bluuebunny/crossref_metadata_2025 huggingface dataset:
Fluvial‐Aeolian Interaction and Compositional Variability in the River‐Fed Yarlung Tsangpo Dune System (Southern Tibet)
Authors: Liang Wendong , Hu Xiumian , Garzanti Eduardo , Dong Xiaolong , Zhang Yiqiu
Published: April 2023

River‐fed dune fields characterized by relatively low quartz content are much more common on Earth than generally assumed, and the aeolian dune field system in the Yarlung Tsangpo (Upper Brahmaputra) river catchment is considered a typical example. As one of the highest‐altitude fluvial‐aeolian systems on Earth, the dune fields in different wide tracts of the Yarlung Tsangpo valley, made of sand entirely blown from the adjacent river bed, provides an excellent natural laboratory in which to investigate the diverse factors controlling textural and compositional changes induced by aeolian processes. To this aim, the textural (grain‐size, roundness) and compositional (petrography, heavy minerals) properties of multiple size classes of fluvial and aeolian sands were quantified. The results show that sediment composition is markedly controlled by grain size, with greater intrasample than intersample variability. Grain‐size controlled compositional differences cannot be exclusively ascribed to hydraulic‐sorting effects. Independent of their density or shape, quartz, sedimentary rock fragments, zircon, apatite, and epidote grains are observed to be on average smaller than feldspars, volcanic rock fragments, and pyroxenes. This indicates that the original size of minerals in source rocks also played a significant role, limiting their availability in finer (e.g., garnet) or coarser (e.g., apatite) classes. In the river‐fed dune system, the lower content of phyllosilicates and higher grain roundness could represent useful criteria to distinguish aeolian from fluvial sand. The efficient aeolian abrasion of river‐fed sediments on the Tibetan Plateau may be an effective mechanism for the production of dust deposited as vast loess covers during the Quaternary.
Paleoceanographic Implications of Diatom Seasonal Laminations in the Upper Miocene Pisco Formation (Ica Desert, Peru) and Their Clues on the Development of the Pisco Fossil‐Lagerstätte
Authors: Gariboldi Karen , Pike Jennifer , Malinverno Elisa , Di Celma Claudio , Gioncada Anna , Bianucci Giovanni
Published: April 2023

The detailed study of diatom laminations conducted by means of backscattered electron imaging serves as tool to unravel details of past ocean dynamics. In this paper we apply this method to the analysis of the diatomites of Cerro Los Quesos, Upper Miocene Pisco Fm, Peru. Numerous studies have been conducted on the Pisco Fm; however, a focus on its paleoceanographic significance is still lacking. In this work, we provide information on the oceanographic setting in the area at the time of diatomites deposition. The high abundance of deep‐living Coscinodiscus laminae, proceeded by either a mixed lamina or a terrigenous one, let us hypothesize a deep position of the thermocline during the deposition of the Pisco diatomites; together with the scarcity of Chaetoceros Hyalochaete spp. resting spores, this evidence confutes the belief that equals high biogenic silica content in marine sediments with enhanced upwelling. Conversely, the depositional setting of the Pisco Fm diatomites is more similar to what is known as “permanent El Niño” (or “El Padre”) state, meaning a constant weakened upwelling (or upwelling of nutrients‐poor waters). Climate modeling warns that an increase in atmospheric CO2 may lead to this mean state in the near future. Thanks to this study we also obtained refined information on the diatomites sedimentations rates. The comparison of the Pisco diatomites sedimentation rates with those of Quaternary diatomites gave strength to the hypothesis that the formation of the vertebrate Lagerstätte may have been enhanced, among others, by the so‐called “impact‐burial” mechanism.
Substantial Upper Plate Faulting Above a Shallow Subduction Megathrust Earthquake: Mechanics and Implications of the Surface Faulting During the 2016 Kaikoura, New Zealand, Earthquake
Authors: Herman M. W. , Furlong K. P. , Benz H. M.
Published: April 2023

The 2016 moment magnitude 7.8 Kaikoura, New Zealand, earthquake occurred at the southern end of the Hikurangi subduction zone where the upper plate above the shallow megathrust is exposed sub‐aerially. As a result, the substantial co‐seismic deformation in the upper plate above the megathrust rupture was observed geologically and geodetically. We explore the relationship between this surface faulting and the subduction megathrust rupture and find that the greatest upper plate fault slip occurred coincident (in time and location) with the megathrust rupture. Models of Coulomb stress change demonstrate that these surface faults become positively loaded as the upper plate rebounds during the megathrust event, favoring fault slip. In addition, during the megathrust rupture these faults terminate against an uncoupled subduction plate interface. We simulate the effects of decoupling at the base of these faults and find that very large fault slip is an expected consequence of this decoupling, allowing near‐complete strain release. In contrast, typical strike‐slip faults, pinned at their base, would have lower amounts of fault slip. These two conditions—increased Coulomb stress and basal decoupling—combine to produce the extreme co‐seismic upper plate faulting observed above the shallow Kaikoura megathrust earthquake. Similar conditions occur in other global subduction zones, but in most subduction zones the region above the coupled megathrust is underwater and poorly observed. Our analysis of the Kaikoura earthquake indicates a need to reevaluate patterns of strain accumulation and release in these regions, rather than assuming simple models of elastic rebound.
Carbon Sink Models Need Nitrogen
Authors: Fritts Rachel
Published: April 2023

If terrestrial biosphere models don’t include nitrogen, they will overestimate carbon sequestration.
AML classification in the year 2023: How to avoid a Babylonian confusion of languages
Authors: Huber Sandra , Baer Constance , Hutter Stephan , Dicker Frank , Meggendorfer Manja , Pohlkamp Christian , Kern Wolfgang , Haferlach Torsten , Haferlach Claudia , Hoermann Gregor
Published: April 2023

In parallel to the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO 2022), an alternative International Consensus Classification (ICC) has been proposed. To evaluate the impact of the new classifications on AML diagnoses and ELN-based risk classification, we analyzed 717 MDS and 734 AML non-therapy-related patients diagnosed according to the revised 4th WHO edition (WHO 2017) by whole genome and transcriptome sequencing. In both new classifications, the purely morphologically defined AML entities decreased from 13% to 5%. Myelodysplasia-related (MR) AML increased from 22% to 28% (WHO 2022) and 26% (ICC). Other genetically-defined AML remained the largest group, and the abandoned AML-RUNX1 was mainly reclassified as AML-MR (WHO 2022: 77%; ICC: 96%). Different inclusion criteria of AML-CEBPA and AML-MR (i.a. exclusion of TP53 mutated cases according to ICC) were associated with differences in overall survival. In conclusion, both classifications focus on more genetics-based definitions with similar basic concepts and a large degree of agreement. The remaining non-comparability (e.g., TP53 mutated AML) needs additional studies to definitely answer open questions on disease categorization in an unbiased way.
Functional roles of SRC signaling in pancreatic cancer: Recent insights provide novel therapeutic opportunities
Authors: Poh Ashleigh R. , Ernst Matthias
Published: April 2023

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.
The readability of parent information leaflets in paediatric studies
Authors: Nash Elizabeth , Bickerstaff Matthew , Chetwynd Andrew J. , Hawcutt Daniel B. , Oni Louise
Published: April 2023

Background

Poor literacy can impact achieving optimal health outcomes. The aim of this project was to assess the readability of parent information leaflets (PILs).

Methods

A single-centre study using paediatric PILs. Five readability tests were applied (Gunning Fog Index (GFI), Simple Measure of Gobbledygook (SMOG), Flesch Kincaid Grade Level (FKGL), Coleman–Liau Index (CLI) and Automated Readability Index (ARI)). Results were compared to standards and by subtype.

Results

A total of 109 PILs were obtained; mean (±SD) number of characters was 14,365 (±12,055), total words 3066 (±2541), number of sentences 153 (±112), lexical density 49 (±3), number of characters per word 4.7 (±0.1), number of syllables per word 1.6 (±0.1) and number of words per sentence 19.1 (±2.5). The Flesch reading ease score was 51.1 (±5.6), equating to reading age 16–17 years. The mean PIL readability scores were GFI (12.18), SMOG (11.94), FKGL (10.89), CLI (10.08) and ARI (10.1). There were 0 (0%) PILs classed as easy (score <6), 21 (19%) mid-range (6–10) and 88 (81%) were difficult (>10). They were significantly above the recommended reading age (p < 0.0001) and commercial studies were least accessible (p < 0.01).

Conclusion

Existing PILs are above the national reading level. Researchers should use readability tools to ensure that they are accessible.

Impact

Poor literacy is a barrier to accessing research and achieving good health outcomes.

Current parent information leaflets are pitched far higher than the national reading age.

This study provides data to demonstrate the reading age of a large portfolio of research studies.

This work raises awareness of literacy as a barrier to research participation and provides tips on how to improve the readability of patient information leaflets to guide investigators.
In silico enhancer mining reveals SNS-032 and EHMT2 inhibitors as therapeutic candidates in high-grade serous ovarian cancer
Authors: Quintela Marcos , James David W. , Garcia Jetzabel , Edwards Kadie , Margarit Lavinia , Das Nagindra , Lutchman-Singh Kerryn , Beynon Amy L. , Rioja Inmaculada , Prinjha Rab K. , Harker Nicola R. , Gonzalez Deyarina , Steven Conlan R. , Francis Lewis W.
Published: April 2023

Background

Epigenomic dysregulation has been linked to solid tumour malignancies, including ovarian cancers. Profiling of re-programmed enhancer locations associated with disease has the potential to improve stratification and thus therapeutic choices. Ovarian cancers are subdivided into histological subtypes that have significant molecular and clinical differences, with high-grade serous carcinoma representing the most common and aggressive subtype.

Methods

We interrogated the enhancer landscape(s) of normal ovary and subtype-specific ovarian cancer states using publicly available data. With an initial focus on H3K27ac histone mark, we developed a computational pipeline to predict drug compound activity based on epigenomic stratification. Lastly, we substantiated our predictions in vitro using patient-derived clinical samples and cell lines.

Results

Using our in silico approach, we highlighted recurrent and privative enhancer landscapes and identified the differential enrichment of a total of 164 transcription factors involved in 201 protein complexes across the subtypes. We pinpointed SNS-032 and EHMT2 inhibitors BIX-01294 and UNC0646 as therapeutic candidates in high-grade serous carcinoma, as well as probed the efficacy of specific inhibitors in vitro.

Conclusion

Here, we report the first attempt to exploit ovarian cancer epigenomic landscapes for drug discovery. This computational pipeline holds enormous potential for translating epigenomic profiling into therapeutic leads.
A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer
Authors: Kristeleit Rebecca , Plummer Ruth , Jones Robert , Carter Louise , Blagden Sarah , Sarker Debashis , Arkenau Tobias , Evans Thomas R. Jeffry , Danson Sarah , Symeonides Stefan N. , Veal Gareth J. , Klencke Barbara J. , Kowalski Mark M. , Banerji Udai
Published: April 2023

Background

This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737.

Methods

Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers.

Results

In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen.

Conclusions

SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy.

Clinical trial registration

Clinicaltrials.gov NCT02797964.
Clinical biomarker-based biological aging and risk of cancer in the UK Biobank
Authors: Mak Jonathan K. L. , McMurran Christopher E. , Kuja-Halkola Ralf , Hall Per , Czene Kamila , Jylhävä Juulia , Hägg Sara
Published: April 2023

Background

Despite a clear link between aging and cancer, there has been inconclusive evidence on how biological age (BA) may be associated with cancer incidence.

Methods

We studied 308,156 UK Biobank participants with no history of cancer at enrolment. Using 18 age-associated clinical biomarkers, we computed three BA measures (Klemera-Doubal method [KDM], PhenoAge, homeostatic dysregulation [HD]) and assessed their associations with incidence of any cancer and five common cancers (breast, prostate, lung, colorectal, and melanoma) using Cox proportional-hazards models.

Results

A total of 35,426 incident cancers were documented during a median follow-up of 10.9 years. Adjusting for common cancer risk factors, 1-standard deviation (SD) increment in the age-adjusted KDM (hazard ratio = 1.04, 95% confidence interval = 1.03–1.05), age-adjusted PhenoAge (1.09, 1.07–1.10), and HD (1.02, 1.01–1.03) was significantly associated with a higher risk of any cancer. All BA measures were also associated with increased risks of lung and colorectal cancers, but only PhenoAge was associated with breast cancer risk. Furthermore, we observed an inverse association between BA measures and prostate cancer, although it was attenuated after removing glycated hemoglobin and serum glucose from the BA algorithms.

Conclusions

Advanced BA quantified by clinical biomarkers is associated with increased risks of any cancer, lung cancer, and colorectal cancer.
Targeting fatty acid oxidation via Acyl-CoA binding protein hinders glioblastoma invasion
Authors: Duman Ceren , Di Marco Barbara , Nevedomskaya Ekaterina , Ulug Berk , Lesche Ralf , Christian Sven , Alfonso Julieta
Published: April 2023

The diffuse nature of Glioblastoma (GBM) tumors poses a challenge to current therapeutic options. We have previously shown that Acyl-CoA Binding Protein (ACBP, also known as DBI) regulates lipid metabolism in GBM cells, favoring fatty acid oxidation (FAO). Here we show that ACBP downregulation results in wide transcriptional changes affecting invasion-related genes. In vivo experiments using patient-derived xenografts combined with in vitro models demonstrated that ACBP sustains GBM invasion via binding to fatty acyl-CoAs. Blocking FAO mimics ACBPKD-induced immobility, a cellular phenotype that can be rescued by increasing FAO rates. Further investigation into ACBP-downstream pathways served to identify Integrin beta-1, a gene downregulated upon inhibition of either ACBP expression or FAO rates, as a mediator for ACBP’s role in GBM invasion. Altogether, our findings highlight a role for FAO in GBM invasion and reveal ACBP as a therapeutic vulnerability to stall FAO and subsequent cell invasion in GBM tumors.
Therapeutic efficacy of a MMAE-based anti-DR5 drug conjugate Oba01 in preclinical models of pancreatic cancer
Authors: Zheng Chao , Zhou Dongdong , Li Weisong , Duan Yanhui , Xu Minwen , Liu Jie , Cheng Jingpei , Xiao Youban , Xiao Han , Gan Tao , Liang Jianmin , Zheng Dexian , Wang Liefeng , Zhang Shuyong
Published: April 2023

Pancreatic cancer (PC) is among the most aggressive malignancies associated with a 5-year survival rate of <9%, and the treatment options remain limited. Antibody–drug conjugates (ADCs) are a new class of anticancer agents with superior efficacy and safety profiles. We studied the antitumor activity of Oba01 ADC and the mechanism underlying the targeting of death receptor 5 (DR5) in preclinical PC models. Our data revealed that DR5 was highly expressed on the plasma membrane of PC cells and Oba01 showed potent in vitro antitumor activity in a panel of human DR5-positive PC cell lines. DR5 was readily cleaved by lysosomal proteases after receptor-mediated internalization. Monomethyl auristatin E (MMAE) was then released into the cytosol to induce G2/M-phase growth arrest, cell death via apoptosis induction, and the bystander effect. Furthermore, Oba01 mediated cell death via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. For improved potency, we investigated the synergetic effect of Oba01 in combination with approved drugs. Oba01 combined with gemcitabine showed better antiproliferative activity than either standalone treatment. In cell- and patient-derived xenografts, Oba01 showed excellent tumoricidal activity in mono- or combinational therapy. Thus, Oba01 may provide a novel biotherapeutic approach and a scientific basis for clinical trials in DR5-expressing patients with PC.
Positive feedback induces switch between distributive and processive phosphorylation of Hog1
Authors: Mosbacher Maximilian , Lee Sung Sik , Yaakov Gilad , Nadal-Ribelles Mariona , de Nadal Eulàlia , van Drogen Frank , Posas Francesc , Peter Matthias , Claassen Manfred
Published: April 2023

Cellular decision making often builds on ultrasensitive MAPK pathways. The phosphorylation mechanism of MAP kinase has so far been described as either distributive or processive, with distributive mechanisms generating ultrasensitivity in theoretical analyses. However, the in vivo mechanism of MAP kinase phosphorylation and its activation dynamics remain unclear. Here, we characterize the regulation of the MAP kinase Hog1 in Saccharomyces cerevisiae via topologically different ODE models, parameterized on multimodal activation data. Interestingly, our best fitting model switches between distributive and processive phosphorylation behavior regulated via a positive feedback loop composed of an affinity and a catalytic component targeting the MAP kinase-kinase Pbs2. Indeed, we show that Hog1 directly phosphorylates Pbs2 on serine 248 (S248), that cells expressing a non-phosphorylatable (S248A) or phosphomimetic (S248E) mutant show behavior that is consistent with simulations of disrupted or constitutively active affinity feedback and that Pbs2-S248E shows significantly increased affinity to Hog1 in vitro. Simulations further suggest that this mixed Hog1 activation mechanism is required for full sensitivity to stimuli and to ensure robustness to different perturbations.
Interfacial engineering of ferromagnetism in wafer-scale van der Waals Fe4GeTe2 far above room temperature
Authors: Wang Hangtian , Lu Haichang , Guo Zongxia , Li Ang , Wu Peichen , Li Jing , Xie Weiran , Sun Zhimei , Li Peng , Damas Héloïse , Friedel Anna Maria , Migot Sylvie , Ghanbaja Jaafar , Moreau Luc , Fagot-Revurat Yannick , Petit-Watelot Sébastien , Hauet Thomas , Robertson John , Mangin Stéphane , Zhao Weisheng , Nie Tianxiao
Published: April 2023

Despite recent advances in exfoliated vdW ferromagnets, the widespread application of 2D magnetism requires a Curie temperature (Tc) above room temperature as well as a stable and controllable magnetic anisotropy. Here we demonstrate a large-scale iron-based vdW material Fe4GeTe2 with the Tc reaching ~530 K. We confirmed the high-temperature ferromagnetism by multiple characterizations. Theoretical calculations suggested that the interface-induced right shift of the localized states for unpaired Fe d electrons is the reason for the enhanced Tc, which was confirmed by ultraviolet photoelectron spectroscopy. Moreover, by precisely tailoring Fe concentration we achieved arbitrary control of magnetic anisotropy between out-of-plane and in-plane without inducing any phase disorders. Our finding sheds light on the high potential of Fe4GeTe2 in spintronics, which may open opportunities for room-temperature application of all-vdW spintronic devices.
Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome
Authors: Barry Alexandra , McNulty Michelle T. , Jia Xiaoyuan , Gupta Yask , Debiec Hanna , Luo Yang , Nagano China , Horinouchi Tomoko , Jung Seulgi , Colucci Manuela , Ahram Dina F. , Mitrotti Adele , Sinha Aditi , Teeninga Nynke , Jin Gina , Shril Shirlee , Caridi Gianluca , Bodria Monica , Lim Tze Y. , Westland Rik , Zanoni Francesca , Marasa Maddalena , Turudic Daniel , Giordano Mario , Gesualdo Loreto , Magistroni Riccardo , Pisani Isabella , Fiaccadori Enrico , Reiterova Jana , Maringhini Silvio , Morello William , Montini Giovanni , Weng Patricia L. , Scolari Francesco , Saraga Marijan , Tasic Velibor , Santoro Domenica , van Wijk Joanna A. E. , Milošević Danko , Kawai Yosuke , Kiryluk Krzysztof , Pollak Martin R. , Gharavi Ali , Lin Fangmin , Simœs e Silva Ana Cristina , Loos Ruth J. F. , Kenny Eimear E. , Schreuder Michiel F. , Zurowska Aleksandra , Dossier Claire , Ariceta Gema , Drozynska-Duklas Magdalena , Hogan Julien , Jankauskiene Augustina , Hildebrandt Friedhelm , Prikhodina Larisa , Song Kyuyoung , Bagga Arvind , Cheong Hae , Ghiggeri Gian Marco , Vachvanichsanong Prayong , Nozu Kandai , Lee Dongwon , Vivarelli Marina , Raychaudhuri Soumya , Tokunaga Katsushi , Sanna-Cherchi Simone , Ronco Pierre , Iijima Kazumoto , Sampson Matthew G.
Published: April 2023

Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations—eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace
Authors: Qian Jingyang , Liao Jie , Liu Ziqi , Chi Ying , Fang Yin , Zheng Yanrong , Shao Xin , Liu Bingqi , Cui Yongjin , Guo Wenbo , Hu Yining , Bao Hudong , Yang Penghui , Chen Qian , Li Mingxiao , Zhang Bing , Fan Xiaohui
Published: April 2023

Tissues are highly complicated with spatial heterogeneity in gene expression. However, the cutting-edge single-cell RNA-seq technology eliminates the spatial information of individual cells, which contributes to the characterization of cell identities. Herein, we propose single-cell spatial position associated co-embeddings (scSpace), an integrative method to identify spatially variable cell subpopulations by reconstructing cells onto a pseudo-space with spatial transcriptome references (Visium, STARmap, Slide-seq, etc.). We benchmark scSpace with both simulated and biological datasets, and demonstrate that scSpace can accurately and robustly identify spatially variated cell subpopulations. When employed to reconstruct the spatial architectures of complex tissue such as the brain cortex, the small intestinal villus, the liver lobule, the kidney, the embryonic heart, and others, scSpace shows promising performance on revealing the pairwise cellular spatial association within single-cell data. The application of scSpace in melanoma and COVID-19 exhibits a broad prospect in the discovery of spatial therapeutic markers.
Nanoparticle-mediated TRPV1 channel blockade amplifies cancer thermo-immunotherapy via heat shock factor 1 modulation
Authors: Li Ting , Jiang Shuhui , Zhang Ying , Luo Jie , Li Ming , Ke Hengte , Deng Yibin , Yang Tao , Sun Xiaohui , Chen Huabing
Published: April 2023

The survival of malignant tumors is highly dependent on their intrinsic self-defense pathways such as heat shock protein (HSP) during cancer therapy. However, precisely dismantling self-defenses to amplify antitumor potency remains unexplored. Herein, we demonstrate that nanoparticle-mediated transient receptor potential vanilloid member 1 (TRPV1) channel blockade potentiates thermo-immunotherapy via suppressing heat shock factor 1 (HSF1)-mediated dual self-defense pathways. TRPV1 blockade inhibits hyperthermia-induced calcium influx and subsequent nuclear translocation of HSF1, which selectively suppresses stressfully overexpressed HSP70 for enhancing thermotherapeutic efficacy against a variety of primary, metastatic and recurrent tumor models. Particularly, the suppression of HSF1 translocation further restrains the transforming growth factor β (TGFβ) pathway to degrade the tumor stroma, which improves the infiltration of antitumor therapeutics (e.g. anti-PD-L1 antibody) and immune cells into highly fibrotic and immunosuppressive pancreatic cancers. As a result, TRPV1 blockade retrieves thermo-immunotherapy with tumor-eradicable and immune memory effects. The nanoparticle-mediated TRPV1 blockade represents as an effective approach to dismantle self-defenses for potent cancer therapy.
A sensitive high repetition rate arrival time monitor for X-ray free electron lasers
Authors: Diez Michael , Kirchberg Henning , Galler Andreas , Schulz Sebastian , Biednov Mykola , Bömer Christina , Choi Tae-Kyu , Rodriguez-Fernandez Angel , Gawelda Wojciech , Khakhulin Dmitry , Kubicek Katharina , Lima Frederico , Otte Florian , Zalden Peter , Coffee Ryan , Thorwart Michael , Bressler Christian
Published: April 2023

X-ray free-electron laser sources enable time-resolved X-ray studies with unmatched temporal resolution. To fully exploit ultrashort X-ray pulses, timing tools are essential. However, new high repetition rate X-ray facilities present challenges for currently used timing tool schemes. Here we address this issue by demonstrating a sensitive timing tool scheme to enhance experimental time resolution in pump-probe experiments at very high pulse repetition rates. Our method employs a self-referenced detection scheme using a time-sheared chirped optical pulse traversing an X-ray stimulated diamond plate. By formulating an effective medium theory, we confirm subtle refractive index changes, induced by sub-milli-Joule intense X-ray pulses, that are measured in our experiment. The system utilizes a Common-Path-Interferometer to detect X-ray-induced phase shifts of the optical probe pulse transmitted through the diamond sample. Owing to the thermal stability of diamond, our approach is well-suited for MHz pulse repetition rates in superconducting linear accelerator-based free-electron lasers.
Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis
Authors: Tan Huanhuan , Wang Weixu , Zhou Congjin , Wang Yanfeng , Zhang Shu , Yang Pinglan , Guo Rui , Chen Wei , Zhang Jinwen , Ye Lan , Cui Yiqiang , Ni Ting , Zheng Ke
Published: April 2023

Mammalian spermatogenesis shows prominent chromatin and transcriptomic switches in germ cells, but it is unclear how such dynamics are controlled. Here we identify RNA helicase DDX43 as an essential regulator of the chromatin remodeling process during spermiogenesis. Testis-specificDdx43knockout mice show male infertility with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. The loss of its ATP hydrolysis activity by a missense mutation replicates the infertility phenotype in globalDdx43knockout mice. Single-cell RNA sequencing analyses of germ cells depleted ofDdx43or expressing theDdx43ATPase-dead mutant reveals that DDX43 regulates dynamic RNA regulatory processes that underlie spermatid chromatin remodeling and differentiation. Transcriptomic profiling focusing on early-stage spermatids combined with enhanced crosslinking immunoprecipitation and sequencing further identifiesElfn2as DDX43-targeted hub gene. These findings illustrate an essential role for DDX43 in spermiogenesis and highlight the single-cell-based strategy to dissect cell-state-specific regulation of male germline development.
Virus diversity, wildlife-domestic animal circulation and potential zoonotic viruses of small mammals, pangolins and zoo animals
Authors: Cui Xinyuan , Fan Kewei , Liang Xianghui , Gong Wenjie , Chen Wu , He Biao , Chen Xiaoyuan , Wang Hai , Wang Xiao , Zhang Ping , Lu Xingbang , Chen Rujian , Lin Kaixiong , Liu Jiameng , Zhai Junqiong , Liu Ding Xiang , Shan Fen , Li Yuqi , Chen Rui Ai , Meng Huifang , Li Xiaobing , Mi Shijiang , Jiang Jianfeng , Zhou Niu , Chen Zujin , Zou Jie-Jian , Ge Deyan , Yang Qisen , He Kai , Chen Tengteng , Wu Ya-Jiang , Lu Haoran , Irwin David M. , Shen Xuejuan , Hu Yuanjia , Lu Xiaoman , Ding Chan , Guan Yi , Tu Changchun , Shen Yongyi
Published: April 2023

Wildlife is reservoir of emerging viruses. Here we identified 27 families of mammalian viruses from 1981 wild animals and 194 zoo animals collected from south China between 2015 and 2022, isolated and characterized the pathogenicity of eight viruses. Bats harbor high diversity of coronaviruses, picornaviruses and astroviruses, and a potentially novel genus of Bornaviridae. In addition to the reported SARSr-CoV-2 and HKU4-CoV-like viruses, picornavirus and respiroviruses also likely circulate between bats and pangolins. Pikas harbor a new clade of Embecovirus and a new genus of arenaviruses. Further, the potential cross-species transmission of RNA viruses (paramyxovirus and astrovirus) and DNA viruses (pseudorabies virus, porcine circovirus 2, porcine circovirus 3 and parvovirus) between wildlife and domestic animals was identified, complicating wildlife protection and the prevention and control of these diseases in domestic animals. This study provides a nuanced view of the frequency of host-jumping events, as well as assessments of zoonotic risk.
The origin of magnetization-caused increment in water oxidation
Authors: Ren Xiao , Wu Tianze , Gong Zizhao , Pan Lulu , Meng Jianling , Yang Haitao , Dagbjartsdottir Freyja Bjork , Fisher Adrian , Gao Hong-Jun , Xu Zhichuan J.
Published: April 2023

Magnetization promoted activity of magnetic catalysts towards the oxygen evolution reaction (OER) has attracted great attention, but remains a puzzle where the increment comes from. Magnetization of a ferromagnetic material only changes its magnetic domain structure. It does not directly change the spin orientation of unpaired electrons in the material. The confusion is that each magnetic domain is a small magnet and theoretically the spin-polarization promoted OER already occurs on these magnetic domains, and thus the enhancement should have been achieved without magnetization. Here, we demonstrate that the enhancement comes from the disappeared domain wall upon magnetization. Magnetization leads to the evolution of the magnetic domain structure, from a multi-domain one to a single domain one, in which the domain wall disappears. The surface occupied by the domain wall is reformatted into one by a single domain, on which the OER follows the spin-facilitated pathways and thus the overall increment on the electrode occurs. This study fills the missing gap for understanding the spin-polarized OER and it further explains the type of ferromagnetic catalysts which can give increment by magnetization.
The diffuse gamma-ray flux from clusters of galaxies
Authors: Hussain Saqib , Alves Batista Rafael , de Gouveia Dal Pino Elisabete M. , Dolag Klaus
Published: April 2023

The origin of the diffuse gamma-ray background (DGRB), the one that remains after subtracting all individual sources from observed gamma-ray sky, is unknown. The DGRB possibly encompasses contributions from different source populations such as star-forming galaxies, starburst galaxies, active galactic nuclei, gamma-ray bursts, or galaxy clusters. Here, we combine cosmological magnetohydrodynamical simulations of clusters of galaxies with the propagation of cosmic rays (CRs) using Monte Carlo simulations, in the redshift range z ≤ 5.0, and show that the integrated gamma-ray flux from clusters can contribute up to 100% of the DGRB flux observed by Fermi-LAT above 100 GeV, for CRs spectral indices α = 1.5 − 2.5 and energy cutoffs $${E}_{\max }=1{0}^{16}-1{0}^{17}$$

E

max

=
1

0

16

−
1

0

17

eV. The flux is dominated by clusters with masses 1013 ≲ M/M⊙ ≲ 1015 and redshift z ≲ 0.3. Our results also predict the potential observation of high-energy gamma rays from clusters by experiments like the High Altitude Water Cherenkov (HAWC), the Large High Altitude Air Shower Observatory (LHAASO), and potentially the upcoming Cherenkov Telescope Array (CTA).
Nucleotide exchange is sufficient for Hsp90 functions in vivo
Authors: Reidy Michael , Garzillo Kevin , Masison Daniel C.
Published: April 2023

Hsp90 is an essential eukaryotic chaperone that regulates the activity of many client proteins. Current models of Hsp90 function, which include many conformational rearrangements, specify a requirement of ATP hydrolysis. Here we confirm earlier findings that the Hsp82-E33A mutant, which binds ATP but does not hydrolyze it, supports viability ofS. cerevisiae, although it displays conditional phenotypes. We find binding of ATP to Hsp82-E33A induces the conformational dynamics needed for Hsp90 function. Hsp90 orthologs with the analogous EA mutation from several eukaryotic species, including humans and disease organisms, support viability of bothS. cerevisiaeandSz. pombe. We identify second-site suppressors of EA that rescue its conditional defects and allow EA versions of all Hsp90 orthologs tested to support nearly normal growth of both organisms, without restoring ATP hydrolysis. Thus, the requirement of ATP for Hsp90 to maintain viability of evolutionarily distant eukaryotic organisms does not appear to depend on energy from ATP hydrolysis. Our findings support earlier suggestions that exchange of ATP for ADP is critical for Hsp90 function. ATP hydrolysis is not necessary for this exchange but provides an important control point in the cycle responsive to regulation by co-chaperones.
PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis
Authors: Bertschi Nicole L. , Steck Oliver , Luther Fabian , Bazzini Cecilia , von Meyenn Leonhard , Schärli Stefanie , Vallone Angela , Felser Andrea , Keller Irene , Friedli Olivier , Freigang Stefan , Begré Nadja , Radonjic-Hoesli Susanne , Lamos Cristina , Gabutti Max Philip , Benzaquen Michael , Laimer Markus , Simon Dagmar , Nuoffer Jean-Marc , Schlapbach Christoph
Published: April 2023

T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells.
Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis
Authors: Obeidat Alia M. , Wood Matthew J. , Adamczyk Natalie S. , Ishihara Shingo , Li Jun , Wang Lai , Ren Dongjun , Bennett David A. , Miller Richard J. , Malfait Anne-Marie , Miller Rachel E.
Published: April 2023

Non-opioid targets are needed for addressing osteoarthritis pain, which is mechanical in nature and associated with daily activities such as walking and climbing stairs. Piezo2 has been implicated in the development of mechanical pain, but the mechanisms by which this occurs remain poorly understood, including the role of nociceptors. Here we show that nociceptor-specific Piezo2 conditional knock-out mice were protected from mechanical sensitization associated with inflammatory joint pain in female mice, joint pain associated with osteoarthritis in male mice, as well as both knee swelling and joint pain associated with repeated intra-articular injection of nerve growth factor in male mice. Single cell RNA sequencing of mouse lumbar dorsal root ganglia and in situ hybridization of mouse and human lumbar dorsal root ganglia revealed that a subset of nociceptors co-express Piezo2 and Ntrk1 (the gene that encodes the nerve growth factor receptor TrkA). These results suggest that nerve growth factor-mediated sensitization of joint nociceptors, which is critical for osteoarthritic pain, is also dependent on Piezo2, and targeting Piezo2 may represent a therapeutic option for osteoarthritis pain control.
Clustering of charged colloidal particles in the microgravity environment of space
Authors: Miki Hiroyuki , Ishigami Teruyoshi , Yamanaka Junpei , Okuzono Tohru , Toyotama Akiko , Mata Jitendra , Komazawa Honoka , Takeda Yushi , Minami Madoka , Fujita Minori , Doi Maho , Higuchi Tsunehiko , Takase Hiroshi , Adachi Satoshi , Sakashita Tetsuya , Shimaoka Taro , Nagai Masae , Watanabe Yuki , Fukuyama Seijiro
Published: April 2023

We conducted a charge–charge clustering experiment of positively and negatively charged colloidal particles in aqueous media under a microgravity environment at the International Space Station. A special setup was used to mix the colloid particles in microgravity and then these structures were immobilized in gel cured using ultraviolet (UV) light. The samples returned to the ground were observed by optical microscopy. The space sample of polystyrene particles with a specific gravity ρ (=1.05) close to the medium had an average association number of ~50% larger than the ground control and better structural symmetry. The effect of electrostatic interactions on the clustering was also confirmed for titania particles (ρ ~ 3), whose association structures were only possible in the microgravity environment without any sedimentation they generally suffer on the ground. This study suggests that even slight sedimentation and convection on the ground significantly affect the structure formation of colloids. Knowledge from this study will help us to develop a model which will be used to design photonic materials and better drugs.
Cortical thinning in relation to impaired insight into illness in patients with treatment resistant schizophrenia
Authors: Kim Julia , Song Jianmeng , Kambari Yasaman , Plitman Eric , Shah Parita , Iwata Yusuke , Caravaggio Fernando , Brown Eric E. , Nakajima Shinichiro , Chakravarty M. Mallar , De Luca Vincenzo , Remington Gary , Graff-Guerrero Ariel , Gerretsen Philip
Published: April 2023

Impaired insight into illness is a common element of schizophrenia that contributes to treatment nonadherence and negative clinical outcomes. Previous studies suggest that impaired insight may arise from brain abnormalities. However, interpretations of these findings are limited due to small sample sizes and inclusion of patients with a narrow range of illness severity and insight deficits. In a large sample of patients with schizophrenia, the majority of which were designated as treatment-resistant, we investigated the associations between impaired insight and cortical thickness and subcortical volumes. A total of 94 adult participants with a schizophrenia spectrum disorder were included. Fifty-six patients (60%) had treatment-resistant schizophrenia. The core domains of insight were assessed with the VAGUS insight into psychosis scale. We obtained 3T MRI T1-weighted images, which were analysed using CIVET and MAGeT-Brain. Whole-brain vertex-wise analyses revealed impaired insight, as measured by VAGUS average scores, was related to cortical thinning in left frontotemporoparietal regions. The same analysis in treatment-resistant patients showed thinning in the same regions, even after controlling for age, sex, illness severity, and chlorpromazine antipsychotic dose equivalents. No association was found in non-treatment-resistant patients. Region-of-interest analyses revealed impaired general illness awareness was associated with cortical thinning in the left supramarginal gyrus when controlling for covariates. Reduced right and left thalamic volumes were associated with VAGUS symptom attribution and awareness of negative consequences subscale scores, respectively, but not after correction for multiple testing. Our results suggest impaired insight into illness is related to cortical thinning in left frontotemporoparietal regions in patients with schizophrenia, particularly those with treatment resistance where insight deficits may be more chronic.
An intuitionistic approach for the predictability of anti-angiogenic inhibitors in cancer diagnosis
Authors: Ansar Syed Anas , Aggarwal Shruti , Arya Swati , Haq Mohd. Anul , Mittal Vikas , Gared Fikreselam
Published: April 2023

Malignant cancer angiogenesis has historically attracted enormous scientific attention. Although angiogenesis is requisite for a child’s development and conducive to tissue homeostasis, it is deleterious when cancer lurks. Today, anti-angiogenic biomolecular receptor tyrosine kinase inhibitors (RTKIs) to target angiogenesis have been prolific in treating various carcinomas. Angiogenesis is a pivotal component in malignant transformation, oncogenesis, and metastasis that can be activated by a multiplicity of factors (e.g., VEGF (Vascular endothelial growth factor), (FGF) Fibroblast growth factor, (PDGF) Platelet-derived growth factor and others). The advent of RTKIs, which primarily target members of the VEGFR (VEGF Receptor) family of angiogenic receptors has greatly ameliorated the outlook for some cancer forms, including hepatocellular carcinoma, malignant tumors, and gastrointestinal carcinoma. Cancer therapeutics have evolved steadily with active metabolites and strong multi-targeted RTK inhibitors such as E7080, CHIR-258, SU 5402, etc. This research intends to determine the efficacious anti-angiogenesis inhibitors and rank them by using the Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE- II) decision-making algorithm. The PROMETHEE-II approach assesses the influence of growth factors (GFs) in relation to the anti-angiogenesis inhibitors. Due to their capacity to cope with the frequently present vagueness while ranking alternatives, fuzzy models constitute the most suitable tools for producing results for analyzing qualitative information. This research’s quantitative methodology focuses on ranking the inhibitors according to their significance concerning criteria. The evaluation findings indicate the most efficacious and idle alternative for inhibiting angiogenesis in cancer.
Prenatal phthalate exposure and cord blood DNA methylation
Authors: Lee Jooah , Kim Jeeyoung , Zinia Sabrina Shafi , Park Jaehyun , Won Sungho , Kim Woo Jin
Published: April 2023

Exposure to phthalates has been shown to impede the human endocrine system, resulting in deleterious effects on pregnant women and their children. Phthalates modify DNA methylation patterns in infant cord blood. We examined the association between prenatal phthalate exposure and DNA methylation patterns in cord blood in a Korean birth cohort. Phthalate levels were measured in 274 maternal urine samples obtained during late pregnancy and 102 neonatal urine samples obtained at birth, and DNA methylation levels were measured in cord blood samples. For each infant in the cohort, associations between CpG methylation and both maternal and neonate phthalate levels were analyzed using linear mixed models. The results were combined with those from a meta-analysis of the levels of phthalates in maternal and neonatal urine samples, which were also analyzed for MEOHP, MEHHP, MnBP, and DEHP. This meta-analysis revealed significant associations between the methylation levels of CpG sites near the CHN2 and CUL3 genes, which were also associated with MEOHP and MnBP in neonatal urine. When the data were stratified by the sex of the infant, MnBP concentration was found to be associated with one CpG site near the OR2A2 and MEGF11 genes in female infants. In contrast, the concentrations of the three maternal phthalates showed no significant association with CpG site methylation. Furthermore, the data identified distinct differentially methylated regions in maternal and neonatal urine samples following exposure to phthalates. The CpGs with methylation levels that were positively associated with phthalate levels (particularly MEOHP and MnBP) were found to be enriched genes and related pathways. These results indicate that prenatal phthalate exposure is significantly associated with DNA methylation at multiple CpG sites. These alterations in DNA methylation may serve as biomarkers of maternal exposure to phthalates in infants and are potential candidates for investigating the mechanisms by which phthalates impact maternal and neonatal health.