i$ of Norway spruce. The results of this study provide necessary information for upscaling and process-based modelling of whole-crown gas exchange. Moreover, experimental studies of gas exchange should take into consideration the branch position effect to prevent possible bias errors

How often should we monitor for reliable detection of atrial fibrillation recurrence? Efficiency considerations and implications for study design

OBJECTIVE: Although atrial fibrillation (AF) recurrence is unpredictable in terms of onset and duration, current intermittent rhythm monitoring (IRM) diagnostic modalities are short-termed and discontinuous. The aim of the present study was to investigate the necessary IRM frequency required to reliably detect recurrence of various AF recurrence patterns. METHODS: The rhythm histories of 647 patients (mean AF burden: 12±22% of monitored time; 687 patient-years) with implantable continuous monitoring devices were reconstructed and analyzed. With the use of computationally intensive simulation, we evaluated the necessary IRM frequency to reliably detect AF recurrence of various AF phenotypes using IRM of various durations. RESULTS: The IRM frequency required for reliable AF detection depends on the amount and temporal aggregation of the AF recurrence (p<0.0001) as well as the duration of the IRM (p<0.001). Reliable detection (>95% sensitivity) of AF recurrence required higher IRM frequencies (>12 24-hour; >6 7-day; >4 14-day; >3 30-day IRM per year; p<0.0001) than currently recommended. Lower IRM frequencies will under-detect AF recurrence and introduce significant bias in the evaluation of therapeutic interventions. More frequent but of shorter duration, IRMs (24-hour) are significantly more time effective (sensitivity per monitored time) than a fewer number of longer IRM durations (p<0.0001). CONCLUSIONS: Reliable AF recurrence detection requires higher IRM frequencies than currently recommended. Current IRM frequency recommendations will fail to diagnose a significant proportion of patients. Shorter duration but more frequent IRM strategies are significantly more efficient than longer IRM durations. CLINICAL TRIAL REGISTRATION URL: Unique identifier: NCT00806689

Penumbra Pattern Assessment in Acute Stroke Patients: Comparison of Quantitative and Non-Quantitative Methods in Whole Brain CT Perfusion

Background and Purpose: While penumbra assessment has become an important part of the clinical decision making for acute stroke patients, there is a lack of studies measuring the reliability and reproducibility of defined assessment techniques in the clinical setting. Our aim was to determine reliability and reproducibility of different types of three-dimensional penumbra assessment methods in stroke patients who underwent whole brain CT perfusion imaging (WB-CTP). Materials and Methods: We included 29 patients with a confirmed MCA infarction who underwent initial WB-CTP with a scan coverage of 100 mm in the z-axis. Two blinded and experienced readers assessed the flow-volume-mismatch twice and in two quantitative ways: Performing a volumetric mismatch analysis using OsiriX imaging software (MMVOL) and visual estimation of mismatch (MMEST). Complementarily, the semiquantitative Alberta Stroke Programme Early CT Score for CT perfusion was used to define mismatch (MMASPECTS). A favorable penumbral pattern was defined by a mismatch of >= 30% in combination with a cerebral blood flow deficit of = 1, respectively. Inter-and intrareader agreement was determined by Kappa-values and ICCs. Results: Overall, MMVOL showed considerably higher inter-/intrareader agreement (ICCs: 0.751/0.843) compared to MMEST (0.292/0.749). In the subgroup of large (>= 50 mL) perfusion deficits, inter-and intrareader agreement of MMVOL was excellent (ICCs: 0.961/0.942), while MMEST interreader agreement was poor (0.415) and intrareader agreement was good (0.919). With respect to penumbra classification, MMVOL showed the highest agreement (interreader agreement: 25 agreements/4 non-agreements/kappa: 0.595;intrareader agreement 27/2/0.833), followed by MMEST (22/7/0.471;23/6/0.577), and MMASPECTS (18/11/0.133;21/8/0.340). Conclusion: The evaluated approach of volumetric mismatch assessment is superior to pure visual and ASPECTS penumbra pattern assessment in WB-CTP and helps to precisely judge the extent of 3-dimensional mismatch in acute stroke patients

The morphology of average solar flare time profiles from observations of the Sun's lower atmosphere

We study the decay phase of solar flares in several spectral bands using a method basedon that successfully applied to white light flares observed on an M4 dwarf. We selectedand processed 102 events detected in the Sun-as-a-star flux obtained with SDO/AIAimages in the 1600 ̊A and 304 ̊A channels and 54 events detected in the 1700 ̊A channel.The main criterion for the selection of time profiles was a slow, continuous flux decaywithout significant new bursts. The obtained averaged time profiles were fitted withanalytical templates, using different time intervals, that consisted of a combination oftwo independent exponents or a broken power law. The average flare profile observedin the 1700 ̊A channel decayed more slowly than the average flare profile observed onthe M4 dwarf. As the 1700 ̊A emission is associated with a similar temperature to thatusually ascribed to M dwarf flares, this implies that the M dwarf flare emission comesfrom a more dense layer than solar flare emission in the 1700 ̊A band. The coolingprocesses in solar flares were best described by the two exponents model, fitted overthe intervals t1=[0, 0.5]t1/2and t2=[3, 10]t1/2wheret1/2is time taken for the profileto decay to half the maximum value. The broken power law model provided a goodfit to the first decay phase, as it was able to account for the impact of chromosphericplasma evaporation, but it did not successfully fit the second decay phase

