Asparagine Dependency is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.

The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme catalyzing the synthesis of asparagine. Mechanistically, loss or mutation of TP53 transcriptionally activated ASNS expression, directly as well as via mTORC1-mediated ATF4 induction, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to asparagine restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine, respectively, and cell viability was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting asparagine production to treat these lethal prostate cancers.

Violations of Hyperscaling in Finite-Size Scaling above the Upper Critical Dimension.

We consider how finite-size scaling (FSS) is modified above the upper critical dimension, du=4, due to hyperscaling violations, which in turn arise from a dangerous irrelevant variable. In addition to the commonly studied case of periodic boundary conditions, we also consider new effects that arise with free boundary conditions. Some numerical results are presented in addition to theoretical arguments.

Risk assessment of cyclohexasiloxane D6 in cosmetic products.

Dodecamethylcyclohexasiloxane (D6) is a siloxane substance mainly used in cosmetics and personal care products. While octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) were once commonly used in personal care products, their usage has been restricted due to the classification as persistent, bioaccumulative, and toxic (PBT)/very persistent and very bio-accumulative (vPvB) substances. While D6 has emerged as a substitute for D4 and D5, the risk assessment for D6 remains limited compared to the evaluations for D4 and D5. To address this gap, we conducted a comprehensive risk assessment of D6. In this study, we reviewed the toxicity information on D6 and calculated the exposure level to D6, considering the content of D6 in cosmetic products. No observed adverse effect level (NOAEL) of 1500 mg/kg bw/day was established in a repeated dose toxicity study after oral administration to rats. Negative results were found in tests on the ocular and skin irritation, skin sensitization, and genotoxicity of D6. According to the product content of up to 48% of D6 reported in 2012, the Systemic Exposure Dose (SED) was 5.4E-06 to 7.04 mg/kg bw/day for a 60 kg adult using the exposure factors from Korean cosmetic usage. The Margin of Safety was estimated to be between 35.5 and 4.63E+07, posing a potential health risk of D6 according to the maximum concentration and the product type. Further consideration of the potential of D6 as PBT or vPvB is also required.

Safety assessment of cocamidopropyl betaine, a cosmetic ingredient.

Cocamidopropyl betaine (CAPB) is a surfactant derived from coconut oil that is widely used in cosmetics and personal products for several purposes, such as a surfactant, foam booster, mildness, and viscosity control. Cocamidopropyl betaine is used at concentrations up to 30% in cosmetics. The acute toxicity, skin irritation, eye irritation, skin sensitization, repeated dose toxicity, genotoxicity, carcinogenicity, and phototoxicity of cocamidopropyl betaine were evaluated. Cocamidopropyl betaine was observed to induce mild skin irritation, eye irritation and skin sensitization. The NOAEL of cocamidopropyl betaine was determined to be 250 mg/kg/day based on the results of a 92-day repeated-dose oral toxicity study in rats. The systemic exposure dose of cocamidopropyl betaine was estimated to range from 0.00120 to 0.93195 mg/kg/day when used in cosmetic products. The margin of safety of cocamidopropyl betaine was calculated to be greater than 100 when used at a maximum concentration of 6% in leave-on products and 30% in rinse-off products, suggesting that its use in cosmetic products is safe under current usage conditions.

Synthesis and luminescent properties of a linear difluorene pyrazine (D-A-D) derivative as a selective indicator for a reversible acid-base vapour sensor.

We have synthesized a structure in which pyrazine is the core structure and fluorene derivatives are attached to both sides. Photo physical investigations such as aprotic solvents (Hexane to DMF) were carried out. A redshift was revealed from non-polar aprotic solvents to polar aprotic solvents. The luminescence intensity was gradually decreased, which is incredibly more complex towards changes in the solvent polarization than their UV/Vis absorption spectra. The compound showed a redshift from 445 nm to 473 nm when slowly increasing the water fraction (fw) from 0 to 30 %. Also, rising water fraction (fw > 40-90 %) effectively attenuated the instantaneous emission intensity was observed. At the same time, the intensity of the emission peak was reduced due to the TICT effect on fluorene and pyrazine rings due to enhanced solvent polarity. In addition, optically reversible acidofluorochromic properties were performed experimentally in both solvent and solid phases. For the acidic substances TFA and HF, which contain fluorine, new redshift peaks from 425 nm and 503 nm were observed upon reaction with the PDF solution, and the emission intensity was extinguished by more than 90 % and 60 %, respectively. Upon addition of TFA up to 1500 equal, the PDF mixture suffered from 50 % lower energy absorption intensity. The 1H NMR spectrum confirmed the proposed mechanism (TFA/TEA, ON-OFF-ON). Therefore, the present work presents a novel approach to fabricating ON-OFF-ON active-pull pyrazine scaffolds that can be used in DSEgens, referred to as "ON-OFF-ON" fluorescent sensors, for multifunctional applications.

