Identification of Naegleria fowleri proteins linked to primary amoebic meningoencephalitis

Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis, a rapidly fatal disease of the central nervous system. N. fowleri can exist in cyst, flagellate or amoebic forms, depending on environmental conditions. The amoebic form can invade the brain following introduction into the nasal passages. When applied intranasally to a mouse model, cultured N. fowleri amoebae exhibit low virulence. However, upon serial passage in mouse brain, the amoebae acquire a highly virulent state. In the present study, a proteomics approach was applied to the identification of N. fowleri amoeba proteins whose expression was associated with the highly virulent state in mice. Mice were inoculated intranasally with axenically cultured amoebae or with mouse-passaged amoebae. Examination by light and electron microscopy revealed no morphological differences. However, mouse-passaged amoebae were more virulent in mice as indicated by exhibiting a two log10 titre decrease in median infective dose 50 (ID50). Scatter plot analysis of amoebic lysates revealed a subset of proteins, the expression of which was associated with highly virulent amoebae. MS-MS indicated that this subset contained proteins that shared homology with those linked to cytoskeletal rearrangement and the invasion process. Invasion assays were performed in the presence of a select inhibitor to expand on the findings. The collective results suggest that N. fowleri gene products linked to cytoskeletal rearrangement and invasion may be candidate targets in the management of primary amoebic meningoencephalitis

User Disengagement And The Turnaround Of A Failing Project

This paper reports on an in-depth case study of a large and strategic IT development project facing business user disengagement and potential system rejection. Somewhat belatedly senior management recognised the threat and appointed a new project manager with a brief to rescue the project whilst keeping to the original implementation deadline. Much to almost everyone\u27s surprise the new project manager, and his radical approach, produced the required significant results. The paper examines the changes instigated by the new project manager and a group of newly appointed Business Analysts (BAs). The approach, based on participation ideas, utilized an adapted state modelling technique, and was framed within the agile informed management approach, succeeded in achieving an emergence of business users’ belief and the feeling that they could not just influence the system but design it in a way that was needed by the business and that would support the current required workflows as well as for the future, which was somewhat uncertain. The detail of the approach is described and the way in which the disengagement and turnaround was achieved is provided. The paper concludes by outlining the contributions of the case and the approach and suggesting a relevance not only to the systems development and participation literature but potentially to the concept of systems ownership and Psychological Ownership (PO) which it could be argued were invoked in the case

Adipocyte-derived endotrophin promotes malignant tumor progression

Adipocytes represent a major cell type in the mammary tumor microenvironment and are important for tumor growth. Collagen VI (COL6) is highly expressed in adipose tissue, upregulated in the obese state, and enriched in breast cancer lesions and is a stimulator of mammary tumor growth. Here, we have described a cleavage product of the COL6??3 chain, endotrophin (ETP), which serves as the major mediator of the COL6-mediated tumor effects. ETP augmented fibrosis, angiogenesis, and inflammation through recruitment of macrophages and endothelial cells. Moreover, ETP expression was associated with aggressive mammary tumor growth and high metastatic growth. These effects were partially mediated through enhanced TGF-?? signaling, which contributes to tissue fibrosis and epithelial-mesenchymal transition (EMT) of tumor cells. Our results highlight the crucial role of ETP as an obesity-associated factor that promotes tumor growth in the context of adipocyte interactions with tumor and stromal cells.open302

Closing yield gaps in South Asian wheat production (Bihar, India and Terai of Nepal)

Rising wheat consumption and recurring climate extremes threaten food security in the Eastern Indo-Gangetic Plain. Closing wheat yield gaps in this region through agronomic practices currently available to farmers can contribute to a more secure future in this region. In Nepal and Bihar, India, a set of complementary management practices were associated with higher yields, namely: 1) early sowing with long maturing varieties, 2) higher rates of N, P and particularly K application, 3) transitions to zero-till for crop establishment, and 4) encouraging more frequent irrigation. Financial and policy support for infrastructure and agricultural inputs, extension, research and development of private service networks made a marked improvement in yield outcomes in Bihar. Nepal is at a crossroads of diminishing farm-labor and inadequate investment into farming operations that, among other factors, have stagnated domestic wheat yield. Cultural and economic constraints have hindered the widespread adoption of more expensive precision agriculture technologies like zero-till that have the capacity to improve labor and farm input efficiencies. To capture the benefits from added precision of application but with the ability to fit within the current semi-mechanized seed bed preparation and tillage system, we introduced a low-cost, chest mounted seed and fertilizer. We found that simple mechanization caused yield efficiencies to be positive and significant for nitrogen and phosphate. Seed rates using this method were positively associated with seedling density. This led to both yield and profit being more predictable for farmers. Conversely, hand-applied inputs caused a disassociation between inputs and end of season yield and therefore added a large measure of risk to their farming operations. Nepali farmers endure many types of risks in producing wheat. Some, such as those affiliated with socioeconomic and demographic pressures, they have little control over. Other sources of risk, such as stresses associated with particular agronomic practices, can be mitigated through better management. In this research, we found that waterlogging stress early in wheat phenology reduced yield. This was attributed to farmers applying flood irrigation to the crop to the point of ponding at early wheat growth stages when the plants were more vulnerable. Waterlogging stress was exacerbated by the common practice of applying seed and fertilizer by hand which created in-field heterogeneity of nutrient distribution, thereby reducing individual plant access to nutrients and making them less resilient to waterlogging stress. Two different solutions, one a technological intervention and the other a change in irrigation practices, reduced this stress. The first was the introduction of a chest-mounted spreader that added a greater measure of uniformity to input application and reduced the impact that waterlogging stress had on crop productivity by ensuring greater availability of nutrients across fields. The second was a delay in the timing of flood irrigation to coincide with greater crop maturity. Plants at the tillering development stage (zadoks stage 20) demonstrated a greater resilience to waterlogging stress and promoted greater yield. At the policy level, increasing the availability of diesel pumps on the landscape, and splitting irrigations, would offer farmers greater flexibility in their management to reduce crop stresses and overall risk

