Testosterone enables growth and hypertrophy in fusion impaired myoblasts that display myotube atrophy: deciphering the role of androgen and IGF-I receptors

We have previously highlighted the ability of testosterone to improve differentiation and myotube hypertrophy in fusion impaired myoblasts that display reduced myotube hypertrophy at 72hrs (after transfer to low serum media) via multiple population doublings (PD) vs. their parental controls (CON); an observation which is abrogated via PI3K/Akt inhibition (Deane et al. 2013). However, whether the most predominant molecular mechanism responsible for T induced hypertrophy occurs directly via androgen receptor or indirectly via IGF-IR/PI3K/Akt pathway is currently debated. PD and CON C2C12 muscle cells were exposed to low serum conditions in the presence or absence of T (100 nM) ± inhibitors of AR (flutamide/F, 40 μm) and IGF-IR (Picropodophyllin/PPP, 150 nM) for 72 hrs and 7 days (early/late muscle differentiation respectively). T increased AR and Akt abundance, myogenin expression, and myotube hypertrophy, but not ERK1/2 activity in both CON and PD cell types. Akt activity was not increased significantly in either cell type with T. Testosterone was unable to promote early differentiation in the presence of IGF-IR inhibitor (PPP) yet still able to promote appropriate later increases in myotube hypertrophy and AR abundance despite IGF-IR inhibition. The addition of the AR inhibitor powerfully attenuated all T induced increases in differentiation and myotube hypertrophy with corresponding reductions in AR abundance, phosphorylated Akt, ERK1/2 and gene expression of IGF-I, myoD and myogenin with increases in myostatin mRNA both cell types. Interestingly, despite basally reduced differentiation and myotube hypertrophy, PD cells showed larger increased in AR abundance vs. CON cells, a response abrogated in the presence of AR but not IGF-IR inhibitors. Furthermore, T induced increases in Akt abundance were sustained despite the presence of IGF-IR inhibition in PD cells only. However, flutamide alone reduced IGF-IR mRNA in both cell types across time points, with an observed reduction in activity of ERK and Akt, perhaps suggesting that IGF-IR was transcriptionally regulated by AR. However, where testosterone increased AR protein content there was no increases observed in IGF-IR gene expression. Overall, this suggested that sufficient AR was important to enable normal gene expression of IGF-IR and downstream signalling, yet elevated levels of AR due to testosterone had no further effect on IGF-IR, despite testosterone increasing Akt abundance in the presence of IGF-IR inhibitor. In conclusion, testosterones ability to improve differentiation and myotube hypertrophy occurred predominately via increases in AR and Akt abundance in both CON and PD cells, with fusion impaired cells (PD) showing an increased responsiveness to T induced AR levels. Finally, T induced increases in myotube hypertrophy (but not early differentiation) occurred independently of upstream IGF-IR input, however it appears that normal AR function in basal conditions is required for adequate IGF-IR gene expression and downstream Akt abundance

Two-microphone spatial filtering provides speech reception benefits for cochlear implant users in difficult acoustic environments

This article introduces and provides an assessment of a spatial-filtering algorithm based on two closely-spaced (∼1 cm) microphones in a behind-the-ear shell. The evaluated spatial-filtering algorithm used fast (∼10 ms) temporal-spectral analysis to determine the location of incoming sounds and to enhance sounds arriving from straight ahead of the listener. Speech reception thresholds (SRTs) were measured for eight cochlear implant (CI) users using consonant and vowel materials under three processing conditions: An omni-directional response, a dipole-directional response, and the spatial-filtering algorithm. The background noise condition used three simultaneous time-reversed speech signals as interferers located at 90°, 180°, and 270°. Results indicated that the spatial-filtering algorithm can provide speech reception benefits of 5.8 to 10.7 dB SRT compared to an omni-directional response in a reverberant room with multiple noise sources. Given the observed SRT benefits, coupled with an efficient design, the proposed algorithm is promising as a CI noise-reduction solution.National Institutes of Health (U.S.) (Grant R01 DC 000117)National Institutes of Health (U.S.) (Grant R01 DC DC7152)National Institutes of Health (U.S.) (Grant 2R44DC010524-02

Ambient air quality standards and policies in eastern mediterranean countries: a review