Development of a novel sensory material for rapid detection of mercury ions in various water sources: Solution and solid-state analysis.

A xanthene propane nitrile-based sensor material was successfully prepared, and an attempt towards the preparation of polymer bead form was made for the sensitive or selective detection of mercury ions (Hg2+) in water. The sensor material in solution as well as in polymeric form showed amazing selectivity over other added metal ions with a naked eye color change, UV visible spectral and fluorescence spectral change, and a rapid and excellent color change from colorless to purple. The 1H NMR study exposed the probable binding site of the probe with the added mercury ion. In this study, the imine nitrogen and the C = O interact with the mercury ion, resulting in the ring opening of lactam with a vivid color change. The EDTA test was done to verify the reversible behavior of the probe and confirmed its reversibility by UV-visible and fluorescence spectral studies. The polymer bead made using this probe can be used as a tool for monitoring mercury ions in real time in different sources of water samples. The sensor molecule itself senses the mercury ion in its solid state by simple grinding and changes its color from pale yellow to deep purple. The sensor color change response is very rapid towards mercury detection, which is confirmed by the prepared test strip.

M(II) effect on encapsulation of guests into a series of M3L2 chiral cages: enantio-recognition.

Self-assembly of M(ClO4)2 (M2+ = Ni2+, Cu2+, and Zn2+) with (1S,1'S,1''S,2R,2'R,2''R)-(benzenetricarbonyltris(azanediyl))tris(2,3-dihydro-1H-indene-2,1-diyl) trinicotinate (s,r-L) and the corresponding enantiomer (r,s-L) as a pair of chiral tridentate donors gives rise to the chiral cage pairs [M3(s,r- and r,s-L)2](ClO4)6. For the two pairs of [(Me2CO)(H2O)@M3(r,-s and s,r-L)2](ClO4)6 (M2+ = Ni2+ and Zn2+), the inner cavity is occupied by both an acetone and a single water molecule, whereas for the copper(II) pair of [Me2CO@Cu3(r,s- and s,r-L)2](ClO4)6 under the same conditions, the cavity is filled by only one acetone molecule. Thus, the encapsulation of guest molecules into the cages during self-assembly shows significant metal(II) ion effects. These chiral cages are effective for the enantio-recognition of chiral (S)-2-butanol and (R)-2-butanol via the shifts of the electrochemical oxidation potentials obtained by the linear sweep voltammetry (LSV) technique, density functional theory (DFT) calculations, and the chiral 2-butanol adsorption in the single-crystal-to-single-crystal (SCSC) mode.

The Graded Incomplete Letters Test (GILT): a rapid test to detect cortical visual loss, with UK Biobank implementation.

Impairments of object recognition are core features of neurodegenerative syndromes, in particular posterior cortical atrophy (PCA; the 'visual-variant Alzheimer's disease'). These impairments arise from damage to higher-level cortical visual regions and are often missed or misattributed to common ophthalmological conditions. Consequently, diagnosis can be delayed for years with considerable implications for patients. We report a new test for the rapid measurement of cortical visual loss - the Graded Incomplete Letters Test (GILT). The GILT is an optimised psychophysical variation of a test used to diagnose cortical visual impairment, which measures thresholds for recognising letters under levels of increasing visual degradation (decreasing "completeness") in a similar fashion to ophthalmic tests. The GILT was administered to UK Biobank participants (total n=2,359) and participants with neurodegenerative conditions characterised by initial cortical visual (PCA, n=18) or memory loss (typical Alzheimer's disease, n=9). UK Biobank participants, including both typical adults and those with ophthalmological conditions, were able to recognise letters under low levels of completeness. In contrast, participants with PCA consistently made errors with only modest decreases in completeness. GILT sensitivity to PCA was 83.3% for participants reaching the 80% accuracy cut-off, increasing to 88.9% using alternative cut-offs (60% or 100% accuracy). Specificity values were consistently over 94% when compared to UK Biobank participants without or with documented visual conditions, regardless of accuracy cut-off. These first-release UK Biobank and clinical verification data suggest the GILT has utility in both rapidly detecting visual perceptual losses following posterior cortical damage and differentiating perceptual losses from common eye-related conditions.