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis

Trastuzumab deruxtecán; Cáncer de mama metastásico; Metástasis cerebralesTrastuzumab deruxtecan; Metastatic breast cancer; Brain metastasesTrastuzumab deruxtecan; Càncer de mama metastàtic; Metàstasis cerebralsDESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%–77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7–18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. Significance: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs.AstraZeneca (AstraZeneca PLC) i American Regent (American Regent, Inc.)

Relationship Between Image Quality and Bias in 3D Echocardiographic Measures: Data From the SABRE (Southall and Brent Revisited) Study

Background: Image‐quality (IQ) compromises left ventricle assessment by 3‐dimensional echocardiography (3DE). Sicker/frailer patients often have suboptimal IQ, and therefore observed associations may be biased by IQ. We investigated its effect in an observational study of older people and when IQ was modified experimentally in healthy volunteers. / Methods and Results: 3DE feasibility by IQ was assessed in 1294 individuals who attended the second wave of the Southall and Brent Revisited study and was compared with 2‐dimensional (2D)‐echocardiography feasibility in 147 individuals. Upon successful analysis, means of ejection fraction (3D‐EF) and global longitudinal strain (3D‐GLS) (plus 2D‐EF) were compared in individuals with poor versus good IQ. In 2 studies of healthy participants, 3DE‐IQ was impaired by (1) intentionally poor echocardiographic technique, and (2) use of a sheet of ultrasound‐attenuating material (neoprene rubber; 2–4 mm). The feasibility was 41% (529/1294) for 3DE versus 61% (89/147) for 2D‐EF, P<0.0001. Among acceptable images (n=529), good IQ by the 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging criteria was 33.6% (178/529) and 71.3% (377/529) for 3D‐EF and 3D‐GLS, respectively. Individuals with poor IQ had lower 3D‐EF and 3D‐GLS (absolute) than those with good IQ (3D‐EF: 52.8±6.0% versus 55.7±5.7%, Mean‐Δ −2.9 [−3.9, 1.8]; 3D‐GLS: 18.6±3.2% versus 19.2±2.9%, Mean‐Δ −0.6 [−1.1, 0.0]). In 2 experimental models of poor IQ (n=36 for both), mean differences were (−2.6 to −3.2) for 3D‐EF and (−1.2 to −2.0) for 3D‐GLS. Similar findings were found for other 3DE left ventricle volumes and strain parameters. / Conclusions: 3DE parameters have low feasibility and values are systematically lower in individuals with poor IQ. Although 3D‐EF and 3D‐GLS have potential advantages over conventional echocardiography, further technical improvements are required to improve the utility of 3DE in clinical practice

The ecdysis triggering hormone system, via ETH/ETHR-B, is essential for successful reproduction of a major pest insect, Bactrocera dorsalis (Hendel)

Ecdysis triggering hormone (ETH), released by the Inka cells, is a master hormone in regulating the ecdysis process in insect. Here we investigated the presence and role of the ETH signaling in the female adult of the oriental fruit fly, Bactrocera dorsalis (Hendel) that is one of the most important invasive pest insects in agriculture worldwide. In the female adult, ETH was confirmed in the lnka cells at the tracheae by immunostaining and also in vitro exposure to ETH stimulated the isolated corpora allata of adult in activity. Then we prepared cDNA of females at 0, 5, 10, 15, and 20 days after adult eclosion, and RT-qPCR showed that the expression pattern of ETH and its receptor ETHR-B started from a peak at the day of adult eclosion (day 0), then dropped to basal levels and increased again between day 10 and 15 which is also the period corresponding to ovary growth. In contrast, ETHR-A was absent with Ct values of > 33. The expression patterns of the ecdysteroid-producing Halloween genes Spook and Shade, and the vitellogenin genes Vg1 , Vg2, and Vg3 co-occurred with peak levels at days 10-15, and also juvenile hormone acid methyltransferase (JHAMT) showed increased levels on day 15. Further in RNAi assays to better understand the role of ETH and ETHR, dsRNA was injected to adult and this led to a respective decrease in expression of 62 and 56% for ETH and ETHR-B, while ETHR-A stayed absent with Ct values of 33. In these RNAi-females, there was an apparently decreased expression for JHAMT and Vg2, together with a significant decrease of the JH titer and egg production. Injection of the JH mimetic methoprene could rescue Vg2 expression and egg production. Upstream, in dsETH/dsETHR-injected females, 20-hydroxyecdysone (20E) injection rescued the transcriptions of ETH and ETHR and also egg production. In summary, our results shed more light on the pivotal role that the ETH peptide hormone and its receptor ETHR-B play an essential role in the reproduction of the female adult of B. dorsalis, via the regulation of JH and vitellogenin, which are controlled by a pulse of 20E