Objectives: National ambient air quality standards (NAAQS) are critical tools for controlling air pollution and protecting public health. We designed this study to 1) gather the NAAQS for six classical air pollutants: PM(2.5), PM(10), O(3), NO(2), SO(2), and CO in the Eastern Mediterranean Region (EMR) countries, 2) compare those with the updated World Health Organizations Air Quality Guidelines (WHO AQGs 2021), 3) estimate the potential health benefits of achieving annual PM(2.5) NAAQS and WHO AQGs per country, and 4) gather the information on air quality policies and action plans in the EMR countries. Methods: To gather information on the NAAQS, we searched several bibliographic databases, hand-searched the relevant papers and reports, and analysed unpublished data on NAAQS in the EMR countries reported from these countries to the WHO/Regional office of the Eastern Mediterranean/Climate Change, Health and Environment Unit (WHO/EMR/CHE). To estimate the potential health benefits of reaching the NAAQS and AQG levels for PM(2.5), we used the average of ambient PM(2.5) exposures in the 22 EMR countries in 2019 from the Global Burden of Disease (GBD) dataset and AirQ+ software. Results: Almost all of the EMR countries have national ambient air quality standards for the critical air pollutants except Djibouti, Somalia, and Yemen. However, the current standards for PM(2.5) are up to 10 times higher than the current health-based WHO AQGs. The standards for other considered pollutants exceed AQGs as well. We estimated that the reduction of annual mean PM(2.5) exposure level to the AQG level (5 mug m(-3)) would be associated with a decrease of all natural-cause mortality in adults (age 30+) by 16.9%-42.1% in various EMR countries. All countries would even benefit from the achievement of the Interim Target-2 (25 mug m(-3)) for annual mean PM(2.5): it would reduce all-cause mortality by 3%-37.5%. Less than half of the countries in the Region reported having policies relevant to air quality management, in particular addressing pollution related to sand and desert storms (SDS) such as enhancing the implementation of sustainable land management practices, taking measures to prevent and control the main factors of SDS, and developing early warning systems as tools to combat SDS. Few countries conduct studies on the health effects of air pollution or on a contribution of SDS to pollution levels. Information from air quality monitoring is available for 13 out of the 22 EMR countries. Conclusion: Improvement of air quality management, including international collaboration and prioritization of SDS, supported by an update (or establishment) of NAAQSs and enhanced air quality monitoring are essential elements for reduction of air pollution and its health effects in the EMR

