Stability and Reversibility of Lithium Borohydrides Doped by Metal Halides and Hydrides

In an effort to develop reversible metal borohydrides with high hydrogen storage capacities and low dehydriding temperature, doping LiBH4 with various metal halides and hydrides has been conducted. Several metal halides such as TiCl3, TiF3, and ZnF2 effectively reduced the dehydriding temperature through a cation exchange interaction. Some of the halide doped LiBH4 are partially reversible. The LiBH4 + 0.1TiF3 desorbed 3.5 wt % and 8.5 wt % hydrogen at 150 and 450 °C, respectively, with subsequent reabsorption of 6 wt % hydrogen at 500 °C and 70 bar observed. XRD and NMR analysis of the rehydrided samples confirmed the reformation of LiBH4. The existence of the (B12H12)−2 species in dehydrided and rehydrided samples gives insight into the resultant partial reversibility. A number of other halides, MgF2, MgCl2, CaCl2, SrCl2, and FeCl3, did not reduce the dehydriding temperature of LiBH4 significantly. XRD and TGA-RGA analyses indicated that an increasing proportion of halides such as TiCl3, TiF3, and ZnCl2 from 0.1 to 0.5 mol makes lithium borohydrides less stable and volatile. Although the less stable borohydrides such as LiBH4 + 0.5TiCl3, LiBH4 + 0.5TiF3, and LiBH4 + 0.5ZnCl2 release hydrogen at room temperature, they are not reversible due to unrecoverable boron loss caused by diborane emission. In most cases, doping that produced less stable borohydrides also reduced the reversible hydrogen uptake. It was also observed that halide doping changed the melting points and reduced air sensitivity of lithium borohydrides

User Feedback on Celebratory Technology Model for Reducing Stigma

Social stigma is a complex manifestation that affects humanity, particularly individuals with disabilities and other marginalized groups, including those with physical, cognitive, and emotional conditions. Society often judges these individuals\u27 interactions with the world, and many technologies designed to assist those with disabilities attempt to change their daily interactions and behaviors. Nonetheless, when the emphasis is placed on validating disabled identities, there is a potential for it to be seen as inspiration porn. This approach might inadvertently reduce inclusivity and do little to challenge negative stereotypes; it can also lead to the objectification of individuals with disabilities. Therefore, this project presents the notion of Celebratory Technologies for Neurodiversity, which aims to promote inclusivity and empower stigmatized individuals. This concept strives to level the playing field, rather than serving as a solitary source of inspiration for nondisabled observers. In this context, a Figma diagram and a user survey were created using Maze to gather feedback from students at Chapman University on the concept of Celebratory Technology. This valuable input will help refine and develop Celebratory Technologies for Neurodiversity, drawing upon social change frameworks, principles of the Neurodiversity movement, and insights from marginalized groups on how to reduce stigma. The Figma prototype introduces Celebratory Technology in the form of a colorful visual representation of the participants’ answers to a personality survey, with the goal of showcasing users from different backgrounds and identities in an abstract way. This in turn has a goal of celebrating uniqueness and individuality without implementing labels or alienation. This project serves as a preliminary step in introducing Celebratory Technology and aims to expand the conversation of ways to mitigate social stigma. Initial suggestions for creating supportive Celebratory Technologies for Neurodiversity are provided in this project

Selective drug delivery approaches to lesioned brain through blood brain barrier disruption

Introduction: The development of therapeutics for central nervous system (CNS) disorders is still considered a challenging area in drug development due to insufficient translocation through the blood-brain barrier (BBB). Under normal conditions, BBB restrict the penetration of more than 98% of blood-borne molecules including drugs to the CNS. However, recent research findings have proven that the nature of the BBB is altered in several neurological conditions. This complexity encourages revisiting drug delivery strategies to the CNS as this can give a wide range of opportunities for CNS drug development. Areas covered: This review focuses on nanotechnology-based drug delivery platforms designed for selective recruitment into the lesioned brain by taking advantages of BBB disruption that is associated with certain neurological conditions. Expert opinion: Current CNS therapeutic strategies do not fully address the pathophysiological adaptation of BBB in their design. The lack of selective delivery to the brain lesions has been the culprit behind the failure of many CNS therapeutics. This highlighted the need for smart designs of advanced drug delivery systems that take advantage of BBB structural changes in CNS diseases. Recently, promising examples have been reported in this area, however, more work is still required beyond the preclinical testing

Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review

Background: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. Materials and methods: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. Results: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. Conclusion: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice

Misregulation of Scm3p/HJURP Causes Chromosome Instability in Saccharomyces cerevisiae and Human Cells

The kinetochore (centromeric DNA and associated proteins) is a key determinant for high fidelity chromosome transmission. Evolutionarily conserved Scm3p is an essential component of centromeric chromatin and is required for assembly and function of kinetochores in humans, fission yeast, and budding yeast. Overexpression of HJURP, the mammalian homolog of budding yeast Scm3p, has been observed in lung and breast cancers and is associated with poor prognosis; however, the physiological relevance of these observations is not well understood. We overexpressed SCM3 and HJURP in Saccharomyces cerevisiae and HJURP in human cells and defined domains within Scm3p that mediate its chromosome loss phenotype. Our results showed that the overexpression of SCM3 (GALSCM3) or HJURP (GALHJURP) caused chromosome loss in a wild-type yeast strain, and overexpression of HJURP led to mitotic defects in human cells. GALSCM3 resulted in reduced viability in kinetochore mutants, premature separation of sister chromatids, and reduction in Cse4p and histone H4 at centromeres. Overexpression of CSE4 or histone H4 suppressed chromosome loss and restored levels of Cse4p at centromeres in GALSCM3 strains. Using mutant alleles of scm3, we identified a domain in the N-terminus of Scm3p that mediates its interaction with CEN DNA and determined that the chromosome loss phenotype of GALSCM3 is due to centromeric association of Scm3p devoid of Cse4p/H4. Furthermore, we determined that similar to other systems the centromeric association of Scm3p is cell cycle regulated. Our results show that altered stoichiometry of Scm3p/HJURP, Cse4p, and histone H4 lead to defects in chromosome segregation. We conclude that stringent regulation of HJURP and SCM3 expression are critical for genome stability

A short-term in situ CO2 enrichment experiment on Heron Island (GBR)

Ocean acidification poses multiple challenges for coral reefs on molecular to ecological scales, yet previous experimental studies of the impact of projected CO2 concentrations have mostly been done in aquarium systems with corals removed from their natural ecosystem and placed under artificial light and seawater conditions. The Coral–Proto Free Ocean Carbon Enrichment System (CP-FOCE) uses a network of sensors to monitor conditions within each flume and maintain experimental pH as an offset from environmental pH using feedback control on the injection of low pH seawater. Carbonate chemistry conditions maintained in the −0.06 and −0.22 pH offset treatments were significantly different than environmental conditions. The results from this short-term experiment suggest that the CP-FOCE is an important new experimental system to study in situ impacts of ocean acidification on coral reef ecosystems

The swan genome and transcriptome, its not all black and white

BACKGROUND: The Australian black swan (Cygnus atratus) is an iconic species with contrasting plumage to that of the closely related northern hemisphere white swans. The relative geographic isolation of the black swan may have resulted in a limited immune repertoire and increased susceptibility to infectious diseases, notably infectious diseases from which Australia has been largely shielded. Unlike mallard ducks and the mute swan (Cygnus olor), the black swan is extremely sensitive to highly pathogenic avian influenza. Understanding this susceptibility has been impaired by the absence of any available swan genome and transcriptome information. RESULTS: Here, we generate the first chromosome-length black and mute swan genomes annotated with transcriptome data, all using long-read based pipelines generated for vertebrate species. We use these genomes and transcriptomes to show that unlike other wild waterfowl, black swans lack an expanded immune gene repertoire, lack a key viral pattern-recognition receptor in endothelial cells and mount a poorly controlled inflammatory response to highly pathogenic avian influenza. We also implicate genetic differences in SLC45A2 gene in the iconic plumage of the black swan. CONCLUSION: Together, these data suggest that the immune system of the black swan is such that should any avian viral infection become established in its native habitat, the black swan would be in a significant peril. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-022-02838-0

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.</p

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action