NiTi-Cu Bimetallic Structure Fabrication through Wire Arc Additive Manufacturing.

This study endeavors to comprehensively explore and elucidate the seamless integration of NiTi shape memory alloys (SMAs) into multifaceted applications through the utilization of novel joining techniques. The primary focus lies in the utilization of wire arc additive manufacturing (WAAM) to deposit Nitinol (NiTi) onto Copper (Cu), thereby introducing a transformative approach for their integration into electro-mechanical systems and beyond. Through a detailed examination of the NiTi/Cu bimetallic junction, using advanced analytical techniques including SEM, XRD, and DSC analyses, this research aims to unravel the intricate complexities inherent within the interface. The SEM images and X-ray patterns obtained reveal a complex and nuanced interface characterized by a broad mixed zone comprising various constituents, including Ti(Ni,Cu)2, pure Cu, Ti2(Ni,Cu)3 precipitates, and Ni-rich NiTi precipitates. The DSC results, showcasing low-intensity broad peaks during thermal cycling, underscore the inherent challenges in demonstrating functional properties within the NiTi/Cu system. Recognizing the critical importance of an enhanced martensitic transformation, this study delves into the effects of heat treatment. Calorimetric curves post-annealing at 500 °C exhibit distinct transformation peaks, shedding light on the intricate influence of NiTi layer distribution within the junction. The optimal heat treatment parameters for NiTi/Cu junction restoration are meticulously explored and determined at 500 °C for a duration of 12 h. Furthermore, the study offers valuable insights into optimizing NiTi-Cu joints, with micro-hardness values reaching 485 HV and compressive strength scaling up to 650 MPa. These significant findings not only hold promise for diverse applications across various industries but also pave the way for further research directions and explorations into the realm of SMA integration and advanced joining methodologies.

Mechanical Properties, Microstructure, and Actuation Behavior of Wire Arc Additive Manufactured Nitinol: Titanium Bimetallic Structures.

Nitinol (NiTi) is well known for its corrosion resistance, shape memory effect, superelasticity, and biocompatibility, whereas Titanium (Ti) is well known for its high specific strength, corrosion resistance, and biocompatibility. The bimetallic joint of NiTi and Ti is required for applications that require tailored properties at different locations within the same component, as well as to increase design flexibility while reducing material costs. However, because of the formation of brittle intermetallic phases, connecting NiTi and Ti is difficult. In the present study, a systematic experimental investigation is carried out to develop NiTi-Ti bimetallic joint using wire arc additive manufacturing (WAAM) for the first time and to evaluate its microstructure, mechanical properties, martensitic transformation, and actuation behavior in the as-built condition. The defect-free joint is obtained through WAAM and microstructural studies indicate the formation of intermetallics at the NiTi-Ti interface leading to higher microhardness values (600 HV). Shape recovery behavior and phase transformation temperature were also enhanced in comparison to NiTi. An improved actuation and bending angle recovery is observed in comparison with NiTi. The present study lays the way for the use of WAAM in the construction of NiTi and Ti bimetallic structures for engineering and medicinal applications.

Exploring Co-occurring POLE Exonuclease and Non-exonuclease Domain Mutations and Their Impact on Tumor Mutagenicity.

POLE driver mutations in the exonuclease domain (ExoD driver) are prevalent in several cancers, including colorectal cancer and endometrial cancer, leading to dramatically ultra-high tumor mutation burden (TMB). To understand whether POLE mutations that are not classified as drivers (POLE Variant) contribute to mutagenesis, we assessed TMB in 447 POLE-mutated colorectal cancers, endometrial cancers, and ovarian cancers classified as TMB-high ≥10 mutations/Mb (mut/Mb) or TMB-low <10 mut/Mb. TMB was significantly highest in tumors with "POLE ExoD driver plus POLE Variant" (colorectal cancer and endometrial cancer, P < 0.001; ovarian cancer, P < 0.05). TMB increased with additional POLE variants (P < 0.001), but plateaued at 2, suggesting an association between the presence of these variants and TMB. Integrated analysis of AlphaFold2 POLE models and quantitative stability estimates predicted the impact of multiple POLE variants on POLE functionality. The prevalence of immunogenic neoepitopes was notably higher in the "POLE ExoD driver plus POLE Variant" tumors. Overall, this study reveals a novel correlation between POLE variants in POLE ExoD-driven tumors, and ultra-high TMB. Currently, only select pathogenic ExoD mutations with a reliable association with ultra-high TMB inform clinical practice. Thus, these findings are hypothesis-generating, require functional validation, and could potentially inform tumor classification, treatment responses, and clinical outcomes. SIGNIFICANCE: Somatic POLE ExoD driver mutations cause proofreading deficiency that induces high TMB. This study suggests a novel modifier role for POLE variants in POLE ExoD-driven tumors, associated with ultra-high TMB. These data, in addition to future functional studies, may inform tumor classification, therapeutic response, and patient outcomes.

A Dy-based single ion magnet in a SrLaGaO4 matrix: enhanced parameters in an expanded crystal lattice.

Dy3+ doped SrLaGaO4 exhibits unusually slow relaxation of magnetization determined by two widely separated excited Kramers doublets with a second remagnetization energy barrier of 223 cm-1. This value considerably exceeds that for analogous Ca(Y,Dy)AlO4 in spite of the apparently enlarged Dy3+ coordination sphere.

Targeting Methionine Addiction of Cancer Cells with Methioninase.

All types of cancer cells are addicted to methionine, which is known as the Hoffman effect. Restricting methionine inhibits the growth and proliferation of all tested types of cancer cells, leaving normal cells unaffected. Targeting methionine addiction with methioninase (METase), either alone or in combination with common cancer chemotherapy drugs, has been shown as an effective and safe therapy in various types of cancer cells and animal cancer models. About six years ago, recombinant METase (rMETase) was found to be able to be taken orally as a supplement, resulting in anecdotal positive results in patients with advanced cancer. Currently, there are 8 published clinical studies on METase, including two from the 1990s and six more recent ones. This review focuses on the results of clinical studies on METase-mediated methionine restriction, in particular, on the dosage of oral rMETase taken alone as a supplement or in combination with common chemotherapeutic agents in patients with advanced cancer.

The smashHitCore Ontology for GDPR-Compliant Sensor Data Sharing in Smart Cities.

The adoption of the General Data Protection Regulation (GDPR) has resulted in a significant shift in how the data of European Union citizens is handled. A variety of data sharing challenges in scenarios such as smart cities have arisen, especially when attempting to semantically represent GDPR legal bases, such as consent, contracts and the data types and specific sources related to them. Most of the existing ontologies that model GDPR focus mainly on consent. In order to represent other GDPR bases, such as contracts, multiple ontologies need to be simultaneously reused and combined, which can result in inconsistent and conflicting knowledge representation. To address this challenge, we present the smashHitCore ontology. smashHitCore provides a unified and coherent model for both consent and contracts, as well as the sensor data and data processing associated with them. The ontology was developed in response to real-world sensor data sharing use cases in the insurance and smart city domains. The ontology has been successfully utilised to enable GDPR-complaint data sharing in a connected car for insurance use cases and in a city feedback system as part of a smart city use case.

Effect of Methyl Jasmonate on the Growth and Biosynthesis of C13- and C14-Hydroxylated Taxoids in the Cell Culture of Yew (Taxus wallichiana Zucc.) of Different Ages.

The effects of methyl jasmonate (MeJ) on growth and taxoid formation in the cell culture of Taxus wallichiana were investigated to elucidate the specifics of phytohormone action in dedifferentiated plant cells in vitro. The characteristics of the same suspension cell culture were compared in 2017 (the «young¼ culture) and in 2022 (the «old¼ culture)-1.5 or 6 years after culture induction, respectively. MeJ (100 µM) is added to the cell suspension at the end of the exponential growth phase. Cell culture demonstrated good growth (dry weight accumulation 10-18 g/L, specific growth rate µ = 0.15-0.35 day-1) regardless of its «age¼, cultivation system, and MeJ addition. UPLC-ESI-MS analysis revealed the presence of C14-hydroxylated taxoids (yunnanxane, taxuyunnanine C, sinenxane C, and sinenxane B) in the cell biomass. The content of C14-OH taxoids increased from 0.2-1.6 mg/gDW in «young¼ culture to 0.6-10.1 mg/gDW in «old¼ culture. Yunnanxane was the main compound in «young¼ culture, while sinenxane C predominated in «old¼ culture. Without elicitation, small amounts of C13-OH taxoids (<0.05 mg/gDW) were found only in «young¼ cultures. MeJ addition to «young¼ culture had no effect on the content of C14-OH taxoids but caused a 10-fold increase in C13-OH taxoid production (up to 0.12-0.19 mg/gDW, comparable to the bark of yew trees). By contrast, MeJ added to «old¼ culture was not beneficial for the production of C13-OH taxoids but notably increased the content of C14-OH taxoids (1.5-2.0 times in flasks and 5-8 times in bioreactors). These findings suggest that hormonal signaling in dedifferentiated yew cells grown in vitro is different from that in plants and can be affected by the culture's age. This might be a result of the high level of culture heterogeneity and constant auto-selection for intensive proliferation, which leads to the predominant formation of C14-OH taxoids versus C13-OH taxoids and a modified cell response to exogenous MeJ treatment.

Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing.

BACKGROUND: Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. METHODS: Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. RESULTS: Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of [Formula: see text]H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased [Formula: see text]H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. CONCLUSIONS: Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

Profiling of Taxoid Compounds in Plant Cell Cultures of Different Species of Yew (Taxus spp.).

Plant cell cultures of various yew species are a profitable source of taxoids (taxane diterpenoids) with antitumor activity. So far, despite intensive studies, the principles of the formation of different groups of taxoids in cultured in vitro plant cells have not been fully revealed. In this study, the qualitative composition of taxoids of different structural groups was assessed in callus and suspension cell cultures of three yew species (Taxus baccata, T. canadensis, and T. wallichiana) and two T. × media hybrids. For the first time, 14-hydroxylated taxoids were isolated from the biomass of the suspension culture of T. baccata cells, and their structures were identified by high-resolution mass spectrometry and NMR spectroscopy as 7ß-hydroxy-taxuyunnanin C, sinenxane C, taxuyunnanine C, 2α,5α,9α,10ß,14ß-pentaacetoxy-4(20), 11-taxadiene, and yunnanxane. UPLC-ESI-MS screening of taxoids was performed in more than 20 callus and suspension cell lines originating from different explants and grown in over 20 formulations of nutrient media. Regardless of the species, cell line origin, and conditions, most of the investigated cell cultures retained the ability to form taxane diterpenoids. Nonpolar 14-hydroxylated taxoids (in the form of polyesters) were predominant under in vitro culture conditions in all cell lines. These results, together with the literature data, suggest that dedifferentiated cell cultures of various yew species retain the ability to synthesize taxoids, but predominantly of the 14-OH taxoid group compared to the 13-OH taxoids found in plants.

LaSER: Language-specific event recommendation.

While societal events often impact people worldwide, a significant fraction of events has a local focus that primarily affects specific language communities. Examples include national elections, the development of the Coronavirus pandemic in different countries, and local film festivals such as the César Awards in France and the Moscow International Film Festival in Russia. However, existing entity recommendation approaches do not sufficiently address the language context of recommendation. This article introduces the novel task of language-specific event recommendation, which aims to recommend events relevant to the user query in the language-specific context. This task can support essential information retrieval activities, including web navigation and exploratory search, considering the language context of user information needs. We propose LaSER, a novel approach toward language-specific event recommendation. LaSER blends the language-specific latent representations (embeddings) of entities and events and spatio-temporal event features in a learning to rank model. This model is trained on publicly available Wikipedia Clickstream data. The results of our user study demonstrate that LaSER outperforms state-of-the-art recommendation baselines by up to 33 percentage points in MAP@5 concerning the language-specific relevance of recommended events.

Polλ promotes microhomology-mediated end-joining.

The double-strand break (DSB) repair pathway called microhomology-mediated end-joining (MMEJ) is thought to be dependent on DNA polymerase theta (Polθ) and occur independently of nonhomologous end-joining (NHEJ) factors. An unresolved question is whether MMEJ is facilitated by a single Polθ-mediated end-joining pathway or consists of additional undiscovered pathways. We find that human X-family Polλ, which functions in NHEJ, additionally exhibits robust MMEJ activity like Polθ. Polλ promotes MMEJ in mammalian cells independently of essential NHEJ factors LIG4/XRCC4 and Polθ, which reveals a distinct Polλ-dependent MMEJ mechanism. X-ray crystallography employing in situ photo-induced DSB formation captured Polλ in the act of stabilizing a microhomology-mediated DNA synapse with incoming nucleotide at 2.0 Å resolution and reveals how Polλ performs replication across a DNA synapse joined by minimal base-pairing. Last, we find that Polλ is semisynthetic lethal with BRCA1 and BRCA2. Together, these studies indicate Polλ MMEJ as a distinct DSB repair mechanism.

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology.

DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADP-ribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.

RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy.

RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA studies, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3-8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cancers that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to cancers that are unaltered or those that have amplifications in RRM2B or MYC only. Investigation of curated biological interactions revealed that gene products of the amplified 8q22.3-8q24 region have important roles in DNA repair, DNA damage response, oxygen sensing, and apoptosis pathways and interact functionally. Notably, RRM2B-amplified cancers are characterized by mutation signatures of defective DNA repair and oxidative stress, and at least RRM2B-amplified breast cancers are associated with poor clinical outcome. These data suggest alterations in RR2MB and possibly the interacting 8q-proteins could have a profound effect on regulatory pathways such as DNA repair and cellular survival, highlighting therapeutic opportunities in these cancers.

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer.

Pathogenic variants (PVs) in multiple genes are known to increase the risk of early-onset renal cancer (eoRC). However, many eoRC patients lack PVs in RC-specific genes; thus, their genetic risk remains undefined. Here, we determine if PVs in DNA damage response and repair (DDRR) genes are enriched in eoRC patients undergoing cancer risk assessment. Retrospective review of de-identified results from 844 eoRC patients, undergoing testing with a multi-gene panel, for a variety of indications, by Ambry Genetics. PVs in cancer-risk genes were identified in 12.8% of patients-with 3.7% in RC-specific, and 8.55% in DDRR genes. DDRR gene PVs were most commonly identified in CHEK2, BRCA1, BRCA2, and ATM. Among the 2.1% of patients with a BRCA1 or BRCA2 PV, < 50% reported a personal history of hereditary breast or ovarian-associated cancer. No association between age of RC diagnosis and prevalence of PVs in RC-specific or DDRR genes was observed. Additionally, 57.9% patients reported at least one additional cancer; breast cancer being the most common (40.1% of females, 2.5% of males). Multi-gene testing including DDRR genes may provide a more comprehensive risk assessment in eoRC patients. Further validation is needed to characterize the association with eoRC.

Interaction of germline variants in a family with a history of early-onset clear cell renal cell carcinoma.

BACKGROUND: Identification of genetic factors causing predisposition to renal cell carcinoma has helped improve screening, early detection, and patient survival. METHODS: We report the characterization of a proband with renal and thyroid cancers and a family history of renal and other cancers by whole-exome sequencing (WES), coupled with WES analysis of germline DNA from additional affected and unaffected family members. RESULTS: This work identified multiple predicted protein-damaging variants relevant to the pattern of inherited cancer risk. Among these, the proband and an affected brother each had a heterozygous Ala45Thr variant in SDHA, a component of the succinate dehydrogenase (SDH) complex. SDH defects are associated with mitochondrial disorders and risk for various cancers; immunochemical analysis indicated loss of SDHB protein expression in the patient's tumor, compatible with SDH deficiency. Integrated analysis of public databases and structural predictions indicated that the two affected individuals also had additional variants in genes including TGFB2, TRAP1, PARP1, and EGF, each potentially relevant to cancer risk alone or in conjunction with the SDHA variant. In addition, allelic imbalances of PARP1 and TGFB2 were detected in the tumor of the proband. CONCLUSION: Together, these data suggest the possibility of risk associated with interaction of two or more variants.

Luteal phase defect is associated with impaired VEGF mRNA expression in the secretory phase endometrium.

Endometrial morphology and expression of vascular endothelial growth factor (VEGF) was examined in the endometria of women with history of recurrent miscarriage (RM group) and of fertile women without history of gynecological diseases (control group). Luteal phase defect (LPD) was diagnosed in 42% cases in the RM group vs. 13% in controls. Endometrial VEGF mRNA expression was lower in LPD endometria compared to mature endometria. In conclusion, LPD in non-pregnant endometrium is associated with angiogenic abnormalities and may cause pregnancy complications.