UK Cancer Healthcare Professionals Collaborating With Colleagues in Low- and Middle-Income Countries: Mapping the Extent and Nature of Partnerships; Future Implications.

AIMS: In 2020 the UK Global Cancer Network (UKGCN) was formed to unite those in the UK interested in Global Oncology and to strengthen collaborative partnerships with stakeholders working across low- and middle-income countries (LMICs) in cancer health systems, governance, and care. The UKGCN undertook a mapping exercise to document collaborations to inform the UK's global oncology strategy. MATERIALS AND METHODS: A semi-structured survey was developed and disseminated using a snowball method over ten weeks from February 2021 across the UK's cancer community, to identify individuals and institutions engaged in clinical practice, research, and/or education with partners in LMICs. The survey was sent to individuals in NHS hospitals, charities, universities, other organisations, UKGCN members, and to contacts identified by a literature and web search. RESULTS: A total of 639 invitations were sent, and 88 responses were received. Results demonstrate a range of collaborative efforts spanning many areas of cancer control: health promotion, prevention, diagnosis and treatment, survivorship, and palliative care. A wide range of countries were represented from Sub-Saharan Africa, South America, the MENA region, China, and South-East Asia. The projects included education and training (146), clinical practice/care (144), and research (226). CONCLUSION: This mapping exercise demonstrated considerable UK collaboration with stakeholders in LMICs across all three domains of education, clinical care, and research. The survey results provide an initial framework from which to promote in-depth strategic intelligence on the broad range of activities undertaken by the UK global oncology community. This information has been used as a catalyst to create new partnerships and connect colleagues working in similar geographical settings, encouraging bidirectional learning. The UKGCN will galvanise endeavours to improve equitable access to cancer services globally.

Selecting serum-free hepatocyte cryopreservation stage and storage temperature for the application of an "off-the-shelf" bioartificial liver system.

The bioartificial liver (BAL) system can potentially rescue acute liver failure (ALF) patients by providing partial liver function until a suitable donor liver can be found or the native liver has self-regenerated. In this study, we established a suitable cryopreservation process for the development of an off-the-shelf BAL system. The viability of hepatocyte spheroids cryopreserved in liquid nitrogen was comparable to that of fresh primary hepatocyte spheroids. When hepatocyte spheroids were subjected to cryopreservation in a deep freezer, no statistically significant differences were observed in ammonia removal rate or urea secretion rate based on the cryopreservation period. However, the functional activity of the liver post-cryopreservation in a deep freezer was significantly lower than that observed following liquid nitrogen cryopreservation. Moreover, cryopreserving spheroid hydrogel beads in a deep freezer resulted in a significant decrease (approximately 30%) in both ammonia removal and urea secretion rates compared to the group cryopreserved in liquid nitrogen. The viabilities of spheroid hydrogel beads filled into the bioreactor of a BAL system were similar across all four groups. However, upon operating the BAL system for 24 h, the liver function activity was significantly higher in the group comprising hydrogel beads generated after thawing hepatocyte spheroids cryopreserved in liquid nitrogen. Consequently, the manufacturing of beads after the cryopreservation of hepatocyte spheroids is deemed the most suitable method, considering efficiency, economic feasibility, and liver function activity, for producing a BAL system.

Self-assembly of Ni(II) with a chiral ligand pair vs. mixture of the chiral ligand pair: structural features and recognition ability of Ni2L4 cages.