Hydrology, hydrobiology and environmental pollution in the southern Caspian Sea

The project investigates the relationship between the biological parameters (phytoplankton, zooplankton, Macrobenthic and ctenophore- Mnemiopsis leidyi) and environmental parameters, nutrients and environmental pollutants (oil, pesticides, heavy metals, and detergents) in water and sediment, at the southern Caspian Sea in 2010-2011. Sampling was carried out in four seasons (spring, summer, autumn and winter) and in eight transects perpendicular to the coast (Astara, Anzali, Sefidroud, Tonekabon, Noshahr, Babolsar, Amir Abad and Bandar Turkmen). Samples were collected from the different layers at depths of 5, 10, 20, 50 and 100 meters. The relationship between biological and environmental parameters surveyed through parametric and multivariate statistical methods. Result showed that the annual mean of environmental parameters and nutrients concentration such as water temperature, pH, transparency, DO, ammonium, nitrate, inorganic nitrogen (DIN), organic nitrogen (DON), inorganic phosphorus (DIP), organic phosphorus (DOP) and soluble silicon (DSi) at euphotic layer were 16.70±0.43 (ºC), 8.38±0.01 (m), 5.48±0.05 (ml/l), 1.52±0.06 (µM), 1.80±0.08 (µM), 3.41±0.10 (µM), 43.3±0.9 (µM), 0.32±0.01 (µM), 0.52±0.02 (µM), 8.88±0.22 (µM), respectively. Meanwhile, annual mean of environmental pollutant such as PAHs and OCPs in sediment were recorded 0.88±0.16 (µg/g.dw) and 9.78±2.20 (µg/g.dw), respectively. In addition, annual mean of heavy metals such as Zn, Cu, Ni, Pb and Hg in sediment were obtained 247±46 (µg/g.dw), 29.5±1.5 (µg/g.dw), 49.9±4.9 (µg/g.dw) and 0.179±0.800 (µg/g.dw), respectively. Annual mean abundance of biological parameters namely phytoplankton, zooplankton and M. leidyi (0-20m) at photic layer were 238±17 (million cells/m^3), 4808±362 (individuals/m^3) and 26±3 (individuals /m^3) respectively, and for biomass were 747±60 (mg/m3), 44.3±5.0 (mg/m^3), 2.15±0.31 (g/m^3). Annual mean abundance of those biological parameters at below of photic layer (50-100m) were 104±35 (million cells/m^3), 843±92 (individuals/m^3) and 2±1 (individuals /m^3) respectively, and for biomass were 412±93 (mg/m3), 9.1±1.0 (mg/m^3), 0.15±0.05 (g/m^3). Annual mean abundance and biomass of macrobenthic were 5073±1225 (individuals /m^2) and 144±73 (g/m^2), respectively. Annual mean annual percentage of TOM, Gravel, Sand and Silt-clay were recorded 3.74±0.26, 0.92±0.32 , 22.51±4.97 and 76.67±5.01, respectively. The stratification of water column was strongly based on gradient of water temperature and the phenomenon (difference of temperature between water layers) was more clear in this study compared to previous years. Temperature and biological factors (phytoplankton) were effected on changes of dissolved oxygen at warm and cold seasons summer and winter), but coefficient factor of temperature was higher than biological factors in winter. The nutrients concentration (with the exception of inorganic phosphorus) in different years 2008-2009, 2009-2010 and 2010-2011 increased compared to 1995-1996 (the year of stability of ecosystem). One of the reason attribute to the presence of the ctenophore (M. leidyi) in Caspian Sea after 1999. The annual correlation of phytoplankton abundance and temperature was reversed but seasonal pattern was varied at each season (within a year). In this study, the Caspian Sea contained the conditions of nitrogen limitation (55%) and nitrogenphosphorus limitation (6-43%) as well as phosphate limitation (2-39%) (DIN/DIP>20) . Inspite of no silica limitation (sufficient concentration of silica) in the Caspian ecosystem, Bacillariophyta was not dominance phylum at whole seasons.It seems that other factors such as the temperature changes of seasons, the effects of predation and feeding of the next chains of the food chain, the difference of the ability in the growth and reproduction, competition (uptake of nutrients) in dfferent groups of phytoplankton and stoichiometry of the nutrients (nitrogen and phosphorus) were caused of non-diatoms dominance at most seasons. As, Pyrrophyta and Bacillariophyta were dominant at spring and winter, respectively and Cyanophyta was pre-dominant at summer and autumn. Multivariate analysis showed the significant correlation between Coppepoda and oxygen and water temperature only. The other gropus of zooplankton did not show any significant correlation with environmental parameters. It might be due to stronger effects of other parameters such as food and predators on different groups of zooplankton at each season and abundance of zooplankton groups indirectly affected by environmental parameters. In this study, Shannon diversity indices of zooplankton and phytoplankton were closer to 1995-96 values and showed diferent trend compared to 2009-2010. However it is not enough reason for recovery of ecosystem in to the stability of Caspian Sea. It is because of other negative evidiance such as strong increasing trend of phytoplankton to zooplankton biomass ratio in all seasons and regions particularly the 2009-2010 and 2010-2011 years compared to 1995-96 (the year of stable ecosystem). In the other word, the balance between the biomass of the first and second of the food chain has been disturbed and the value was much much higher than the year of stable ecosystem in 1995-96. Based on multivariate analyses, there was not significant correlation between zooplankton groups and some edible phytoplankton species, vise versa zooplankton groups consumed some unsuitable species of phytoplankton (based on size, nutritional value, difficulty of digestion and absorption, the potential of toxicity and harmfulness). The lack of expected relationship and routine rules of nutritional between zooplankton and phytoplankton are the more resons of instability in the ecosystem. In current study, dominant group of macrobenthos (polychaeta) observed in depths less than 20 meters which the percentage of silt-clay and sand were 74 and 26, respectively. It seems that this ratio of silt-caly and sand was suitable for their living and accumulation. PCA analysis showed that increasing the percentage of TOM and siltclay accompanied to the decreasing of macrobenthos abundance while increasing the temperature, dissolved oxygen and pH had a positive effect on macrobenthos abundance in most seasons. Increasing the abundance of macrobenthos at all seasons (except spring) would not be a strong indication of improvement of Caspian ecosystem after the ctenophore introduction stress and unfavorable evidence such as low Shannon diversity index observe in the results. Meanwhile, in the present study, Streblospio and oligochaeta (invasive growth and advantage to the food uptake and habitat and sediment seeding) similar to the years of 2008-2009, 2009-2010 still were dominant groups insteade of Gammaridae family (feeding on suspended solids). This means that sediment has a noteworthy amount of organic matter which indicate to the trophic level of ecosystem tend to eutrophy level. The comparison of results on this study to previous studies on biological parameters (phytoplankton, zooplankton and macrobenthos) indicating to the persistence of stress (such as biological and anthropogenic) on their changing population patterns (quantitative relationships between species) and structural patterns (species composition and seasonal succession of dominant species). In other words, many species (both macroscopic and microscopic) of the Caspian Sea are still vulnerable to complications of stressor factors. In order to protection and sustainable exploitation of this worth ecosystem it is necessary to look more serious studies and practical techniques from the relevant organizations in this area

