bluuebunny/crossref_metadata_2025_split huggingface dataset:
Irreversible electroporation augments checkpoint immunotherapy in prostate cancer and promotes tumor antigen-specific tissue-resident memory CD8+ T cells
Authors: Burbach Brandon J. , O’Flanagan Stephen D. , Shao Qi , Young Katharine M. , Slaughter Joseph R. , Rollins Meagan R. , Street Tami Jo L. , Granger Victoria E. , Beura Lalit. K. , Azarin Samira M. , Ramadhyani Satish , Forsyth Bruce R. , Bischof John C. , Shimizu Yoji 
Published: June 2021

AbstractMemory CD8+ T cells populate non-lymphoid tissues (NLTs) following pathogen infection, but little is known about the establishment of endogenous tumor-specific tissue-resident memory T cells (TRM) during cancer immunotherapy. Using a transplantable mouse model of prostate carcinoma, here we report that tumor challenge leads to expansion of naïve neoantigen-specific CD8+ T cells and formation of a small population of non-recirculating TRM in several NLTs. Primary tumor destruction by irreversible electroporation (IRE), followed by anti-CTLA-4 immune checkpoint inhibitor (ICI), promotes robust expansion of tumor-specific CD8+ T cells in blood, tumor, and NLTs. Parabiosis studies confirm that TRM establishment following dual therapy is associated with tumor remission in a subset of cases and protection from subsequent tumor challenge. Addition of anti-PD-1 following dual IRE + anti-CTLA-4 treatment blocks tumor growth in non-responsive cases. This work indicates that focal tumor destruction using IRE combined with ICI is a potent in situ tumor vaccination strategy that generates protective tumor-specific TRM.
Mining and unearthing hidden biosynthetic potential
Authors: Scherlach Kirstin , Hertweck Christian 
Published: June 2021

AbstractGenetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.
Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer
Authors: Roper Nitin , Velez Moises J. , Chiappori Alberto , Kim Yoo Sun , Wei Jun S. , Sindiri Sivasish , Takahashi Nobuyuki , Mulford Deborah , Kumar Suresh , Ylaya Kris , Trindade Christopher , Manukyan Irena , Brown Anna-Leigh , Trepel Jane B. , Lee Jung-Min , Hewitt Stephen , Khan Javed , Thomas Anish 
Published: June 2021

AbstractImmune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. However, elevated Notch signaling, which positively correlates with low NE differentiation, most significantly predicts clinical benefit to ICB. Activation of Notch signaling in a NE human SCLC cell line induces a low NE phenotype, marked by increased expression of APM genes, demonstrating a mechanistic link between Notch activation, low NE differentiation and increased intrinsic tumor immunity. Our findings suggest Notch signaling as a determinant of response to ICB in SCLC.
High-pressure reversibility in a plastically flexible coordination polymer crystal
Authors: Liu Xiaojiao , Michalchuk Adam A. L. , Bhattacharya Biswajit , Yasuda Nobuhiro , Emmerling Franziska , Pulham Colin R. 
Published: June 2021

AbstractSingle crystals which exhibit mechanical flexibility are promising materials for advanced technological applications. Before such materials can be used, a detailed understanding of the mechanisms of bending is needed. Using single crystal X-ray diffraction and microfocus Raman spectroscopy, we study in atomic detail the high-pressure response of the plastically flexible coordination polymer [Zn(μ-Cl)2(3,5-dichloropyridine)2]n (1). Contradictory to three-point bending, quasi-hydrostatic compression of (1) is completely reversible, even following compression to over 9 GPa. A structural phase transition is observed at ca. 5 GPa. DFT calculations show this transition to result from the pressure-induced softening of low-frequency vibrations. This phase transition is not observed during three-point-bending. Microfocus synchrotron X-ray diffraction revealed that bending yields significant mosaicity, as opposed to compression. Hence, our studies indicate of overall disparate mechanical responses of bulk flexibility and quasi-hydrostatic compression within the same crystal lattice. We suspect this to be a general feature of plastically bendable materials.
ATRX promotes heterochromatin formation to protect cells from G-quadruplex DNA-mediated stress
Authors: Teng Yu-Ching , Sundaresan Aishwarya , O’Hara Ryan , Gant Vincent U. , Li Minhua , Martire Sara , Warshaw Jane N. , Basu Amrita , Banaszynski Laura A. 
Published: June 2021

AbstractATRX is a tumor suppressor that has been associated with protection from DNA replication stress, purportedly through resolution of difficult-to-replicate G-quadruplex (G4) DNA structures. While several studies demonstrate that loss of ATRX sensitizes cells to chemical stabilizers of G4 structures, the molecular function of ATRX at G4 regions during replication remains unknown. Here, we demonstrate that ATRX associates with a number of the MCM replication complex subunits and that loss of ATRX leads to G4 structure accumulation at newly synthesized DNA. We show that both the helicase domain of ATRX and its H3.3 chaperone function are required to protect cells from G4-induced replicative stress. Furthermore, these activities are upstream of heterochromatin formation mediated by the histone methyltransferase, ESET, which is the critical molecular event that protects cells from G4-mediated stress. In support, tumors carrying mutations in either ATRX or ESET show increased mutation burden at G4-enriched DNA sequences. Overall, our study provides new insights into mechanisms by which ATRX promotes genome stability with important implications for understanding impacts of its loss on human disease.
Grain-boundary-rich polycrystalline monolayer WS2 film for attomolar-level Hg2+ sensors
Authors: Liu Lixuan , Ye Kun , Lin Changqing , Jia Zhiyan , Xue Tianyu , Nie Anmin , Cheng Yingchun , Xiang Jianyong , Mu Congpu , Wang Bochong , Wen Fusheng , Zhai Kun , Zhao Zhisheng , Gong Yongji , Liu Zhongyuan , Tian Yongjun 
Published: June 2021

AbstractEmerging two-dimensional (2D) layered materials have been attracting great attention as sensing materials for next-generation high-performance biological and chemical sensors. The sensor performance of 2D materials is strongly dependent on the structural defects as indispensable active sites for analyte adsorption. However, controllable defect engineering in 2D materials is still challenging. In the present work, we propose exploitation of controllably grown polycrystalline films of 2D layered materials with high-density grain boundaries (GBs) for design of ultra-sensitive ion sensors, where abundant structural defects on GBs act as favorable active sites for ion adsorption. As a proof-of-concept, our fabricated surface plasmon resonance sensors with GB-rich polycrystalline monolayer WS2 films have exhibited high selectivity and superior attomolar-level sensitivity in Hg2+ detection owing to high-density GBs. This work provides a promising avenue for design of ultra-sensitive sensors based on GB-rich 2D layered materials.
Long COVID in a prospective cohort of home-isolated patients
Authors: Blomberg Bjørn , Mohn Kristin Greve-Isdahl , Brokstad Karl Albert , Zhou Fan , Linchausen Dagrun Waag , Hansen Bent-Are , Lartey Sarah , Onyango Therese Bredholt , Kuwelker Kanika , Sævik Marianne , Bartsch Hauke , Tøndel Camilla , Kittang Bård Reiakvam ,   Bergen COVID-19 Research Group, Madsen Anders , Bredholt Geir , Vahokoski Juha , Fjelltveit Elisabeth Berg , Bansal Amit , Trieu Mai Chi , Ljostveit Sonja , Olofsson Jan Stefan , Ertesvåg Nina , Sandnes Helene Heitmann , Corydon Anette , Søyland Hanne , Eidsheim Marianne , Jakobsen Kjerstin , Guldseth Nina , Hauge Synnøve , Cox Rebecca Jane , Langeland Nina 
Published: June 2021

AbstractLong-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients—247 home-isolated and 65 hospitalized—comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16–30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.
Thermal stability and diffusion characteristics of ultrathin amorphous carbon films grown on crystalline and nitrogenated silicon substrates by filtered cathodic vacuum arc deposition
Authors: Wang Shengxi , Roy Anurag , Komvopoulos Kyriakos 
Published: June 2021

AbstractAmorphous carbon (a-C) films are widely used as protective overcoats in many technology sectors, principally due to their excellent thermophysical properties and chemical inertness. The growth and thermal stability of sub-5-nm-thick a-C films synthesized by filtered cathodic vacuum arc on pure (crystalline) and nitrogenated (amorphous) silicon substrate surfaces were investigated in this study. Samples of a-C/Si and a-C/SiNx/Si stacks were thermally annealed for various durations and subsequently characterized by high-resolution transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS). The TEM images confirmed the continuity and uniformity of the a-C films and the 5-nm-thick SiNx underlayer formed by silicon nitrogenation using radio-frequency sputtering. The EELS analysis of cross-sectional samples revealed the thermal stability of the a-C films and the efficacy of the SiNx underlayer to prevent carbon migration into the silicon substrate, even after prolonged heating. The obtained results provide insight into the important attributes of an underlayer in heated multilayered media for preventing elemental intermixing with the substrate, while preserving the structural stability of the a-C film at the stack surface. An important contribution of this investigation is the establishment of an experimental framework for accurately assessing the thermal stability and elemental diffusion in layered microstructures exposed to elevated temperatures.
Multi-institutional retrospective analysis of ultrahypofractionated radiotherapy for Japanese prostate cancer patients
Authors: Ishiyama Hiromichi , Tsumura Hideyasu , Nagano Hisato , Watanabe Motoi , Mizuno Eiichi , Taka Masashi , Kobayashi Hiroaki , Eriguchi Takahisa , Imada Hajime , Inaba Koji , Nakamura Katsumasa 
Published: June 2021

AbstractTo report outcomes and risk factors of ultrahypofractionated (UHF) radiotherapy for Japanese prostate cancer patients. This multi-institutional retrospective analysis comprised 259 patients with localized prostate cancer from 6 hospitals. A total dose of 35–36 Gy in 4–5 fractions was prescribed for sequential or alternate-day administration. Biochemical failure was defined according to the Phoenix ASTRO consensus. Toxicities were assessed using National Cancer Institute Common Toxicity Criteria version 4. Tumor control and toxicity rates were analyzed by competing risk frames. Median follow-up duration was 32 months (range 22–97 months). 2- and 3-year biochemical control rates were 97.7% and 96.4%, respectively. Initial prostate-specific antigen (p < 0.01) and neoadjuvant androgen deprivation therapy (p < 0.05) were identified as risk factors for biochemical recurrence. 2- and 3-year cumulative ≥ Grade 2 late genitourinary (GU) toxicities were 5.8% and 7.4%, respectively. Corresponding rates of gastrointestinal (GI) toxicities were 3.9% and 4.5%, respectively. Grade 3 rates were lower than 1% for both GU and GI toxicities. No grade 4 or higher toxicities were encountered. Biologically effective dose was identified as a risk factor for ≥ Grade 2 late GU and GI toxicities (p < 0.05). UHF radiotherapy offered effective, safe treatment for Japanese prostate cancer with short-term follow-up. Our result suggest higher prescribed doses are related to higher toxicity rates.
The place of millet in food globalization during Late Prehistory as evidenced by new bioarchaeological data from the Caucasus
Authors: Martin Lucie , Messager Erwan , Bedianashvili Giorgi , Rusishvili Nana , Lebedeva Elena , Longford Catherine , Hovsepyan Roman , Bitadze Liana , Chkadua Marine , Vanishvili Nikoloz , Le Mort Françoise , Kakhiani Kakha , Abramishvili Mikheil , Gogochuri Giorgi , Murvanidze Bidzina , Giunashvili Gela , Licheli Vakhtang , Salavert Aurélie , Andre Guy , Herrscher Estelle 
Published: June 2021

AbstractTwo millets, Panicum miliaceum and Setaria italica, were domesticated in northern China, around 6000 BC. Although its oldest evidence is in Asia, possible independent domestication of these species in the Caucasus has often been proposed. To verify this hypothesis, a multiproxy research program (Orimil) was designed to detect the first evidence of millet in this region. It included a critical review of the occurrence of archaeological millet in the Caucasus, up to Antiquity; isotopic analyses of human and animal bones and charred grains; and radiocarbon dating of millet grains from archaeological contexts dated from the Early Bronze Age (3500–2500 BC) to the 1st Century BC. The results show that these two cereals were cultivated during the Middle Bronze Age (MBA), around 2000–1800 BC, especially Setaria italica which is the most ancient millet found in Georgia. Isotopic analyses also show a significant enrichment in 13C in human and animal tissues, indicating an increasing C4 plants consumption at the same period. More broadly, our results assert that millet was not present in the Caucasus in the Neolithic period. Its arrival in the region, based on existing data in Eurasia, was from the south, without excluding a possible local domestication of Setaria italica.
Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
Authors: Nakamura Makoto , Meguri Yusuke , Ikegawa Shuntaro , Kondo Takumi , Sumii Yuichi , Fukumi Takuya , Iwamoto Miki , Sando Yasuhisa , Sugiura Hiroyuki , Asada Noboru , Ennishi Daisuke , Tomida Shuta , Fukuda-Kawaguchi Emi , Ishii Yasuyuki , Maeda Yoshinobu , Matsuoka Ken-ichi 
Published: June 2021

AbstractPosttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.
Identification of biological pathway and process regulators using sparse partial least squares and triple-gene mutual interaction
Authors: Hong Junyan , Gunasekara Chathura , He Cheng , Liu Sanzhen , Huang Jianqin , Wei Hairong 
Published: June 2021

AbstractIdentification of biological process- and pathway-specific regulators is essential for advancing our understanding of regulation and formation of various phenotypic and complex traits. In this study, we applied two methods, triple-gene mutual interaction (TGMI) and Sparse Partial Least Squares (SPLS), to identify the regulators of multiple metabolic pathways in Arabidopsis thaliana and Populus trichocarpa using high-throughput gene expression data. We analyzed four pathways: (1) lignin biosynthesis pathway in A. thaliana and P. trichocarpa; (2) flavanones, flavonol and anthocyannin biosynthesis in A. thaliana; (3) light reaction pathway and Calvin cycle in A. thaliana. (4) light reaction pathway alone in A. thaliana. The efficiencies of two methods were evaluated by examining the positive known regulators captured, the receiver operating characteristic (ROC) curves and the area under ROC curves (AUROC). Our results showed that TGMI is in general more efficient than SPLS in identifying true pathway regulators and ranks them to the top of candidate regulatory gene lists, but the two methods are to some degree complementary because they could identify some different pathway regulators. This study identified many regulators that potentially regulate the above pathways in plants and are valuable for genetic engineering of these pathways.
A microfluidic device enabling drug resistance analysis of leukemia cells via coupled dielectrophoretic detection and impedimetric counting
Authors: Demircan Yalçın Yağmur , Töral Taylan Berkin , Sukas Sertan , Yıldırım Ender , Zorlu Özge , Gündüz Ufuk , Külah Haluk 
Published: June 2021

AbstractWe report the development of a lab-on-a-chip system, that facilitates coupled dielectrophoretic detection (DEP-D) and impedimetric counting (IM-C), for investigating drug resistance in K562 and CCRF-CEM leukemia cells without (immuno) labeling. Two IM-C units were placed upstream and downstream of the DEP-D unit for enumeration, respectively, before and after the cells were treated in DEP-D unit, where the difference in cell count gave the total number of trapped cells based on their DEP characteristics. Conductivity of the running buffer was matched the conductivity of cytoplasm of wild type K562 and CCRF-CEM cells. Results showed that DEP responses of drug resistant and wild type K562 cells were statistically discriminative (at p = 0.05 level) at 200 mS/m buffer conductivity and at 8.6 MHz working frequency of DEP-D unit. For CCRF-CEM cells, conductivity and frequency values were 160 mS/m and 6.2 MHz, respectively. Our approach enabled discrimination of resistant cells in a group by setting up a threshold provided by the conductivity of running buffer. Subsequent selection of drug resistant cells can be applied to investigate variations in gene expressions and occurrence of mutations related to drug resistance.
Cultural values shape the expression of self-evaluative social emotions
Authors: von Suchodoletz Antje , Hepach Robert 
Published: June 2021

AbstractSocial emotions are key to everyday social life and therefore shaped by cultural values in their expression. Prior research has focused on facial expressions of emotions. What is less clear, however, is the extent to which cultural values shape other modalities of emotional expression. In the present study, we applied a novel paradigm using depth sensor imaging technology to capture changes in participants’ body posture in real time. We aimed to (1) identify the nuances in the postural expression that are thought to characterize social emotions and (2) assess how individual differences in cultural values impact the postural expression of emotions. Participants in two separate studies were 132 undergraduate college students whose upper-body postural expansion was recorded after they recalled emotion episodes. Positive emotions elevated participants’ upper-body posture whereas negative emotions resulted in lowered upper-body posture. The effects on changes in upper-body posture were moderated by participants’ self-ratings of the vertical and horizontal dimensions of individualism and collectivism. The findings provide initial evidence of the nuances in the way cultural values influence the postural expression of emotions.
Pharmacologic targeting of Cdc42 GTPase by a small molecule Cdc42 activity-specific inhibitor prevents platelet activation and thrombosis
Authors: Duan Xin , Perveen Rehana , Dandamudi Akhila , Adili Reheman , Johnson James , Funk Kevin , Berryman Mark , Davis Ashley Kuenzi , Holinstat Michael , Zheng Yi , Akbar Huzoor 
Published: June 2021

AbstractGene targeting of Cdc42 GTPase has been shown to inhibit platelet activation. In this study, we investigated a hypothesis that inhibition of Cdc42 activity by CASIN, a small molecule Cdc42 Activity-Specific INhibitor, may down regulate platelet activation and thrombus formation. We investigated the effects of CASIN on platelet activation in vitro and thrombosis in vivo. In human platelets, CASIN, but not its inactive analog Pirl7, blocked collagen induced activation of Cdc42 and inhibited phosphorylation of its downstream effector, PAK1/2. Moreover, addition of CASIN to washed human platelets inhibited platelet spreading on immobilized fibrinogen. Treatment of human platelets with CASIN inhibited collagen or thrombin induced: (a) ATP secretion and platelet aggregation; and (b) phosphorylation of Akt, ERK and p38-MAPK. Pre-incubation of platelets with Pirl7, an inactive analog of CASIN, failed to inhibit collagen induced aggregation. Washing of human platelets after incubation with CASIN eliminated its inhibitory effect on collagen induced aggregation. Intraperitoneal administration of CASIN to wild type mice inhibited ex vivo aggregation induced by collagen but did not affect the murine tail bleeding times. CASIN administration, prior to laser-induced injury in murine cremaster muscle arterioles, resulted in formation of smaller and unstable thrombi compared to control mice without CASIN treatment. These data suggest that pharmacologic targeting of Cdc42 by specific and reversible inhibitors may lead to the discovery of novel antithrombotic agents.