The self-assembly of NiCl2 with a chiral bidentate ligand pair, (1R,2S)-(+)- and (1S,2R)-(-)-1-(nicotinamido)-2,3-dihydro-1H-inden-2-yl nicotinate (r,s-L and s,r-L) in a mixture of ethanol and dioxane, gives rise to stable crystals consisting of [2Cl@Ni2Cl2(s,r-L)4(H2O)2]·4C4H8O2·EtOH and [2Cl@Ni2Cl2(r,s-L)4(H2O)2]·4C4H8O2·EtOH chiral cages, respectively, with two encapsulated chloride anions in the cavities. The most interesting feature is that the self-assembly of NiCl2 with the mixture of r,s-L and s,r-L (1 : 1-1 : 4) produces crystals of thermodynamically stable achiral cages, [2Cl·2H2O@Ni2Cl2(s,r-L)2(r,s-L)2(H2O)2]·7C4H8O2, in the molar ratio range. Furthermore, the [2Cl@Ni2Cl2(s,r-L)4(H2O)2]·4C4H8O2·EtOH and [2Cl@Ni2Cl2(r,s-L)4(H2O)2]·4C4H8O2·EtOH chiral crystals can recognize the pairs of L-,D-tryptophan and L-,D-cysteine via cyclic voltammetry (CV) signals, in contrast to the [2Cl·2H2O@Ni2Cl2(s,r-L)2(r,s-L)2(H2O)2]·7C4H8O2 achiral crystal.

Scintillation characteristics of the EJ-299-02H scintillator.

A study of the dead layer thickness and quenching factor of a plastic scintillator for use in ultracold neutron (UCN) experiments is described. Alpha spectroscopy was used to determine the thickness of a thin surface dead layer to be 630 ± 110 nm. The relative light outputs from the decay of 241Am and Compton scattering of electrons were used to extract Birks' law coefficient, yielding a kB value of 0.087 ± 0.003 mm/MeV, consistent with some previous reports for other polystyrene-based scintillators. The results from these measurements are incorporated into the simulation to show that an energy threshold of (∼9 keV) can be achieved for the UCNProBe experiment. This low threshold enables high beta particle detection efficiency and the indirect measurement of UCN. The ability to make the scintillator deuterated, accompanied by its relatively thin dead layer, gives rise to unique applications in a wide range of UCN experiments, where it can be used to trap UCN and detect charged particles in situ.

Modeling future cliff-front waves during sea level rise and implications for coastal cliff retreat rates.

It is often assumed that future coastal cliff retreat rates will accelerate as global sea level rises, but few studies have investigated how SLR (sea level rise) might change cliff-front wave dynamics. Using a new simple numerical model, this study simulates the number and type (breaking, broken, or unbroken) of cliff-front waves under future SLR scenarios. Previous research shows breaking waves deliver more energy to cliffs than broken waves, and unbroken waves generate minimal impact. Here, we investigated six cliff-platform profiles from three regions (USA, New Zealand, and UK) with varied tidal ranges and wave climates. Model inputs included 2013-2100 hindcast/forecast incident wave height and tidal water level, and three future SLR scenarios. Results show the number of both cliff-front breaking and broken waves generally increase for a high-elevation (relative to tide) cliff-platform junction. In contrast, breaking/broken wave occurrence decrease by 38-92% for a near-horizontal shore platform with a low-elevation cliff-platform junction under a high SRL scenario, leading to high (96-97%) unbroken wave occurrence. Overall, results suggest the response of cliff-front waves to future SLR is complex and depends on shore platform geometries and SLR scenarios, indicating that future cliff retreat rates may not homogeneously accelerate under SLR.

Distinct spatiotemporal atrophy patterns in corticobasal syndrome are associated with different underlying pathologies.

Objective: To identify imaging subtypes of the cortico-basal syndrome (CBS) based solely on a data-driven assessment of MRI atrophy patterns, and investigate whether these subtypes provide information on the underlying pathology. Methods: We applied Subtype and Stage Inference (SuStaIn), a machine learning algorithm that identifies groups of individuals with distinct biomarker progression patterns, to a large cohort of 135 CBS cases (52 had a pathological or biomarker defined diagnosis) and 252 controls. The model was fit using volumetric features extracted from baseline T1-weighted MRI scans and validated using follow-up MRI. We compared the clinical phenotypes of each subtype and investigated whether there were differences in associated pathology between the subtypes. Results: SuStaIn identified two subtypes with distinct sequences of atrophy progression; four-repeat-tauopathy confirmed cases were most commonly assigned to the Subcortical subtype (83% of CBS-PSP and 75% of CBS-CBD), while CBS-AD was most commonly assigned to the Fronto-parieto-occipital subtype (81% of CBS-AD). Subtype assignment was stable at follow-up (98% of cases), and individuals consistently progressed to higher stages (100% stayed at the same stage or progressed), supporting the model's ability to stage progression. Interpretation: By jointly modelling disease stage and subtype, we provide data-driven evidence for at least two distinct and longitudinally stable spatiotemporal subtypes of atrophy in CBS that are associated with different underlying pathologies. In the absence of sensitive and specific biomarkers, accurately subtyping and staging individuals with CBS at baseline has important implications for screening on entry into clinical trials, as well as for tracking disease progression.

Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity.

Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.

Factors Affecting Abdominal Obesity: Analyzing National Data.

The purpose of this study is to understand the factors affecting abdominal obesity. A secondary data analysis was conducted to analyze 5262 individuals' data from the 2020 Korea National Health and Nutrition Examination Survey. The prevalence of obesity was slightly higher in men than women, while abdominal obesity was more prevalent in women. A higher correlation with obesity was observed in young and middle-aged individuals, unmarried individuals, urban residents, those with good subjective health, low-stress perception, moderate alcohol consumption, nonsmokers, regular aerobic exercisers, and those getting more than seven hours of sleep. In contrast, middle-aged and elderly individuals, married individuals, rural residents, those with an elementary school or lower education level, those with low-to-moderate income, those with fair or poor subjective health, high stress perception, nondrinkers, smokers, nonregular aerobic exercisers, and those getting less than seven hours of sleep had a higher correlation with abdominal obesity. Health education suggests that everyone should maintain healthy lifestyle habits, such as getting sufficient sleep, exercise, smoking cessation, and moderate drinking. Specifically, diverse health management support focusing on population groups with demographic factors related to the risk of obesity and abdominal obesity is necessary.

Barriers to opioid use disorder treatment among people who use drugs in the rural United States: A qualitative, multi-site study.

BACKGROUND: In 2020, 2.8 million people required substance use disorder (SUD) treatment in nonmetropolitan or 'rural' areas in the U.S. Among this population, only 10% received SUD treatment from a specialty facility, and 1 in 500 received medication for opioid use disorder (MOUD). We explored the context surrounding barriers to SUD treatment in the rural United States. METHODS: We conducted semi-structured, in-depth interviews from 2018 to 2019 to assess barriers to SUD treatment among people who use drugs (PWUD) across seven rural U.S. study sites. Using the social-ecological model (SEM), we examined individual, interpersonal, organizational, community, and policy factors contributing to perceived barriers to SUD treatment. We employed deductive and inductive coding and analytical approaches to identify themes. We also calculated descriptive statistics for participant characteristics and salient themes. RESULTS: Among 304 participants (55% male, mean age 36 years), we identified barriers to SUD treatment in rural areas across SEM levels. At the individual/interpersonal level, relevant themes included: fear of withdrawal, the need to "get things in order" before entering treatment, close-knit communities and limited confidentiality, networks and settings that perpetuated drug use, and stigma. Organizational-level barriers included: strict facility rules, treatment programs managed like corrections facilities, lack of gender-specific treatment programs, and concerns about jeopardizing employment. Community-level barriers included: limited availability of treatment in local rural communities, long distances and limited transportation, waitlists, and a lack of information about treatment options. Policy-level themes included insurance challenges and system-imposed barriers such as arrest and incarceration. CONCLUSION: Our findings highlight multi-level barriers to SUD treatment in rural U.S. communities. Salient barriers included the need to travel long distances to treatment, challenges to confidentiality due to small, close-knit communities where people are highly familiar with one another, and high-threshold treatment program practices. Our findings point to the need to facilitate the elimination of treatment barriers at each level of the SEM in rural America.

Optimizing cyanine dye properties for enhanced dyeing and inkjet printing on diverse Substrates: Photophysical and colorimetric investigations.

Cyanine-based cationic dyes with different substituents in the donor unit were easily synthesized using readily available starting materials. The prepared dye molecules were spectroscopically characterized by NMR, FT-IR, and HR-Mass, and their thermal stability was measured by TGA, DSC, and XRD. Based on the TGA and DSC measurements, it was concluded that all the dyes are thermally stable up to 200 °C. Also, powder XRD was studied for all dyes to identify the explicit crystallinity and morphological nature of the dyes. A dye dispersion solution was prepared for the proper dyeing of modacrylic fabric and the dyed fabric showed good color strength K/S for dyes R1, R2, and R6 and fragile color strength for R3, R4,and R5. These dyes are also used for printing on substrates like paper and fabric using ink-jet printing. These dyes were also used for transferability printing applications on various fabrics.