bluuebunny/crossref_metadata_2025_split huggingface dataset:
Advancements in melanoma immunotherapy: the emergence of Extracellular Vesicle Vaccines
Authors: He Guijuan , Li Yichuan , Zeng Yuyang , Zhang Yong , Jiang Qiong , Zhang Qi , Zhu Jinjin , Gong Jun 
Published: August 2024

AbstractMalignant melanoma represents a particularly aggressive type of skin cancer, originating from the pathological transformation of melanocytes. While conventional interventions such as surgical resection, chemotherapy, and radiation therapy are available, their non-specificity and collateral damage to normal cells has shifted the focus towards immunotherapy as a notable approach. Extracellular vesicles (EVs) are naturally occurring transporters, and are capable of delivering tumor-specific antigens and directly engaging in the immune response. Multiple types of EVs have emerged as promising platforms for melanoma vaccination. The effectiveness of EV-based melanoma vaccines manifests their ability to potentiate the immune response, particularly by activating dendritic cells (DCs) and CD8+ T lymphocytes, through engineering a synergy of antigen presentation and targeted delivery. Here, this review mainly focuses on the construction strategies for EV vaccines from various sources, their effects, and immunological mechanisms in treating melanoma, as well as the shortcomings and future perspectives in this field. These findings will provide novel insights into the innovative exploitation of EV-based vaccines for melanoma immune therapy.
Autosomal dominant stromal corneal dystrophy associated with a SPARCL1 missense variant
Authors: Braddock Freddie L. , Gardner Jessica C. , Bhattacharyya Nihar , Sanchez-Pintado Beatriz , Costa Marcos , Zarouchlioti Christina , Szabo Anita , Lišková Petra , Cheetham Michael E. , Young Robert D. , Thaung Caroline , Davidson Alice E. , Tuft Stephen J. , Hardcastle Alison J. 
Published: August 2024

AbstractCorneal dystrophies are phenotypically and genetically heterogeneous, often resulting in visual impairment caused by corneal opacification. We investigated the genetic cause of an autosomal dominant corneal stromal dystrophy in a pedigree with eight affected individuals in three generations. Affected individuals had diffuse central stromal opacity, with reduced visual acuity in older family members. Histopathology of affected cornea tissue removed during surgery revealed mild stromal textural alterations with alcianophilic deposits. Whole genome sequence data were generated for four affected individuals. No rare variants (MAF < 0.001) were identified in established corneal dystrophy genes. However, a novel heterozygous missense variant in exon 4 of SPARCL1, NM_004684: c.334G > A; p.(Glu112Lys), which is predicted to be damaging, segregated with disease. SPARC-like protein 1 (SPARCL1) is a secreted matricellular protein involved in cell migration, cell adhesion, tissue repair, and remodelling. Interestingly, SPARCL1 has been shown to regulate decorin. Heterozygous variants in DCN, encoding decorin, cause autosomal dominant congenital stromal corneal dystrophy, suggesting a common pathogenic pathway. Therefore, we performed immunohistochemistry to compare SPARCL1 and decorin localisation in corneal tissue from an affected family member and an unaffected control. Strikingly, the level of decorin was significantly decreased in the corneal stroma of the affected tissue, and SPARCL1 appeared to be retained in the epithelium. In summary, we describe a novel autosomal dominant corneal stromal dystrophy associated with a missense variant in SPARCL1, extending the phenotypic and genetic heterogeneity of inherited corneal disease.
A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma
Authors: Zhang Min , Bzura Aleksandra , Baitei Essa Y. , Zhou Zisen , Spicer Jake B. , Poile Charlotte , Rogel Jan , Branson Amy , King Amy , Barber Shaun , Kamata Tamihiro , Dzialo Joanna , Harber James , Greystoke Alastair , Nusrat Nada , Faulkner Daniel , Sun Qianqian , Nolan Luke , Hahne Jens C. , Scotland Molly , Walter Harriet , Darlison Liz , Morgan Bruno , Bajaj Amrita , Brookes Cassandra , Hollox Edward J. , Lubawska Dominika , Jama Maymun , Griffiths Gareth , Nakas Apostolos , Kutywayo Kudzayi , Luo Jin-Li , Klampatsa Astero , Cooper Andrea , Halder Koirobi , Wells-Jordan Peter , Zhou Huiyu , Dudbridge Frank , Thomas Anne , Richards Catherine Jane , Pritchard Catrin , Yang Hongji , Barer Michael , Fennell Dean A. 
Published: August 2024

AbstractMalignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.
Mechanism and regulation of cargo entry into the Commander endosomal recycling pathway
Authors: Butkovič Rebeka , Walker Alexander P. , Healy Michael D. , McNally Kerrie E. , Liu Meihan , Veenendaal Tineke , Kato Kohji , Liv Nalan , Klumperman Judith , Collins Brett M. , Cullen Peter J. 
Published: August 2024

AbstractCommander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.
Rapid heating rates define the volatile emission and regolith composition of (3200) Phaethon
Authors: Suttle Martin D. , Olbrich Lorenz. F. , Bays Charlotte. L. , Riches Liza 
Published: August 2024

AbstractAsteroid (3200) Phaethon experiences extreme solar radiant heating ( ~ 750 °C) during perihelion (0.14 au), leading to comet-like activity. The regolith composition and mechanism of volatile emission are unknown but key to understanding JAXA’s DESTINY+ mission data (fly-by in 2029) and the fate of near-Sun asteroids more generally. By subjecting CM chondrite fragments to fast, open system, cyclic heating (2-20 °C/min), simulating conditions on Phaethon we demonstrate that rapid heating rates combine with the low permeability, resulting in reactions between volatile gases and decomposing minerals. The retention of S-bearing gas limits the thermal decomposition of Fe-sulphides, allowing these minerals to survive repeated heating cycles. Slow escape of S-bearing gases provides a mechanism for repeated gas release from a thermally processed surface and, therefore the comet-like activity without requiring surface renewal to expose fresh material each perihelion cycle. We predict Phaethon regolith is composed of olivine, Fe-sulphides, Ca-sulphates and hematite.
Detecting single gravitons with quantum sensing
Authors: Tobar Germain , Manikandan Sreenath K. , Beitel Thomas , Pikovski Igor 
Published: August 2024

AbstractThe quantization of gravity is widely believed to result in gravitons – particles of discrete energy that form gravitational waves. But their detection has so far been considered impossible. Here we show that signatures of single graviton exchange can be observed in laboratory experiments. We show that stimulated and spontaneous single-graviton processes can become relevant for massive quantum acoustic resonators and that stimulated absorption can be resolved through continuous sensing of quantum jumps. We analyze the feasibility of observing the exchange of single energy quanta between matter and gravitational waves. Our results show that single graviton signatures are within reach of experiments. In analogy to the discovery of the photo-electric effect for photons, such signatures can provide the first experimental clue of the quantization of gravity.
Structural insights into Frizzled3 through nanobody modulators
Authors: Hillier James , Zhao Yuguang , Carrique Loic , Malinauskas Tomas , Ruza Reinis R. , Chang Tao-Hsin , Yi Gangshun , Duyvesteyn Helen M. E. , Yu Jing , Lu Weixian , Pardon Els , Steyaert Jan , Zhu Yanan , Ni Tao , Jones E. Yvonne 
Published: August 2024

AbstractThe Wnt receptor Frizzled3 (FZD3) is important for brain axonal development and cancer progression. We report structures of FZD3 in complex with extracellular and intracellular binding nanobodies (Nb). The crystal structure of Nb8 in complex with the FZD3 cysteine-rich domain (CRD) reveals that the nanobody binds at the base of the lipid-binding groove and can compete with Wnt5a. Nb8 fused with the Dickkopf-1 C-terminal domain behaves as a FZD3-specific Wnt surrogate, activating β-catenin signalling. The cryo-EM structure of FZD3 in complex with Nb9 reveals partially resolved density for the CRD, which exhibits positional flexibility, and a transmembrane conformation that resembles active GPCRs. Nb9 binds to the cytoplasmic region of FZD3 at the putative Dishevelled (DVL) or G protein-binding site, competes with DVL binding, and inhibits GαS coupling. In combination, our FZD3 structures with nanobody modulators map extracellular and intracellular interaction surfaces of functional, and potentially therapeutic, relevance.
Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection
Authors: Ko Sung Hee , Radecki Pierce , Belinky Frida , Bhiman Jinal N. , Meiring Susan , Kleynhans Jackie , Amoako Daniel , Guerra Canedo Vanessa , Lucas Margaret , Kekana Dikeledi , Martinson Neil , Lebina Limakatso , Everatt Josie , Tempia Stefano , Bylund Tatsiana , Rawi Reda , Kwong Peter D. , Wolter Nicole , von Gottberg Anne , Cohen Cheryl , Boritz Eli A. 
Published: August 2024

AbstractPrevious studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/μL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/μL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern.
Predictions enable top-down pattern separation in the macaque face-processing hierarchy
Authors: Nigam Tarana , Schwiedrzik Caspar M. 
Published: August 2024

AbstractDistinguishing faces requires well distinguishable neural activity patterns. Contextual information may separate neural representations, leading to enhanced identity recognition. Here, we use functional magnetic resonance imaging to investigate how predictions derived from contextual information affect the separability of neural activity patterns in the macaque face-processing system, a 3-level processing hierarchy in ventral visual cortex. We find that in the presence of predictions, early stages of this hierarchy exhibit well separable and high-dimensional neural geometries resembling those at the top of the hierarchy. This is accompanied by a systematic shift of tuning properties from higher to lower areas, endowing lower areas with higher-order, invariant representations instead of their feedforward tuning properties. Thus, top-down signals dynamically transform neural representations of faces into separable and high-dimensional neural geometries. Our results provide evidence how predictive context transforms flexible representational spaces to optimally use the computational resources provided by cortical processing hierarchies for better and faster distinction of facial identities.
Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition
Authors: Ealo Thais , Sanchez-Gaya Victor , Respuela Patricia , Muñoz-San Martín María , Martin-Batista Elva , Haro Endika , Rada-Iglesias Alvaro 
Published: August 2024

AbstractThe specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants.
The translocation assembly module (TAM) catalyzes the assembly of bacterial outer membrane proteins in vitro
Authors: Wang Xu , Nyenhuis Sarah B. , Bernstein Harris D. 
Published: August 2024

AbstractThe translocation and assembly module (TAM) has been proposed to play a crucial role in the assembly of a small subset of outer membrane proteins (OMPs) in Proteobacteria based on experiments conducted in vivo using tamA and tamB mutant strains and in vitro using biophysical methods. TAM consists of an OMP (TamA) and a periplasmic protein that is anchored to the inner membrane by a single α helix (TamB). Here we examine the function of the purified E. coli complex in vitro after reconstituting it into proteoliposomes. We find that TAM catalyzes the assembly of four model OMPs nearly as well as the β-barrel assembly machine (BAM), a universal heterooligomer that contains a TamA homolog (BamA) and that catalyzes the assembly of almost all E. coli OMPs. Consistent with previous results, both TamA and TamB are required for significant TAM activity. Our study provides direct evidence that TAM can function as an independent OMP insertase and describes a new method to gain insights into TAM function.
Translation in Bacillus subtilis is spatially and temporally coordinated during sporulation
Authors: Iwańska Olga , Latoch Przemysław , Kopik Natalia , Kovalenko Mariia , Lichocka Małgorzata , Serwa Remigiusz , Starosta Agata L. 
Published: August 2024

AbstractThe transcriptional control of sporulation in Bacillus subtilis is reasonably well understood, but its translational control is underexplored. Here, we use RNA-seq, ribosome profiling and fluorescence microscopy to study the translational dynamics of B. subtilis sporulation. We identify two events of translation silencing and describe spatiotemporal changes in subcellular localization of ribosomes during sporulation. We investigate the potential regulatory role of ribosomes during sporulation using a strain lacking zinc-independent paralogs of three zinc-dependent ribosomal proteins (L31, L33 and S14). The mutant strain exhibits delayed sporulation, reduced germination efficiency, dysregulated translation of metabolic and sporulation-related genes, and disruptions in translation silencing, particularly in late sporulation.
A phase 3 study (PATHWAY) of palbociclib plus tamoxifen in patients with HR-positive/HER2-negative advanced breast cancer
Authors: Noguchi Emi , Yamanaka Takashi , Mukai Hirofumi , Yamamoto Naohito , Chung Chi-Feng , Lu Yen-Shen , Chang Dwan-Ying , Sohn Joohyuk , Kim Gun Min , Lee Kyung-Hun , Lee Soo-Chin , Iwasa Tsutomu , Iwata Hiroji , Watanabe Kenichi , Jung Kyung Hae , Tanabe Yuko , Kang Seok Yun , Yasojima Hiroyuki , Aogi Kenjiro , Tokunaga Eriko , Sim Sung Hoon , Yap Yoon Sim , Matsumoto Koji , Tseng Ling-Ming , Umeyama Yoshiko , Sudo Kazuki , Kojima Yuki , Hata Tomomi , Kuchiba Aya , Shibata Taro , Nakamura Kenichi , Fujiwara Yasuhiro , Tamura Kenji , Yonemori Kan 
Published: August 2024

AbstractPalbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.
Beating one bit of communication with and without quantum pseudo-telepathy
Authors: Márton István , Bene Erika , Diviánszky Péter , Vértesi Tamás 
Published: August 2024

AbstractAccording to Bell’s theorem, certain entangled states cannot be simulated classically using local hidden variables (LHV). Suppose that we can augment LHV by some amount of classical communication. The question then arises as to how many bits are needed to simulate entangled states? There is very strong evidence that a single bit of communication is powerful enough to simulate projective measurements on any two-qubit entangled state. However, the problem of simulating measurements on higher-dimensional systems remains largely unexplored. In this study, we present Bell-like scenarios, even with three inputs per party, in which bipartite correlations resulting from measurements on higher-dimensional states cannot be simulated with a single bit of communication. We consider the case where the communication direction is fixed and the case where it is bidirectional. To this end, we introduce constructions based on parallel repetition of pseudo-telepathy games and an original algorithm based on branch-and-bound technique to compute the one-bit classical bound. Two copies of emblematic Bell expressions, such as the Magic square pseudo-telepathy game, prove to be particularly powerful, requiring a 16 × 16 state to beat the bidirectional one-bit classical bound, and look a promising candidate for implementation on an optical platform.
Bolometric detection of Josephson radiation
Authors: Karimi Bayan , Steffensen Gorm Ole , Higginbotham Andrew P. , Marcus Charles M. , Levy Yeyati Alfredo , Pekola Jukka P. 
Published: August 2024

AbstractOne of the most promising approaches towards large-scale quantum computation uses devices based on many Josephson junctions. Yet, even today, open questions regarding the single junction remain unsolved, such as the detailed understanding of the quantum phase transitions, the coupling of the Josephson junction to the environment or how to improve the coherence of a superconducting qubit. Here we design and build an engineered on-chip reservoir connected to a Josephson junction that acts as an efficient bolometer for detecting the Josephson radiation under non-equilibrium, that is, biased conditions. The bolometer converts the a.c. Josephson current at microwave frequencies up to about 100 GHz into a temperature rise measured by d.c. thermometry. A circuit model based on realistic parameter values captures both the current–voltage characteristics and the measured power quantitatively. The present experiment demonstrates an efficient, wide-band, thermal detection scheme of microwave photons and provides a sensitive detector of Josephson dynamics beyond the standard conductance measurements.