bluuebunny/crossref_metadata_2025 huggingface dataset:
All you need to know about sperm RNAs
Authors: Santiago Joana , Silva Joana V , Howl John , Santos Manuel A S , Fardilha Margarida
Published: September 2021

BACKGROUND

Spermatogenesis generates a small and highly specialised type of cell that is apparently incapable of transcription and translation. For many years, this dogma was supported by the assumption that (i) the compact sperm nucleus, resulting from the substitution of histones by protamine during spermatogenesis, renders the genome inaccessible to the transcriptional machinery; and (ii) the loss of most organelles, including endoplasmic reticulum and ribosomes, limits or prevents translational activity. Despite these observations, several types of coding and non-coding RNAs have been identified in human sperm. Their functional roles, particularly during fertilisation and embryonic development, are only now becoming apparent.

OBJECTIVE AND RATIONALE

This review aimed to summarise current knowledge of the origin, types and functional roles of sperm RNAs, and to evaluate the clinical benefits of employing these transcripts as biomarkers of male fertility and reproductive outcomes. The possible contribution of sperm RNAs to intergenerational or transgenerational phenotypic inheritance is also addressed.

SEARCH METHODS

A comprehensive literature search on PubMed was conducted using the search terms ‘sperm’ AND ‘RNA’. Searches focussed upon articles written in English and published prior to August 2020.

OUTCOMES

The development of more sensitive and accurate RNA technologies, including RNA sequencing, has enabled the identification and characterisation of numerous transcripts in human sperm. Though a majority of these RNAs likely arise during spermatogenesis, other data support an epididymal origin of RNA transmitted to maturing sperm by extracellular vesicles. A minority may also be synthesised by de novo transcription in mature sperm, since a small portion of the sperm genome remains packed by histones. This complex RNA population has important roles in paternal chromatin packaging, sperm maturation and capacitation, fertilisation, early embryogenesis and developmental maintenance. In recent years, additional lines of evidence from animal models support a role for sperm RNAs in intergenerational or transgenerational inheritance, modulating both the genotype and phenotype of progeny. Importantly, several reports indicate that the sperm RNA content of fertile and infertile men differs considerably and is strongly modulated by the environment, lifestyle and pathological states.

WIDER IMPLICATIONS

Transcriptional profiling has considerable potential for the discovery of fertility biomarkers. Understanding the role of sperm transcripts and comparing the sperm RNA fingerprint of fertile and infertile men could help to elucidate the regulatory pathways contributing to male factor infertility. Such data might also provide a molecular explanation for several causes of idiopathic male fertility. Ultimately, transcriptional profiling may be employed to optimise ART procedures and overcome some of the underlying causes of male infertility, ensuring the birth of healthy children.
Identifying impacts of air pollution on subacute asthma symptoms using digital medication sensors
Authors: Su Jason G , Barrett Meredith A , Combs Veronica , Henderson Kelly , Van Sickle David , Hogg Chris , Simrall Grace , Moyer Sarah S , Tarini Paul , Wojcik Oktawia , Sublett James , Smith Ted , Renda Andrew M , Balmes John , Gondalia Rahul , Kaye Leanne , Jerrett Michael
Published: September 2021

Background

Objective tracking of asthma medication use and exposure in real-time and space has not been feasible previously. Exposure assessments have typically been tied to residential locations, which ignore exposure within patterns of daily activities.

Methods

We investigated the associations of exposure to multiple air pollutants, derived from nearest air quality monitors, with space-time asthma rescue inhaler use captured by digital sensors, in Jefferson County, Kentucky. A generalized linear mixed model, capable of accounting for repeated measures, over-dispersion and excessive zeros, was used in our analysis. A secondary analysis was done through the random forest machine learning technique.

Results

The 1039 participants enrolled were 63.4% female, 77.3% adult (>18) and 46.8% White. Digital sensors monitored the time and location of over 286 980 asthma rescue medication uses and associated air pollution exposures over 193 697 patient-days, creating a rich spatiotemporal dataset of over 10 905 240 data elements. In the generalized linear mixed model, an interquartile range (IQR) increase in pollutant exposure was associated with a mean rescue medication use increase per person per day of 0.201 [95% confidence interval (CI): 0.189-0.214], 0.153 (95% CI: 0.136-0.171), 0.131 (95% CI: 0.115-0.147) and 0.113 (95% CI: 0.097-0.129), for sulphur dioxide (SO2), nitrogen dioxide (NO2), fine particulate matter (PM2.5) and ozone (O3), respectively. Similar effect sizes were identified with the random forest model. Time-lagged exposure effects of 0–3 days were observed.

Conclusions

Daily exposure to multiple pollutants was associated with increases in daily asthma rescue medication use for same day and lagged exposures up to 3 days. Associations were consistent when evaluated with the random forest modelling approach.
Diaspora organizations, political settlements, and the migration-development nexus: the case of the Indonesian Diaspora Network
Authors: Rosser Andrew
Published: September 2021

This article examines the Indonesian Diaspora Network (IDN), an organization that seeks to ‘facilitate’ and ‘empower’ Indonesia’s diaspora and enhance its contribution to the country’s development. IDN portrays itself as an expression of the collective will of a unified and coherent Indonesian diaspora that is working to promote development-for-all, while critics suggest it is the instrument of elite and professional elements within the diaspora pursuing narrower interests and agendas. By contrast, this article suggests that IDN is a political settlement between these and other elements within the diaspora, each of which has distinct interests and agendas with regard to Indonesia’s development. Its impact on Indonesia’s development is consequently much less clear-cut than existing analyses suggest while also being contingent on processes of political and social struggle. In theoretical terms, the article encourages an understanding of diaspora organizations in terms of political settlements analysis.
Absence of drug–drug interactions between γ-hydroxybutyric acid (GHB) and cobicistat
Authors: Moltó José , Bailón Lucía , Pérez-Mañá Clara , Papaseit Ester , Miranda Cristina , Martín Soraya , Mothe Beatriz , Farré Magí
Published: September 2021

Objectives

Potential interactions between CYP3A4 inhibitors and γ-hydroxybutyric acid (GHB) have been suggested as a possible explanation for cases of GHB overdose in recent years among people living with HIV engaged in chemsex. Our objective was to assess the effect of cobicistat on the pharmacokinetics of GHB.

Methods

Fifteen healthy adults were enrolled in this randomized, double-blind, placebo-controlled, two-arm, crossover clinical trial. Participants underwent two 5 day treatment periods with at least a 1 week washout period between them. In each treatment period, participants received cobicistat (150 mg q24h orally) or matched placebo. On day 5 of each treatment period, participants were given a single oral dose of GHB (25 mg/kg). Plasma concentrations of GHB, subjective effects, blood pressure, heart rate and oxygen saturation were monitored for 5 h after dosing. GHB pharmacokinetic and pharmacodynamic parameters were calculated for each participant during each study period by non-compartmental analysis and were compared using linear mixed-effects models. The study was registered at https://www.clinicaltrialsregister.eu (Eudra-CT number 2019-002122-71) and at https://clinicaltrials.gov (NCT04322214).

Results

Ten participants completed the two study periods. No drug-related adverse events that necessitated subject withdrawal or medical intervention occurred during the study. Compared with placebo, none of the primary pharmacokinetic parameters of GHB was substantially changed by the administration of GHB with cobicistat. Similarly, no differences regarding subjective or physiological effects were observed when GHB was administered alone or with cobicistat.

Conclusions

Neither pharmacokinetic nor pharmacodynamic drug–drug interactions between cobicistat and GHB were identified in this study.
Plasmodium falciparum metacaspase-2 capture its natural substrate in a non-canonical way
Authors: Vandana   , Pandey Rajan , Srinivasan E , Kalia Inderjeet , Singh Agam P , Saxena Ajay , Rajaekaran R , Gupta Dinesh , Pandey Kailash C
Published: September 2021