The survey of diversity, distribution and abundance of phytoplankton in the southern part of Caspian Sea

Since phytoplankton are the base of life and productivity of aquatic ecosystems, sustainable ecological study of the Caspian Sea, particularly the distribution and identification of species composition, density and biomass, seasonal and regional variations in phytoplankton before each study seems necessary. Due to various circumstances physical and chemical rivers leading to the sea, seabed topography in different situation appears to be of primary production in the eastern and western between the Caspian Sea in the season, may be altered.Identifying species and determining the distribution and biomass of the changes and how they are affected by environmental changes and we are environmentally conscious. We also compare the current situation with previous studies, we find that the number and types of plankton biomass have been what it is. During 1389 in spring, summer, autumn and winter, in a study of 8 transects of 40 stations. In each transect from Astara to the Turkmen. 5 stations at depths of 5. 10. 20. 50. 100 m were selected for sampling. The total number of 182 species from seven branches Bacillariophyta, Pyrrophyta, Cyanophyta, Chlorophyta, Euglenophyta, Xantophyta and Chrysophyta phytoplankton were identified. Including 81 species of Bacillariophyta, 33 Cyanophyta, 25 Pyrrophyta, 31Chlorophyta, 9 Euglenophyta, 1 Xantophyta and Chrysophyta had 1 specie. Studies have shown that density and biomass of Bacillariophyta were 228 (± 471) per cubic meter × 106) and 6157 (± 290) mg per cubic meter) respectivity and Pyrrophyta were 28/17( ± 27/14) cubic meter × 106in cubic meters) and 3349 ( ± 336) mg per cubic meter) and Cyanophyta 120/40 (± 123/87 ) per cubic meter × 106 per cubic meter), biomass (55 ± 57mg per cubic meter) were the branches of the dominant phytoplankton. Abundance and biomass in different seasons have been significant differences (p <0.05). Most of Bacillariophyta (61 species) was in Autumn and then in winter (48 species). Dominant species of Bacillariophyta were Pseudonitzschia seriata, Rhizosolenia fragilissima, Stephanodiscos sp. , Melosira varians, Nitzschia acicularis and Cyclotella menenghiniana Pyrrophyta was greatest diversity of branches in summer, autumn and winter (19 species), which includes Exuviaella cordata, Exuviaella marina, Prorocentrum praximum and Prorocentrum scutllum. In the autumn density of Cyanophyta was 285.7(±137.1) cubic meters × 106 and biomass was 95(±54) mg per cubic meter) and 18 species were observed. The dominant species in this category were Oscillatoria sp., Nodularia spumigena and Oscillatoria agardhii. Most species of Chlorophyta branche in autumn and winter and summer median region with the highest density at the density of 26.2% and most of it is Binuclearia lauterbornii. Identified as the branches Euglenophyta were Trachelomonas, Euglena and Phacus that were observed in all seasons. In winter, the highest mean biomass was 9(±0.818) mg per cubic meter and the highest density of in summer was 0.5 (±0.5) in cubic meters ×10^6. In winter the depth of 10 meters and surface of Babolsar, Amir Abad and Anzali, a kind of Chrysophyta and in surface of Tonekabon and Anzali a species of Xantophyta were observed that had negligible density and biomass

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe