A Classification Of Ice Crystal Habits Using Combined CPL And RSP Observations During The Seac4rs Campaign

Using collocated NASA’s Cloud Physics Lidar (CPL) and Research Scanning Polarimeter (RSP) data from the SEAC4RS campaign, a new observational-based method was developed which uses a K-means clustering technique to classify ice crystal habit types into seven categories: column, plates, rosettes, spheroids and three different type of irregulars. Inter-compared with the collocated SPEC Inc. Cloud Particle Imager (CPI) data, the frequency of the detected ice crystal habits from the proposed method presented in the study agree within 5% of the CPI reported values for columns, irregulars, rosettes, and spheroids, with more disagreement for plates. This study suggests that a detailed ice crystal habit retrieval could be applied to combined space-based lidar and polarimeter observations such as CALIPSO and POLDER in addition to future missions such as the Aerosols, Clouds, Convection, and Precipitation (A-CCP)

Residence Time (RT), a new parameter to predict neurosteroidogenic efficacy of Translocator Protein (TSPO) ligands: N,N-dialkyl-2-arylindol-3-ylglyoxylamides, a case study

Targeting neuroactive steroid biosynthetic pathway by specific 18 kDa Translocator Protein (TSPO) ligands may represent a therapeutic approach in a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between the binding affinity and the in vitro steroidogenic efficacy has limited the identification of lead compounds by a traditional affinity-based drug discovery strategy. Our recent researches indicate that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends into the target, namely its Residence Time (RT). The assessment of this kinetic parameter during the in vitro characterization of compounds appears mandatory in order to obtain structure-efficacy relationships suitable for the future development of novel molecules with promising pharmacological properties

Extramitochondrial OPA1 and adrenocortical function

We have previously described that silencing of the mitochondrial protein OPA1 enhances mitochondrial 27 Ca2+ signaling and aldosterone production in H295R adrenocortical cells. Since extramitochondrial OPA1 28 (emOPA1) was reported to facilitate cAMP-induced lipolysis, we hypothesized that emOPA1, via the 29 enhanced hydrolysis of cholesterol esters, augments aldosterone production in H295R cells. A few 30 OPA1 immunopositive spots were detected in �40% of the cells. In cell fractionation studies OPA1/COX 31 IV (mitochondrial marker) ratio in the post-mitochondrial fractions was an order of magnitude higher 32 than that in the mitochondrial fraction. The ratio of long to short OPA1 isoforms was lower in post-mito- 33 chondrial than in mitochondrial fractions. Knockdown of OPA1 failed to reduce db-cAMP-induced phos- 34 phorylation of hormone-sensitive lipase (HSL), Ca2+ signaling and aldosterone secretion. In conclusion, 35 OPA1 could be detected in the post-mitochondrial fractions, nevertheless, OPA1 did not interfere with 36 the cAMP – PKA – HSL mediated activation of aldosterone secretio

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review

Constrained Retrievals of Aerosol Optical Properties Using Combined Lidar and Imager Measurements During the FIREX-AQ Campaign

Smoke aerosols arise from a variety of regional sources and fuel types dependent on the properties of the fire, leading to spatial variability in smoke composition and optical properties. After emission, these aerosols age and mix in the atmosphere with other aerosol species, such as sulfates, altering the optical, and microphysical properties of the smoke aerosols over time. Thus, lidar ratio (extinction to backscatter ratio) derived from lidar sensors exhibit spatiotemporal variability for smoke. Traditional backscatter lidar processing algorithms employ a signal loss method that utilizes the reduction of signals below and above cloud layers, enabling simultaneous retrievals of both layer-averaged lidar ratio and particulate extinction, which avoids the need for assigning lidar ratios based on layer type as is typically used for backscatter lidar algorithms. In this study, the signal loss method, which is traditionally designed for cloud property retrievals, is attempted for elevated smoke plume property retrievals using NASA’s Cloud Physics Lidar (CPL) observations from the 2019 Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ) field campaign. Good agreement (linear correlation coefficient of 0.67) is found between aerosol optical depth (AOD) derived from the signal loss method and the constrained method, utilizing collocated GOES MAGARA AOD values as constraints for lidar ratio retrievals, for the Williams Flats smoke event. Differences in derived lidar ratios from the signal loss method and the constrained method (13.6 and 7.4%) are found to be smaller than the expected signal loss lidar ratio error estimate of ∼17–23%. A good agreement is also found in lidar ratios derived from this study and from using Differential Absorption Lidar-High Spectral Resolution Lidar (DIAL-HSRL) measurements for the Williams Flats Fire. The lidar ratio statistics of smoke plumes presented in this analysis (51 ± 13 sr) also compare favorably with lidar ratio values found in previous studies; however, they remain lower than the assumed smoke lidar ratio of 70 sr (at 532 nm) used by CALIPSO and CPL, and vary with plume transport distance. These findings suggest lidar ratio is likely to be regionally specific and evolve with plume transport. Thus, innovative methods for simultaneous retrieval of lidar ratio and aerosol extinction, such as the signal loss method proposed in this study, are needed for accurate aerosol retrievals from standard backscatter lidars in the future

GnRH-agonist implantation of prepubertal male cats affects their reproductive performance and testicular LH receptor and FSH receptor expression

Show less https://doi.org/10.1016/j.theriogenology.2015.10.031Get rights and content Abstract This study was conducted to investigate the effect of GnRH-agonist implantation in prepubertal tomcats on sexual behavior, reproductive performance, and expression of testicular LH receptor (LHR) and FSH receptor (FSHR) and also to compare the testicular characteristics, LHR and FSHR expression between prepubertal and adult tomcats. In experiment 1, 3-month-old tomcats (n = 6/group) were either treated with or left without 4.7 mg deslorelin implants. Semen collection and evaluation were performed just before castration at 48 weeks after treatment; removed testes were analyzed for mRNA and protein expression of LHR and FSHR. We were able to collect semen from six non-treated cats, whereas in treated cats, semen was uncollectable. The results revealed that sexual behavior was absent in the implanted cats throughout the study period. Testicular volume was found to decrease from 30 weeks after treatment onward in the implanted cats compared to the controls (P < 0.05). Semen production was found only in non-implanted cats. Testicular tissue score, seminiferous tubule diameter, and LHR protein expression were found lower in the implanted cats (P < 0.05), but no differences were observed in mRNA expression of LHR and protein expression of FSHR between groups. The mRNA expression of FSHR was higher in the implanted (P < 0.05) compared to control cats. In experiment 2, testes from prepubertal (n = 6) and adult (n = 6) male cats were collected after castration and analyzed for mRNA and protein expression of LHR and FSHR. No differences were observed in the protein expression of LHR and FSHR between the two groups, whereas mRNA expression of FSHR was higher in prepubertal cats (P < 0.05). Testicular and epididymal weight, diameter of seminiferous tubules, and the testicular grade were higher in the adult compared to prepubertal cats (P < 0.05). In conclusion, deslorelin implants suppressed protein expression of LHR and enhanced mRNA expression of FSHR along with suppression of reproductive function without any adverse effects for at least 48 weeks in male cats

Effect of the metabolic syndrome on male reproductive function: a case-controlled pilot study

The metabolic syndrome (MetS) is a constellation of various risk factors. This study aimed to investigate the effect of MetS on testosterone and progesterone, and semen parameters, in a case-controlled pilot study. Male patients (n = 54) had body mass index, waist-to-hip ratio (WHR) and blood pressure recorded. Blood was analysed for HDL cholesterol, triglycerides and glucose. Saliva was assayed for free testosterone and free progesterone. Ejaculates were analysed for volume, sperm concentration, total sperm count, motility, vitality, mitochondrial membrane potential (MMP), DNA fragmentation and leucocyte concentration. Participants were divided into the control group (n = 28) and the MetS group (n = 26). Differences were found between the groups for body mass index, WHR, blood pressure, high-density lipoprotein (HDL), triglycerides and glucose. The MetS group showed significant reductions in sperm concentration (P = 0.0026), total sperm count (P = 0.0034), total motility (P = 0.0291), sperm vitality (P = 0.002), MMP (P = 0.0039), free testosterone (P = 0.0093) and free progesterone (P = 0.0130), while values for DNA fragmentation increased (P = 0.0287). Results indicate that patients with MetS have compromised sperm parameters in the absence of leucocytospermia. A reduction in free progesterone suggests that steroidogenesis cascades may be compromised. It is hypothesised that a systemic pro-inflammatory state with oxidative stress associated with MetS may provide a novel explanation.Web of Scienc

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

Background and PurposeTo further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR‐101 (PD132301‐02).Experimental ApproachWe compared the effects of ATR‐101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC‐derived cell lines. We examined the effects of these compounds in combination with methyl‐β‐cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds.Key ResultsATR‐101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC‐derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl‐β‐cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR‐101. ATR‐101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR‐101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR‐101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR‐101. ATR‐101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation.Conclusions and ImplicationsInhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR‐101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/1/bph13951-sup-0001-supplementary_material.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/2/bph13951_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138270/3/bph13951.pd

Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular Size in Aging Mice

The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant RO1CA108854