Programmed cell death (PCD) is a multi-step process initiated by a set of proteases, which interacts and cleaves diverse proteins, thus modulating their biochemical and cellular functions. In metazoans, PCD is mediated by proteolytic enzymes called caspases, which triggered cell death by proteolysis of human Tudor staphylococcus nuclease (TSN). Non-metazoans lack a close homologue of caspases but possess an ancestral family of cysteine proteases termed ‘metacaspases’. Studies supported that metacaspases are involved in PCD, but their natural substrates remain unknown. In this study, we performed the Plasmodium falciparum TSN (PfTSN) cleavage assay using wild and selected mutants of P. falciparum metacaspases-2 (PfMCA-2) in vitro and in vivo. Interestingly, PfMCA-2, cleaved a phylogenetically conserved protein, PfTSN at multiple sites. Deletion or substitution mutation in key interacting residues at the active site, Cys157 and His205 of PfMCA-2, impaired its enzymatic activity with the artificial substrate, z-GRR-AMC. However, the mutant Tyr224A did not affect the activity with z-GRR-AMC but abolished the cleavage of PfTSN. These results indicated that the catalytic dyad, Cys157 and His205 of PfMCA-2 was essential for its enzymatic activity with an artificial substrate, whereas Tyr224 and Cys157 residues were responsible for its interaction with the natural substrate and subsequent degradation of PfTSN. Our results suggested that MCA-2 interacts with TSN substrate in a non-canonical way using non-conserved or conformationally available residues for its binding and cleavage. In future, it would be interesting to explore how this interaction leads to the execution of PCD in the Plasmodium.
Variable Signatures of Selection Despite Conserved Recombination Landscapes Early in Speciation
Authors: Turbek Sheela P , Semenov Georgy A , Enbody Erik D , Campagna Leonardo , Taylor Scott A
Published: September 2021

Recently diverged taxa often exhibit heterogeneous landscapes of genomic differentiation, characterized by regions of elevated differentiation on an otherwise homogeneous background. While divergence peaks are generally interpreted as regions responsible for reproductive isolation, they can also arise due to background selection, selective sweeps unrelated to speciation, and variation in recombination and mutation rates. To investigate the association between patterns of recombination and landscapes of genomic differentiation during the early stages of speciation, we generated fine-scale recombination maps for six southern capuchino seedeaters (Sporophila) and two subspecies of White Wagtail (Motacilla alba), two recent avian radiations in which divergent selection on pigmentation genes has likely generated peaks of differentiation. We compared these recombination maps to those of Collared (Ficedula albicollis) and Pied Flycatchers (Ficedula hypoleuca), non-sister taxa characterized by moderate genomic divergence and a heterogenous landscape of genomic differentiation shaped in part by background selection. Although recombination landscapes were conserved within all three systems, we documented a weaker negative correlation between recombination rate and genomic differentiation in the recent radiations. All divergence peaks between capuchinos, wagtails, and flycatchers were located in regions with lower-than-average recombination rates, and most divergence peaks in capuchinos and flycatchers fell in regions of exceptionally reduced recombination. Thus, co-adapted allelic combinations in these regions may have been protected early in divergence, facilitating rapid diversification. Despite largely conserved recombination landscapes, divergence peaks are specific to each focal comparison in capuchinos, suggesting that regions of elevated differentiation have not been generated by variation in recombination rate alone.
The emerging role of jasmonate in the control of flowering time
Authors: Zhao Lirong , Li Xia , Chen Wanqin , Xu Zhiyu , Chen Mifen , Wang Houping , Yu Diqiu
Published: September 2021

Plants dynamically synchronize their flowering time with changes in the internal and external environments through a variety of signaling pathways to maximize fitness. In the last two decades, the major pathways associated with flowering, including the photoperiod, vernalization, age, autonomous, gibberellin, and ambient temperature pathways, have been extensively analyzed. In recent years, an increasing number of signals, such as sugar, thermosensory, stress, and certain hormones, have been shown to be involved in fine-tuning flowering time. Among these signals, the jasmonate signaling pathway has a function in the determination of flowering time that has not been systematically summarized. In this review, we present an overview of current knowledge of jasmonate control of flowering and discuss jasmonate crosstalk with other signals (such as gibberellin, defense, and touch) during floral transition.
Beyond the Douai-Reims Bible: The Changing Publishing Strategies of the Kellam Family in Seventeenth-Century Douai
Authors: Soetaert Alexander , Wyffels Heleen
Published: September 2021

The career of the Catholic Englishman Laurence Kellam is often reduced to his most impressive edition, the Old Testament of the Douay-Rheims Bible (1609–1610), an English Catholic Bible translation edited by the English College of Douai. Yet, there has been scarce attention for the remaining 190 editions, printed in English, as well as in Latin, French and Dutch, that bear a Kellam imprint. The discovery of another fifty editions that should be ascribed to the Kellam press demands a reappraisal of its activities and significance. By analysing both printed and archival sources, this article intends to fit the Bible edition of 1609–1610, and English Catholic printing on the continent more generally, into the wider perspective of three generations of publishing activities and family history, highlighting the increasingly tight connections between several generations of the Kellam family and the authors, institutions, and fellow-publishers of their host society.
What Were Thomas Hearne’s ‘Bad Copies’?
Authors: Day Geoffrey , Junqua Amélie
Published: September 2021

Bodleian, MS Rawl. Q. e. 18 is a twelve-page notebook in which Thomas Hearne recorded income and expenditure relating to his publication of Thomas Caius’ Vindiciae antiquitatis academiae Oxoniensis (1730), together with very brief details of the instructions given to the printer about five other texts. For five of the six titles Hearne specified that, in addition to the numbers required for subscribers, there should be an additional two ‘bad copies’. This note explores possible interpretations of this instruction.
Geospatial mapping of a 16th century transport corridor for Southeast Europe
Authors: Kabadayi M Erdem , Gerrits Piet , Boykov Grigor
Published: September 2021

We need maximum slope values for carts and pack animals to model the historical traffic of people and goods before the advent of steam and internal combustion engines. With this article, we first calculate maximum slope averages for carts and pack animals by using an extensive geo-referenced and vectorized historical transport network for late 19th-century Southeast Europe. Then by utilizing these slopes and making joint use of the least-cost path, accumulated cost surfaces, and network analyses, we model the movement of carts and pack animals for a large segment of an Ottoman military campaign in 1532, which followed the Via Militaris, between Istanbul and Sofia. Lastly, we compare our modelled routes for carts and pack animals for the 16th century with the existing road infrastructure of the late 19th century.
Ice mantles on dust grains: dramatic variation of thickness with grain size
Authors: Silsbee Kedron , Caselli Paola , Ivlev Alexei V
Published: September 2021

We compute the desorption rate of icy mantles on dust grains as a function of the size and composition of both the grain and the mantle. We combine existing models of cosmic ray (CR)-related desorption phenomena with a model of CR transport to accurately calculate the desorption rates in dark regions of molecular clouds. We show that different desorption mechanisms dominate for grains of different sizes and in different regions of the cloud. We then use these calculations to investigate a simple model of the growth of mantles, given a distribution of grain sizes. We find that modest variations of the desorption rate with grain size lead to a strong dependence of mantle thickness on grain size. Furthermore, we show that freeze-out is almost complete in the absence of an external ultraviolet (UV) field, even when photodesorption from CR-produced UV is taken into consideration. Even at gas densities of $10^4\, {\rm cm^{-3}}$, less than 30 per cent of the CO remain in the gas phase after 3 × 105 yr for standard values of the CR ionization rate.
Rotation curves and scaling relations of extremely massive spiral galaxies
Authors: Di Teodoro Enrico M , Posti Lorenzo , Ogle Patrick M , Fall S Michael , Jarrett Thomas
Published: September 2021