Locomotor adaptability in persons with unilateral transtibial amputation

Background Locomotor adaptation enables walkers to modify strategies when faced with challenging walking conditions. While a variety of neurological injuries can impair locomotor adaptability, the effect of a lower extremity amputation on adaptability is poorly understood. Objective Determine if locomotor adaptability is impaired in persons with unilateral transtibial amputation (TTA). Methods The locomotor adaptability of 10 persons with a TTA and 8 persons without an amputation was tested while walking on a split-belt treadmill with the parallel belts running at the same (tied) or different (split) speeds. In the split condition, participants walked for 15 minutes with the respective belts moving at 0.5 m/s and 1.5 m/s. Temporal spatial symmetry measures were used to evaluate reactive accommodations to the perturbation, and the adaptive/de-adaptive response. Results Persons with TTA and the reference group of persons without amputation both demonstrated highly symmetric walking at baseline. During the split adaptation and tied post-adaptation walking both groups responded with the expected reactive accommodations. Likewise, adaptive and de-adaptive responses were observed. The magnitude and rate of change in the adaptive and de-adaptive responses were similar for persons with TTA and those without an amputation. Furthermore, adaptability was no different based on belt assignment for the prosthetic limb during split adaptation walking. Conclusions Reactive changes and locomotor adaptation in response to a challenging and novel walking condition were similar in persons with TTA to those without an amputation. Results suggest persons with TTA have the capacity to modify locomotor strategies to meet the demands of most walking conditions despite challenges imposed by an amputation and use of a prosthetic limb

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Uniparental Genetic Heritage of Belarusians: Encounter of Rare Middle Eastern Matrilineages with a Central European Mitochondrial DNA Pool

Ethnic Belarusians make up more than 80% of the nine and half million people inhabiting the Republic of Belarus. Belarusians together with Ukrainians and Russians represent the East Slavic linguistic group, largest both in numbers and territory, inhabiting East Europe alongside Baltic-, Finno-Permic- and Turkic-speaking people. Till date, only a limited number of low resolution genetic studies have been performed on this population. Therefore, with the phylogeographic analysis of 565 Y-chromosomes and 267 mitochondrial DNAs from six well covered geographic sub-regions of Belarus we strove to complement the existing genetic profile of eastern Europeans. Our results reveal that around 80% of the paternal Belarusian gene pool is composed of R1a, I2a and N1c Y-chromosome haplogroups – a profile which is very similar to the two other eastern European populations – Ukrainians and Russians. The maternal Belarusian gene pool encompasses a full range of West Eurasian haplogroups and agrees well with the genetic structure of central-east European populations. Our data attest that latitudinal gradients characterize the variation of the uniparentally transmitted gene pools of modern Belarusians. In particular, the Y-chromosome reflects movements of people in central-east Europe, starting probably as early as the beginning of the Holocene. Furthermore, the matrilineal legacy of Belarusians retains two rare mitochondrial DNA haplogroups, N1a3 and N3, whose phylogeographies were explored in detail after de novo sequencing of 20 and 13 complete mitogenomes, respectively, from all over Eurasia. Our phylogeographic analyses reveal that two mitochondrial DNA lineages, N3 and N1a3, both of Middle Eastern origin, might mark distinct events of matrilineal gene flow to Europe: during the mid-Holocene period and around the Pleistocene-Holocene transition, respectively

Adapt or die : the views of Unisa student teachers on teaching practice at schools

This study focuses on the views of Unisa distance education (DE) students enrolled for the Postgraduate Certificate in Education (PGCE) who had completed their teaching practice. The research questions were: What are student teachers’ experiences of the way in which Unisa prepared them for teaching practice, the school context in which they practised teaching, the mentoring they received or did not receive and the way they were assessed? Socio-constructivist learning and situated learning theory were used as the theoretical framework. A maximum variation sampling technique was used to select 16 participants who had completed 10 weeks of teaching practice to participate in the study. Data were collected by means of semi-structured interviews. The findings indicate that, in preparing students for teaching practice, all role players need greater clarity on what is expected of students with regard to learning outcomes, assessment criteria and lesson plans. Students need to be placed at schools that will provide constructive learning environments, mentoring teachers should receive training and there should be greater clarity on the who, what and how of the assessment of students during teaching practice.Curriculum and Instructional Studie