Identifying Crystal Structures Beyond Known Prototypes from X-ray Powder Diffraction Spectra

The large amount of powder diffraction data for which the corresponding crystal structures have not yet been identified suggests the existence of numerous undiscovered, physically relevant crystal structure prototypes. In this paper, we present a scheme to resolve powder diffraction data into crystal structures with precise atomic coordinates by screening the space of all possible atomic arrangements, i.e., structural prototypes, including those not previously observed, using a pre-trained machine learning (ML) model. This involves: (i) enumerating all possible symmetry-confined ways in which a given composition can be accommodated in a given space group, (ii) ranking the element-assigned prototype representations using energies predicted using Wren ML model [Sci.\ Adv.\ 8, eabn4117 (2022)], (iii) assigning and perturbing atoms along the degree of freedom allowed by the Wyckoff positions to match the experimental diffraction data (iv) validating the thermodynamic stability of the material using density-functional theory (DFT). An advantage of the presented method is that it does not rely on a database of previously observed prototypes and, therefore is capable of finding crystal structures with entirely new symmetric arrangements of atoms. We demonstrate the workflow on unidentified XRD spectra from the ICDD database and identify a number of stable structures, where a majority turns out to be derivable from known prototypes, but at least two are found to not be part of our prior structural data sets.Comment: 18 pages including citations and supplementary materials, 4 figures; overall text improvement; revision of some results in Page

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992

PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier–penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy

Museums Brand Equity and Social Media: Looking into Current Research Insights and Future Research Propositions

Abstract. Extensive research has repeatedly acknowledged the link between traditional and digital marketing communication tools and branding performance. Particularly, both within For Profit Organizations (henceforth, FPOs) and Non-Profit Organizations (henceforth NPOs), social media as the milestone of the digital era has rebutted the foundations of corporate and personal communication through the emergence of new participatory communication terms, such as ''prod-user'' and “co-creation”. Consequently, a growing research trend has emerged towards e-e marketing tools and social media impact on destination branding, as well. Simultaneously, thanks to its multidimensional benefits both at the communicational, educational, and promotional levels, social media are emerging as an essential feature in the branding of the new museum era. To date, within the NPOs sector, few studies have investigated the effect of social media on brand equity. Moreover, far too little attention has been paid to the link between social media and museums' brand equity. Based on the systematic qualitative critical review methodology, this paper attempts to identify the basic trends and research status by 2018. Drawing on a review of 78 papers that are the result of systematic desk research, this study categorizes and presents, for the first time, the effects of social media use on museums’ brand components. The study offers new and valuable insights into the multidisciplinary research interests of the research and industry community relating to communication and marketing, NPOs, tourism, and museums context. Keywords: Social Media, Museums, Brand Equity, NPOs, Cultural Tourism

Adherence to daily dietary and activity goals set within a Māori and Pacific weight loss competition.

Background: New Zealand Pacific and Māori populations measure disproportionately high on the international body mass index (BMI). Information is needed on what behavioural weight loss goals to recommend and how to attract and retain them in interventions. Our team weight loss competition trial for participants with a BMI ≥30 used cash prizes to incentivise completion of nine daily behaviour goals. This paper evaluates the theoretical merit of and adherence to these goals. Methods: A qualitative component evaluation methodology was used. Trial data on team activity, demographics and anthropometric outcome data were extracted to determine frequency of daily goal completion by teams throughout the competition and to describe participant characteristics. T-tests were used to compare completion rates of the challenges, challenge completion by day of week and between weekdays and weekends. To examine adherence to the daily challenge activity over 24 weeks the total amount of completed challenges adjusted for number of active teams was plotted by week. A Body Shape Index (ABSI) was used to determine individual anthropometric change from baseline to 8, 16 and 24 weeks. Program documents were analysed to identify barriers to adherence and retention of participants. Results: Of 19 teams (N = 130) who began only five teams performed daily goals across the whole 24 weeks. Adherence was highest during the first 8 weeks. No difference in performance between goals was found suggesting they were equally viable, though tasks worth less points were performed more frequently. Goal completion was higher on weekdays. The behaviour goals appeared to have theoretical merit in that more members of high performing teams experienced a positive change in their ABSI. Conclusions: Incentives offer a promising strategy for encouraging retention in weight loss interventions. This study suggests that participants in a competition will perform incentivised tasks. The findings however, are limited by missing data and high drop out of individuals and whole teams. Further research is needed on how to increase retention.New Zealand Ministry of Healt

Rapid discovery of stable materials by coordinate-free coarse graining.

A fundamental challenge in materials science pertains to elucidating the relationship between stoichiometry, stability, structure, and property. Recent advances have shown that machine learning can be used to learn such relationships, allowing the stability and functional properties of materials to be accurately predicted. However, most of these approaches use atomic coordinates as input and are thus bottlenecked by crystal structure identification when investigating previously unidentified materials. Our approach solves this bottleneck by coarse-graining the infinite search space of atomic coordinates into a combinatorially enumerable search space. The key idea is to use Wyckoff representations, coordinate-free sets of symmetry-related positions in a crystal, as the input to a machine learning model. Our model demonstrates exceptionally high precision in finding unknown theoretically stable materials, identifying 1569 materials that lie below the known convex hull of previously calculated materials from just 5675 ab initio calculations. Our approach opens up fundamental advances in computational materials discovery

Nitric Oxide Modulates Ca2+ Leak and Arrhythmias via S-Nitrosylation of CaMKII

BackgroundNitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca2+ release via S-nitrosylation of CaMKIIδ (Ca2+/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of S-nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca2+ handling and arrhythmogenesis before and during β-adrenergic receptor stimulation.MethodsWe measured Ca2+-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the S-nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S-nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L).ResultsBoth WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca2+ transient response as well as increased Ca2+ spark frequency. However, the increase in Ca2+ spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca2+ sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events.ConclusionsWe conclude that prior S-nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor-induced arrhythmias, but that S-nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting