bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining lines of therapy in patients with solid cancers: a proposed new systematic and comprehensive framework
Authors: Saini Kamal S. , Twelves Chris
Published: April 2021

The complexity of neoplasia and its treatment are a challenge to the formulation of general criteria that are applicable across solid cancers. Determining the number of prior lines of therapy (LoT) is critically important for optimising future treatment, conducting medication audits, and assessing eligibility for clinical trial enrolment. Currently, however, no accepted set of criteria or definitions exists to enumerate LoT. In this article, we seek to open a dialogue to address this challenge by proposing a systematic and comprehensive framework to determine LoT uniformly across solid malignancies. First, key terms, including LoT and ‘clinical progression of disease’ are defined. Next, we clarify which therapies should be assigned a LoT, and why. Finally, we propose reporting LoT in a novel and standardised format as LoT N (CLoT + PLoT), where CLoT is the number of systemic anti-cancer therapies (SACT) administered with curative intent and/or in the early setting, PLoT is the number of SACT given with palliative intent and/or in the advanced setting, and N is the sum of CLoT and PLoT. As a next step, the cancer research community should develop and adopt standardised guidelines for enumerating LoT in a uniform manner.
Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids
Authors: Kim Chang H.
Published: April 2021

A mounting body of evidence indicates that dietary fiber (DF) metabolites produced by commensal bacteria play essential roles in balancing the immune system. DF, considered nonessential nutrients in the past, is now considered to be necessary to maintain adequate levels of immunity and suppress inflammatory and allergic responses. Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, are the major DF metabolites and mostly produced by specialized commensal bacteria that are capable of breaking down DF into simpler saccharides and further metabolizing the saccharides into SCFAs. SCFAs act on many cell types to regulate a number of important biological processes, including host metabolism, intestinal functions, and immunity system. This review specifically highlights the regulatory functions of DF and SCFAs in the immune system with a focus on major innate and adaptive lymphocytes. Current information regarding how SCFAs regulate innate lymphoid cells, T helper cells, cytotoxic T cells, and B cells and how these functions impact immunity, inflammation, and allergic responses are discussed.
An update on the regulatory mechanisms of NLRP3 inflammasome activation
Authors: Paik Seungwha , Kim Jin Kyung , Silwal Prashanta , Sasakawa Chihiro , Jo Eun-Kyeong
Published: April 2021

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.
CARAMBA: a first-in-human clinical trial with SLAMF7 CAR-T cells prepared by virus-free Sleeping Beauty gene transfer to treat multiple myeloma
Authors: Prommersberger Sabrina , Reiser Michael , Beckmann Julia , Danhof Sophia , Amberger Maximilian , Quade-Lyssy Patricia , Einsele Hermann , Hudecek Michael , Bonig Halvard , Ivics Zoltán
Published: April 2021

Clinical development of chimeric antigen receptor (CAR)-T-cell therapy has been enabled by advances in synthetic biology, genetic engineering, clinical-grade manufacturing, and complex logistics to distribute the drug product to treatment sites. A key ambition of the CARAMBA project is to provide clinical proof-of-concept for virus-free CAR gene transfer using advanced Sleeping Beauty (SB) transposon technology. SB transposition in CAR-T engineering is attractive due to the high rate of stable CAR gene transfer enabled by optimized hyperactive SB100X transposase and transposon combinations, encoded by mRNA and minicircle DNA, respectively, as preferred vector embodiments. This approach bears the potential to facilitate and expedite vector procurement, CAR-T manufacturing and distribution, and the promise to provide a safe, effective, and economically sustainable treatment. As an exemplary and novel target for SB-based CAR-T cells, the CARAMBA consortium has selected the SLAMF7 antigen in multiple myeloma. SLAMF7 CAR-T cells confer potent and consistent anti-myeloma activity in preclinical assays in vitro and in vivo. The CARAMBA clinical trial (Phase-I/IIA; EudraCT: 2019-001264-30) investigates the feasibility, safety, and anti-myeloma efficacy of autologous SLAMF7 CAR-T cells. CARAMBA is the first clinical trial with virus-free CAR-T cells in Europe, and the first clinical trial that uses advanced SB technology worldwide.
Marginal ice zone fraction benchmarks sea ice and climate model skill
Authors: Horvat Christopher
Published: April 2021

Global climate models (GCMs) consistently underestimate the response of September Arctic sea-ice area (SIA) to warming. Modeled SIA losses are highly correlated to global mean temperature increases, making it challenging to gauge if improvements in modeled sea ice derive from improved sea-ice models or from improvements in forcing driven by other GCM components. I use a set of five large GCM ensembles, and CMIP6 simulations, to quantify GCM internal variability and variability between GCMs from 1979–2014, showing modern GCMs do not plausibly estimate the response of SIA to warming in all months. I identify the marginal ice zone fraction (MIZF) as a metric that is less correlated to warming, has a response plausibly simulated from January–September (but not October–December), and has highly variable future projections across GCMs. These qualities make MIZF useful for evaluating the impact of sea-ice model changes on past, present, and projected sea-ice state.
New hominin remains and revised context from the earliest Homo erectus locality in East Turkana, Kenya
Authors: Hammond Ashley S. , Mavuso Silindokuhle S. , Biernat Maryse , Braun David R. , Jinnah Zubair , Kuo Sharon , Melaku Sahleselasie , Wemanya Sylvia N. , Ndiema Emmanuel K. , Patterson David B. , Uno Kevin T. , Palcu Dan V.
Published: April 2021

The KNM-ER 2598 occipital is among the oldest fossils attributed to Homo erectus but questions have been raised about whether it may derive from a younger horizon. Here we report on efforts to relocate the KNM-ER 2598 locality and investigate its paleontological and geological context. Although located in a different East Turkana collection area (Area 13) than initially reported, the locality is stratigraphically positioned below the KBS Tuff and the outcrops show no evidence of deflation of a younger unit, supporting an age of >1.855 Ma. Newly recovered faunal material consists primarily of C4 grazers, further confirmed by enamel isotope data. A hominin proximal 3rd metatarsal and partial ilium were discovered <50 m from the reconstructed location where KNM-ER 2598 was originally found but these cannot be associated directly with the occipital. The postcrania are consistent with fossil Homo and may represent the earliest postcrania attributable to Homo erectus.
Precisely spun super rotors
Authors: Antonov Ivan O. , Stollenwerk Patrick R. , Venkataramanababu Sruthi , de Lima Batista Ana P. , de Oliveira-Filho Antonio G. S. , Odom Brian C.
Published: April 2021

Improved optical control of molecular quantum states promises new applications including chemistry in the quantum regime, precision tests of fundamental physics, and quantum information processing. While much work has sought to prepare ground state molecules, excited states are also of interest. Here, we demonstrate a broadband optical approach to pump trapped SiO+ molecules into pure super rotor ensembles maintained for many minutes. Super rotor ensembles pumped up to rotational state N = 67, corresponding to the peak of a 9400 K distribution, had a narrow N spread comparable to that of a few-kelvin sample, and were used for spectroscopy of the previously unobserved C2Π state. Significant centrifugal distortion of super rotors pumped up to N = 230 allowed probing electronic structure of SiO+ stretched far from its equilibrium bond length.
Oxidized sulfur-rich arc magmas formed porphyry Cu deposits by 1.88 Ga
Authors: Meng Xuyang , Kleinsasser Jackie M. , Richards Jeremy P. , Tapster Simon R. , Jugo Pedro J. , Simon Adam C. , Kontak Daniel J. , Robb Laurence , Bybee Grant M. , Marsh Jeffrey H. , Stern Richard A.
Published: April 2021

Most known porphyry Cu deposits formed in the Phanerozoic and are exclusively associated with moderately oxidized, sulfur-rich, hydrous arc-related magmas derived from partial melting of the asthenospheric mantle metasomatized by slab-derived fluids. Yet, whether similar metallogenic processes also operated in the Precambrian remains obscure. Here we address the issue by investigating the origin, fO2, and S contents of calc-alkaline plutonic rocks associated with the Haib porphyry Cu deposit in the Paleoproterozoic Richtersveld Magmatic Arc (southern Namibia), an interpreted mature island-arc setting. We show that the ca. 1886–1881 Ma ore-forming magmas, originated from a mantle-dominated source with minor crustal contributions, were relatively oxidized (1‒2 log units above the fayalite-magnetite-quartz redox buffer) and sulfur-rich. These results indicate that moderately oxidized, sulfur-rich arc magma associated with porphyry Cu mineralization already existed in the late Paleoproterozoic, probably as a result of recycling of sulfate-rich seawater or sediments from the subducted oceanic lithosphere at that time.
Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney
Authors: Muto Yoshiharu , Wilson Parker C. , Ledru Nicolas , Wu Haojia , Dimke Henrik , Waikar Sushrut S. , Humphreys Benjamin D.
Published: April 2021

The integration of single cell transcriptome and chromatin accessibility datasets enables a deeper understanding of cell heterogeneity. We performed single nucleus ATAC (snATAC-seq) and RNA (snRNA-seq) sequencing to generate paired, cell-type-specific chromatin accessibility and transcriptional profiles of the adult human kidney. We demonstrate that snATAC-seq is comparable to snRNA-seq in the assignment of cell identity and can further refine our understanding of functional heterogeneity in the nephron. The majority of differentially accessible chromatin regions are localized to promoters and a significant proportion are closely associated with differentially expressed genes. Cell-type-specific enrichment of transcription factor binding motifs implicates the activation of NF-κB that promotes VCAM1 expression and drives transition between a subpopulation of proximal tubule epithelial cells. Our multi-omics approach improves the ability to detect unique cell states within the kidney and redefines cellular heterogeneity in the proximal tubule and thick ascending limb.
Resolving atomic SAPO-34/18 intergrowth architectures for methanol conversion by identifying light atoms and bonds
Authors: Shen Boyuan , Chen Xiao , Fan Xiaoyu , Xiong Hao , Wang Huiqiu , Qian Weizhong , Wang Yao , Wei Fei
Published: April 2021

The micro-structures of catalyst materials basically affect their macro-architectures and catalytic performances. Atomically resolving the micro-structures of zeolite catalysts, which have been widely used in the methanol conversion, will bring us a deeper insight into their structure-property correlations. However, it is still challenging for the atomic imaging of silicoaluminophosphate zeolites by electron microscopy due to the limits of their electron beam sensitivity. Here, we achieve the real-space imaging of the atomic lattices in SAPO-34 and SAPO-18 zeolites, including the Al–O–P atoms and bonds, by the integrated differential phase contrast scanning transmission electron microscopy (iDPC-STEM). The spatial distribution of SAPO-34 and SAPO-18 domains in SAPO-34/18 intergrowths can be clearly resolved. By changing the Si contents and templates in feed, we obtain two SAPO-34/18 catalysts, hierarchical and sandwich catalysts, with highly-mixed and separated SAPO-34 and SAPO-18 lattices respectively. The reduced diffusion distances of inside products greatly improve the catalytic performances of two catalysts in methanol conversion. Based on the observed distributions of lattices and elements in these catalysts, we can have a preliminary understanding on the correlation between the synthesis conditions and structures of SAPO-34/18 intergrowth catalysts to further modify their performances based on unique architectures.
Organic matter mineralization in modern and ancient ferruginous sediments
Authors: Friese André , Bauer Kohen , Glombitza Clemens , Ordoñez Luis , Ariztegui Daniel , Heuer Verena B. , Vuillemin Aurèle , Henny Cynthia , Nomosatryo Sulung , Simister Rachel , Wagner Dirk , Bijaksana Satria , Vogel Hendrik , Melles Martin , Russell James M. , Crowe Sean A. , Kallmeyer Jens
Published: April 2021

Deposition of ferruginous sediment was widespread during the Archaean and Proterozoic Eons, playing an important role in global biogeochemical cycling. Knowledge of organic matter mineralization in such sediment, however, remains mostly conceptual, as modern ferruginous analogs are largely unstudied. Here we show that in sediment of ferruginous Lake Towuti, Indonesia, methanogenesis dominates organic matter mineralization despite highly abundant reactive ferric iron phases like goethite that persist throughout the sediment. Ferric iron can thus be buried over geologic timescales even in the presence of labile organic carbon. Coexistence of ferric iron with millimolar concentrations of methane further demonstrates lack of iron-dependent methane oxidation. With negligible methane oxidation, methane diffuses from the sediment into overlying waters where it can be oxidized with oxygen or escape to the atmosphere. In low-oxygen ferruginous Archaean and Proterozoic oceans, therefore, sedimentary methane production was likely favored with strong potential to influence Earth’s early climate.
Broadband generation of perfect Poincaré beams via dielectric spin-multiplexed metasurface
Authors: Liu Mingze , Huo Pengcheng , Zhu Wenqi , Zhang Cheng , Zhang Si , Song Maowen , Zhang Song , Zhou Qianwei , Chen Lu , Lezec Henri J. , Agrawal Amit , Lu Yanqing , Xu Ting
Published: April 2021

The term Poincaré beam, which describes the space-variant polarization of a light beam carrying spin angular momentum (SAM) and orbital angular momentum (OAM), plays an important role in various optical applications. Since the radius of a Poincaré beam conventionally depends on the topological charge number, it is difficult to generate a stable and high-quality Poincaré beam by two optical vortices with different topological charge numbers, as the Poincaré beam formed in this way collapses upon propagation. Here, based on an all-dielectric metasurface platform, we experimentally demonstrate broadband generation of a generalized perfect Poincaré beam (PPB), whose radius is independent of the topological charge number. By utilizing a phase-only modulation approach, a single-layer spin-multiplexed metasurface is shown to achieve all the states of PPBs on the hybrid-order Poincaré Sphere for visible light. Furthermore, as a proof-of-concept demonstration, a metasurface encoding multidimensional SAM and OAM states in the parallel channels of elliptical and circular PPBs is implemented for optical information encryption. We envision that this work will provide a compact and efficient platform for generation of PPBs for visible light, and may promote their applications in optical communications, information encryption, optical data storage and quantum information sciences.
Tissue-specific cell-free DNA degradation quantifies circulating tumor DNA burden
Authors: Zhu Guanhua , Guo Yu A. , Ho Danliang , Poon Polly , Poh Zhong Wee , Wong Pui Mun , Gan Anna , Chang Mei Mei , Kleftogiannis Dimitrios , Lau Yi Ting , Tay Brenda , Lim Wan Jun , Chua Clarinda , Tan Tira J. , Koo Si-Lin , Chong Dawn Q. , Yap Yoon Sim , Tan Iain , Ng Sarah , Skanderup Anders J.
Published: April 2021

Profiling of circulating tumor DNA (ctDNA) may offer a non-invasive approach to monitor disease progression. Here, we develop a quantitative method, exploiting local tissue-specific cell-free DNA (cfDNA) degradation patterns, that accurately estimates ctDNA burden independent of genomic aberrations. Nucleosome-dependent cfDNA degradation at promoters and first exon-intron junctions is strongly associated with differential transcriptional activity in tumors and blood. A quantitative model, based on just 6 regulatory regions, could accurately predict ctDNA levels in colorectal cancer patients. Strikingly, a model restricted to blood-specific regulatory regions could predict ctDNA levels across both colorectal and breast cancer patients. Using compact targeted sequencing (<25 kb) of predictive regions, we demonstrate how the approach could enable quantitative low-cost tracking of ctDNA dynamics and disease progression.
Moss enables high sensitivity single-nucleotide variant calling from multiple bulk DNA tumor samples
Authors: Zhang Chuanyi , El-Kebir Mohammed , Ochoa Idoia
Published: April 2021

Intra-tumor heterogeneity renders the identification of somatic single-nucleotide variants (SNVs) a challenging problem. In particular, low-frequency SNVs are hard to distinguish from sequencing artifacts. While the increasing availability of multi-sample tumor DNA sequencing data holds the potential for more accurate variant calling, there is a lack of high-sensitivity multi-sample SNV callers that utilize these data. Here we report Moss, a method to identify low-frequency SNVs that recur in multiple sequencing samples from the same tumor. Moss provides any existing single-sample SNV caller the ability to support multiple samples with little additional time overhead. We demonstrate that Moss improves recall while maintaining high precision in a simulated dataset. On multi-sample hepatocellular carcinoma, acute myeloid leukemia and colorectal cancer datasets, Moss identifies new low-frequency variants that meet manual review criteria and are consistent with the tumor’s mutational signature profile. In addition, Moss detects the presence of variants in more samples of the same tumor than reported by the single-sample caller. Moss’ improved sensitivity in SNV calling will enable more detailed downstream analyses in cancer genomics.
Exciton-acoustic phonon coupling revealed by resonant excitation of single perovskite nanocrystals
Authors: Lv Yan , Yin Chunyang , Zhang Chunfeng , Wang Xiaoyong , Yu Zhi-Gang , Xiao Min
Published: April 2021

Single perovskite nanocrystals have attracted great research attention very recently due to their potential quantum-information applications, which critically depend on the development of powerful optical techniques to resolve delicate exciton photophysics. Here we have realized resonant and near-resonant excitations of single perovskite CsPbI3 nanocrystals, with the scattered laser light contributing to only ~10% of the total collected signals. This allows us to estimate an ultranarrow photoluminescence excitation linewidth of ~11.32 µeV for the emission state of a single CsPbI3 nanocrystal, corresponding to an exciton dephasing time of ~116.29 ps. Meanwhile, size-quantized acoustic phonons can be resolved from a single CsPbI3 nanocrystal, whose coupling with the exciton is proposed to arise from the piezoelectric potential. The ability to collect resonance fluorescence from single CsPbI3 nanocrystals, with the subsequent revelation of exciton-acoustic phonon coupling, has marked a critical step towards their steady advancement into superior quantum-light sources.
Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase
Authors: Kalkreuter Edward , Bingham Kyle S. , Keeler Aaron M. , Lowell Andrew N. , Schmidt Jennifer J. , Sherman David H. , Williams Gavin J.
Published: April 2021

Polyketides, one of the largest classes of natural products, are often clinically relevant. The ability to engineer polyketide biosynthesis to produce analogs is critically important. Acyltransferases (ATs) of modular polyketide synthases (PKSs) catalyze the installation of malonyl-CoA extenders into polyketide scaffolds. ATs have been targeted extensively to site-selectively introduce various extenders into polyketides. Yet, a complete inventory of AT residues responsible for substrate selection has not been established, limiting the scope of AT engineering. Here, molecular dynamics simulations are used to prioritize ~50 mutations within the active site of EryAT6 from erythromycin biosynthesis, leading to identification of two previously unexplored structural motifs. Exchanging both motifs with those from ATs with alternative extender specificities provides chimeric PKS modules with expanded and inverted substrate specificity. Our enhanced understanding of AT substrate selectivity and application of this motif-swapping strategy are expected to advance our ability to engineer PKSs towards designer polyketides.
Cell-type-specific profiling of loaded miRNAs from Caenorhabditis elegans reveals spatial and temporal flexibility in Argonaute loading
Authors: Brosnan Christopher A. , Palmer Alexander J. , Zuryn Steven
Published: April 2021

Multicellularity has coincided with the evolution of microRNAs (miRNAs), small regulatory RNAs that are integrated into cellular differentiation and homeostatic gene-regulatory networks. However, the regulatory mechanisms underpinning miRNA activity have remained largely obscured because of the precise, and thus difficult to access, cellular contexts under which they operate. To resolve these, we have generated a genome-wide map of active miRNAs in Caenorhabditis elegans by revealing cell-type-specific patterns of miRNAs loaded into Argonaute (AGO) silencing complexes. Epitope-labelled AGO proteins were selectively expressed and immunoprecipitated from three distinct tissue types and associated miRNAs sequenced. In addition to providing information on biological function, we define adaptable miRNA:AGO interactions with single-cell-type and AGO-specific resolution. We demonstrate spatial and temporal dynamicism, flexibility of miRNA loading, and suggest miRNA regulatory mechanisms via AGO selectivity in different tissues and during ageing. Additionally, we resolve widespread changes in AGO-regulated gene expression by analysing translatomes specifically in neurons.
EFA6B regulates a stop signal for collective invasion in breast cancer
Authors: Fayad Racha , Rojas Monserrat Vázquez , Partisani Mariagrazia , Finetti Pascal , Dib Shiraz , Abelanet Sophie , Virolle Virginie , Farina Anne , Cabaud Olivier , Lopez Marc , Birnbaum Daniel , Bertucci François , Franco Michel , Luton Frédéric
Published: April 2021

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Their identification is of paramount importance. Reduced expression of EFA6B (Exchange Factor for ARF6, B) is associated with breast cancer of poor prognosis. Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer.
High-performance large-area quasi-2D perovskite light-emitting diodes
Authors: Sun Changjiu , Jiang Yuanzhi , Cui Minghuan , Qiao Lu , Wei Junli , Huang Yanmin , Zhang Li , He Tingwei , Li Saisai , Hsu Hsien-Yi , Qin Chaochao , Long Run , Yuan Mingjian
Published: April 2021

Serious performance decline arose for perovskite light-emitting diodes (PeLEDs) once the active area was enlarged. Here we investigate the failure mechanism of the widespread active film fabrication method; and ascribe severe phase-segregation to be the reason. We thereby introduce L-Norvaline to construct a COO−-coordinated intermediate phase with low formation enthalpy. The new intermediate phase changes the crystallization pathway, thereby suppressing the phase-segregation. Accordingly, high-quality large-area quasi-2D films with desirable properties are obtained. Based on this, we further rationally adjusted films’ recombination kinetics. We reported a series of highly-efficient green quasi-2D PeLEDs with active areas of 9.0 cm2. The peak EQE of 16.4% is achieved in  = 3, represent the most efficient large-area PeLEDs yet. Meanwhile, high brightness device with luminance up to 9.1 × 104 cd m−2 has achieved in  = 10 film.
Associations between frontal lobe structure, parent-reported obstructive sleep disordered breathing and childhood behavior in the ABCD dataset
Authors: Isaiah Amal , Ernst Thomas , Cloak Christine C. , Clark Duncan B. , Chang Linda
Published: April 2021

Parents frequently report behavioral problems among children who snore. Our understanding of the relationship between symptoms of obstructive sleep disordered breathing (oSDB) and childhood behavioral problems associated with brain structural alterations is limited. Here, we examine the associations between oSDB symptoms, behavioral measures such as inattention, and brain morphometry in the Adolescent Brain Cognitive Development (ABCD) study comprising 10,140 preadolescents. We observe that parent-reported symptoms of oSDB are associated with composite and domain-specific problem behaviors measured by parent responses to the Child Behavior Checklist. Alterations of brain structure demonstrating the strongest negative associations with oSDB symptoms are within the frontal lobe. The relationships between oSDB symptoms and behavioral measures are mediated by significantly smaller volumes of multiple frontal lobe regions. These results provide population-level evidence for an association between regional structural alterations in cortical gray matter and problem behaviors reported in children with oSDB.
Male fertility thermal limits predict vulnerability to climate warming
Authors: van Heerwaarden Belinda , Sgrò Carla M.
Published: April 2021

Forecasting which species/ecosystems are most vulnerable to climate warming is essential to guide conservation strategies to minimize extinction. Tropical/mid-latitude species are predicted to be most at risk as they live close to their upper critical thermal limits (CTLs). However, these assessments assume that upper CTL estimates, such as CTmax, are accurate predictors of vulnerability and ignore the potential for evolution to ameliorate temperature increases. Here, we use experimental evolution to assess extinction risk and adaptation in tropical and widespreadDrosophilaspecies. We find tropical species succumb to extinction before widespread species. Male fertility thermal limits, which are much lower than CTmax, are better predictors of species’ current distributions and extinction in the laboratory. We find little evidence of adaptive responses to warming in any species. These results suggest that species are living closer to their upper thermal limits than currently presumed and evolution/plasticity are unlikely to rescue populations from extinction.
Steller’s sea cow genome suggests this species began going extinct before the arrival of Paleolithic humans
Authors: Sharko Fedor S. , Boulygina Eugenia S. , Tsygankova Svetlana V. , Slobodova Natalia V. , Alekseev Dmitry A. , Krasivskaya Anna A. , Rastorguev Sergey M. , Tikhonov Alexei N. , Nedoluzhko Artem V.
Published: April 2021

Anthropogenic activity is the top factor directly related to the extinction of several animal species. The last Steller’s sea cow (Hydrodamalis gigas) population on the Commander Islands (Russia) was wiped out in the second half of the 18thcentury due to sailors and fur traders hunting it for the meat and fat. However, new data suggests that the extinction process of this species began much earlier. Here, we present a nuclear de novo assembled genome ofH. gigaswith a 25.4× depth coverage. Our results demonstrate that the heterozygosity of the last population of this animal is low and comparable to the last woolly mammoth population that inhabited Wrangel Island 4000 years ago. Besides, as a matter of consideration, our findings also demonstrate that the extinction of this marine mammal starts along the North Pacific coastal line much earlier than the first Paleolithic humans arrived in the Bering sea region.
Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease
Authors: Carlisle Samantha M. , Qin Hongwei , Hendrickson R. Curtis , Muwanguzi Jordana E. , Lefkowitz Elliot J. , Kennedy Richard E. , Yan Zhaoqi , Yacoubian Talene A. , Benveniste Etty N. , West Andrew B. , Harms Ashley S. , Standaert David G.
Published: April 2021

Increasing evidence supports the role of brain and systemic inflammation in the etiology of Parkinson disease (PD). We used gene expression profiling to examine the activation state of peripheral blood monocytes in 18 patients with early, untreated PD and 16 healthy control (HC) subjects. Monocytes were isolated by negative selection, and gene expression studied by RNA-seq and gene set enrichment analysis. A computational model that incorporated case/control status, sex, and the interaction between case/control status and sex was utilized. We found that there was a striking effect of sex on monocyte gene expression. There was inflammatory activation of monocytes in females with PD, with enrichment of gene sets associated with interferon gamma stimulation. In males, the activation patterns were more heterogeneous. These data point to the importance of systemic monocyte activation in PD, and the importance of studies which examine the differential effects of sex on pathophysiology of the disease.
RETRACTED ARTICLE: Human amniotic membrane grafts for retinal breaks in diabetic tractional retinal detachment and combined tractional and rhegmatogenous retinal detachment
Authors: Chen Yen-Chih , Chen San-Ni
Published: April 2021

To describe the surgical outcomes of using human amniotic membrane (hAM) grafts in the management of retinal breaks in diabetic tractional detachment (TRD) and combined tractional and rhegmatogenous retinal detachment (CTRRD). A retrospective case series of 10 eyes with TRD or CTRRD receiving pars plana vitrectomy with hAM grafts implantation, compared with 13 controls receiving the same surgery without hAM grafts. Best-corrected visual acuity (BCVA) and re-detachment rate were compared between two groups. Postoperatively, all eyes in the hAM group had retina attachment without recurrence, while 9 eyes in the control group had retina re-detachment and required additional surgery (0% vs 69.2%, p = 0.003). The BCVA significantly improved in the hAM group (from 1.96 ± 0.95 to 1.44 ± 0.77 in log MAR, p = 0.03), but not improved in control group (p = 0.20). Postoperative optical coherence tomography of the eyes receiving hAM grafts demonstrated glial tissue regeneration and restoration of ellipsoid zone. In diabetic TRD or CTRRD, hAM grafts could be an effective method, with promising outcome. Compared to standard surgery, it could result in higher retina reattachment rate and significant visual improvement. Moreover, it may offer the adjunctive benefit in tissue regeneration and fasten ellipsoid zone restoration.
Immunomagnetic sequential ultrafiltration (iSUF) platform for enrichment and purification of extracellular vesicles from biofluids
Authors: Zhang Jingjing , Nguyen Luong T. H. , Hickey Richard , Walters Nicole , Wang Xinyu , Kwak Kwang Joo , Lee L. James , Palmer Andre F. , Reátegui Eduardo
Published: April 2021

Extracellular vesicles (EVs) derived from tumor cells have the potential to provide a much-needed source of non-invasive molecular biomarkers for liquid biopsies. However, current methods for EV isolation have limited specificity towards tumor-derived EVs that limit their clinical use. Here, we present an approach called immunomagnetic sequential ultrafiltration (iSUF) that consists of sequential stages of purification and enrichment of EVs in approximately 2 h. In iSUF, EVs present in different volumes of biofluids (0.5–100 mL) can be significantly enriched (up to 1000 times), with up to 99% removal of contaminating proteins (e.g., albumin). The EV recovery rate by iSUF for cell culture media (CCM), serum, and urine corresponded to 98.0% ± 3.6%, 96.0% ± 2.0% and 94.0% ± 1.9%, respectively (p > 0.05). The final step of iSUF enables the separation of tumor-specific EVs by incorporating immunomagnetic beads to target EV subpopulations. Serum from a cohort of clinical samples from metastatic breast cancer (BC) patients and healthy donors were processed by the iSUF platform and the isolated EVs from patients showed significantly higher expression levels of BC biomarkers (i.e., HER2, CD24, and miR21).
Near and mid-infrared optical vortex parametric oscillator based on KTA
Authors: Ababaike Mairihaba , Wang Shutong , Aierken Palidan , Omatsu Takashige , Yusufu Taximaiti
Published: April 2021

We investigated high energy, near and mid-infrared optical vortex lasers formed by a 1 μm optical vortex-pumped KTiOAsO4 (KTA) optical parametric oscillator. The orbital angular momentum (OAM) of the pump beam can be selectively transferred to the signal or idler output by changing the reflectivity of the output coupler. With this system, 1.535 µm vortex signal output with an energy of 2.04 mJ and 3.468 µm vortex idler output with an energy of 1.75 mJ were obtained with a maximum pump energy of 21 mJ, corresponding to slope efficiencies of 14% and 10%, respectively. The spectral bandwidth (full width at half maximum, FWHM) of the signal and idler vortex outputs were measured to be Δλs ~ 1.3 nm (~ 5.5 cm−1) and Δλi ~ 1.7 nm (~ 1.4 cm−1), respectively.
Electrophysiological evidence of different neural processing between visual and audiovisual inhibition of return
Authors: Tang Xiaoyu , Wang Xueli , Peng Xing , Li Qi , Zhang Chi , Wang Aijun , Zhang Ming
Published: April 2021

Inhibition of return (IOR) refers to the slower response to targets appearing on the same side as the cue (valid locations) than to targets appearing on the opposite side as the cue (invalid locations). Previous behaviour studies have found that the visual IOR is larger than the audiovisual IOR when focusing on both visual and auditory modalities. Utilising the high temporal resolution of the event-related potential (ERP) technique we explored the possible neural correlates with the behaviour IOR difference between visual and audiovisual targets. The behavioural results revealed that the visual IOR was larger than the audiovisual IOR. The ERP results showed that the visual IOR effect was generated from the P1 and N2 components, while the audiovisual IOR effect was derived only from the P3 component. Multisensory integration (MSI) of audiovisual targets occurred on the P1, N1 and P3 components, which may offset the reduced perceptual processing due to audiovisual IOR. The results of early and late differences in the neural processing of the visual IOR and audiovisual IOR imply that the two target types may have different inhibitory orientation mechanisms.
Vitamin D and lumisterol derivatives can act on liver X receptors (LXRs)
Authors: Slominski Andrzej T. , Kim Tae-Kang , Qayyum Shariq , Song Yuwei , Janjetovic Zorica , Oak Allen S. W. , Slominski Radomir M. , Raman Chander , Stefan Joanna , Mier-Aguilar Carlos A. , Atigadda Venkatram , Crossman David K. , Golub Andriy , Bilokin Yaroslav , Tang Edith K. Y. , Chen Jake Y. , Tuckey Robert C. , Jetten Anton M. , Song Yuhua
Published: April 2021

The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and β revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and β in LanthaScreen TR-FRET LXRα and β coactivator assays. The majority of metabolites functioned as LXRα/β agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRβ. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.
Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study
Authors: Wan Eric Yuk Fai , Yu Esther Yee Tak , Chin Weng Yee , Lau Christie Sze Ting , Mok Anna Hoi Ying , Wang Yuan , Wong Ian Chi Kei , Chan Esther Wai Yin , Lam Cindy Lo Kuen
Published: April 2021

This study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45–84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008–2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin to creatinine ratio ≥ 3 mg/mmol) were excluded. Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months (0.5 million person-years in total), 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15–1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30–1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74–2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10–1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26–1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46–2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability.
Author Correction: Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation
Authors: Ricobaraza Ana , Mora-Jimenez Lucia , Puerta Elena , Sanchez-Carpintero Rocio , Mingorance Ana , Artieda Julio , Nicolas Maria Jesus , Besne Guillermo , Bunuales Maria , Gonzalez-Aparicio Manuela , Sola-Sevilla Noemi , Valencia Miguel , Hernandez-Alcoceba Ruben
Published: April 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Evaluation and SNP typing of DNA from ultraviolet-irradiated human bloodstains using TaqMan assay
Authors: Tie Jian , Uchigasaki Seisaku , Isobe Eiji
Published: April 2021

When detecting DNA profiles from forensic materials, it is pivotal to know the extent of degradation and which DNA marker can be genotyped. Ultraviolet (UV) is one of the common external factors that causes DNA damage, through which, an attempt to reveal cardinal genetic information can be made. In this study, after irradiation with three different UV wavelengths, UV-damaged DNA in the bloodstains was analyzed with long and short TaqMan assays using real-time PCR. In addition, both short tandem repeat (STR) profiles and single nucleotide polymorphisms (SNPs) from the damaged DNA at different stages of UV exposure were also assessed. With increasing in UV irradiation cycles, there was a delay of the amplification curves accompanied with a decrease in the DNA amounts collected. Despite the amplification of STR genotype was not altered after 75 cycles of UVC irradiation, all 12 SNP loci could still be detected. Furthermore, a short-assay line was detected in the absence of an amplification of the evaluation curve. The results indicate that, although the DNA template might not be useful and suitable for analysis of STR profile, this approach is of some values in detecting SNPs.
New-onset lesions on MRI-DWI and cerebral blood flow changes on 3D-pCASL after carotid artery stenting
Authors: Wang Wen-Xin , Wang Ting , Ma Lin , Sun Zheng-Hui , Wang Ge-Sheng
Published: April 2021

This study aimed to investigate the relationship between the new-onset hyperintense lesions on diffusion-weighted images (DWI) and the changes of cerebral blood flow (CBF) before and after carotid artery stenting (CAS) in patients with symptomatic unilateral carotid artery stenosis. Twenty-four patients with symptomatic unilateral carotid stenosis (50–99%) were enrolled. Routine head magnetic resonance imaging and three-dimensional pseudo-continuous arterial spin labeling were taken 7 days before the surgery and for four consecutive days post CAS. While the incidence of new DWI lesions were high (17/24, 70.8%) and 176 lesions were observed among the 17 cases, there was only one subject showing the symptoms. The majority of the lesions were located at the cortex/subcortex of the ipsilateral frontal and parietal lobes (60.8%) with 92.6% of the lesions size being less than 3 mm. The CBFs in this area were significantly higher than that of the temporal lobe on the first 3 days post stenting (p < 0.05). No periprocedural CBF differences were observed between the two groups, however, the micro-embolism group presented decreased relative CBF in frontal and parietal lobes prior to stenting compared with the non-embolism group. The systolic blood pressure in the micro-embolism group at discharge was significantly lower than that at admission. The high incidence rate of micro-embolism in patients receiving CAS may not be the result of direct changes of hemodynamics in the brain but rather the loss of CBF regulation due to long-term hypoperfusion prior to the stenting.
The impact of indole-3-lactic acid on immature intestinal innate immunity and development: a transcriptomic analysis
Authors: Huang Wuyang , Cho Ky Young , Meng Di , Walker W. Allan
Published: April 2021

An excessive intestinal inflammatory response may have a role in the pathogenesis of necrotizing enterocolitis (NEC) in very preterm infants. Indole-3-lactic acid (ILA) of breastmilk tryptophan was identified as the anti-inflammatory metabolite involved in probiotic conditioned media from Bifidobacteria longum subsp infantis. This study aimed to explore the molecular endocytic pathways involved in the protective ILA effect against inflammation. H4 cells, Caco-2 cells, C57BL/6 pup and adult mice were used to compare the anti-inflammatory mechanisms between immature and mature enterocytes in vitro and in vivo. The results show that ILA has pleiotropic protective effects on immature enterocytes including anti-inflammatory, anti-viral, and developmental regulatory potentials in a region-dependent and an age-dependent manner. Quantitative transcriptomic analysis revealed a new mechanistic model in which STAT1 pathways play an important role in IL-1β-induced inflammation and ILA has a regulatory effect on STAT1 pathways. These studies were validated by real-time RT-qPCR and STAT1 inhibitor experiments. Different protective reactions of ILA between immature and mature enterocytes indicated that ILA’s effects are developmentally regulated. These findings may be helpful in preventing NEC for premature infants.
Radiotherapy for brain metastasis and long-term survival
Authors: Park Kawngwoo , Bae Gi Hwan , Kim Woo Kyung , Yoo Chan-Jong , Park Cheol Wan , Kim Soo-Ki , Cha Jihye , Kim Jin Wook , Jung Jaehun
Published: April 2021

Patients with brain metastases (BM) can benefit from radiotherapy (RT), although the long-term benefits of RT remain unclear. We searched a Korean national health insurance claims database and identified 135,740 patients with newly diagnosed BM during 2002–2017. Propensity score matching (PSM) was used to evaluate survival according to RT modality, which included whole-brain radiotherapy (WBRT) and/or stereotactic radiosurgery (SRS). The 84,986 eligible patients were followed for a median interval of 6.6 months, and 37,046 patients underwent RT (43.6%). After the PSM, patients who underwent RT had significantly better overall survival after 1 year (42.4% vs. 35.3%, P < 0.001), although there was no significant difference at 2.6 years, and patients who did not undergo RT had better survival after 5 years. Among patients with BM from lung cancer, RT was also associated with a survival difference after 1 year (57.3% vs. 32.8%, P < 0.001) and a median survival increase of 3.7 months. The 1-year overall survival rate was significantly better for SRS than for WBRT (46.4% vs. 38.8%, P < 0.001). Among Korean patients with BM, especially patients with primary lung cancer, RT improved the short-term survival rate, and SRS appears to be more useful than WBRT in this setting.