We study the kinematics and scaling relations of a sample of 43 giant spiral galaxies that have stellar masses exceeding $10^{11} \, {\rm M}_\odot$ and optical discs up to 80 kpc in radius. We use a hybrid 3D–1D approach to fit 3D kinematic models to long-slit observations of the H α-$\rm{[N\, \small {II}]}$ emission lines and we obtain robust rotation curves of these massive systems. We find that all galaxies in our sample seem to reach a flat part of the rotation curve within the outermost optical radius. We use the derived kinematics to study the high-mass end of the two most important scaling relations for spiral galaxies: the stellar/baryonic mass Tully–Fisher relation and the Fall (mass-angular momentum) relation. All galaxies in our sample, with the possible exception of the two fastest rotators, lie comfortably on both these scaling relations determined at lower masses, without any evident break or bend at the high-mass regime. When we combine our high-mass sample with low-mass data from the Spitzer Photometry & Accurate Rotation Curves catalogue, we find a slope of α = 4.25 ± 0.19 for the stellar Tully–Fisher relation and a slope of γ = 0.64 ± 0.11 for the Fall relation. Our results indicate that most, if not all, of these rare, giant spiral galaxies are scaled up versions of less massive discs and that spiral galaxies are a self-similar population of objects up to the very high-mass end.
Fast galaxy bars continue to challenge standard cosmology
Authors: Roshan Mahmood , Ghafourian Neda , Kashfi Tahere , Banik Indranil , Haslbauer Moritz , Cuomo Virginia , Famaey Benoit , Kroupa Pavel
Published: September 2021

Many observed disc galaxies harbour a central bar. In the standard cosmological paradigm, galactic bars should be slowed down by dynamical friction from the dark matter halo. This friction depends on the galaxy’s physical properties in a complex way, making it impossible to formulate analytically. Fortunately, cosmological hydrodynamical simulations provide an excellent statistical population of galaxies, letting us quantify how simulated galactic bars evolve within dark matter haloes. We measure bar strengths, lengths, and pattern speeds in barred galaxies in state-of-the-art cosmological hydrodynamical simulations of the IllustrisTNG and EAGLE projects, using techniques similar to those used observationally. We then compare our results with the largest available observational sample at redshift z = 0. We show that the tension between these simulations and observations in the ratio of corotation radius to bar length is 12.62σ (TNG50), 13.56σ (TNG100), 2.94σ (EAGLE50), and 9.69σ (EAGLE100), revealing for the first time that the significant tension reported previously persists in the recently released TNG50. The lower statistical tension in EAGLE50 is actually caused by it only having five galaxies suitable for our analysis, but all four simulations give similar statistics for the bar pattern speed distribution. In addition, the fraction of disc galaxies with bars is similar between TNG50 and TNG100, though somewhat above EAGLE100. The simulated bar fraction and its trend with stellar mass both differ greatly from observations. These dramatic disagreements cast serious doubt on whether galaxies actually have massive cold dark matter haloes, with their associated dynamical friction acting on galactic bars.
Radiation pressure confinement – V. The predicted free–free absorption and emission in active galactic nuclei
Authors: Baskin Alexei , Laor Ari
Published: September 2021

The effect of radiation pressure compression (RPC) on ionized gas in active galactic nuclei (AGNs) likely sets the photoionized gas density structure. The photoionized gas free–free absorption and emission are therefore uniquely set by the incident ionizing flux. We use the photoionization code cloudy RPC model results to derive the expected relations between the free–free emission and absorption properties and the distance from the AGN centre, for a given AGN luminosity. The free–free absorption frequency of RPC gas is predicted to increase from ∼100 MHz on the kpc scale to ∼100 GHz on the sub-pc scale, consistent with observations of spatially resolved free–free absorption. The free–free emission at 5 GHz is predicted to yield a radio loudness (R) of ∼0.03, below the typical observed values of R ∼ 0.1–1 in radio-quiet AGNs. However, the flat free–free radio continuum may become dominant above 100 GHz. The suggested detection of optically thin free–free emission in NGC 1068, on the sub-pc torus scale, is excluded as the brightness temperature is too high for optically thin free–free emission. However, excess emission observed with Atacama Large Millimeter/submillimeter Array (ALMA) above 150 GHz in NGC 1068 is consistent with the predicted free–free emission from gas just outside the broad-line region, a region that overlaps the hot dust disc resolved with GRAVITY. Extended ∼100 pc-scale free–free emission is also likely present in NGC 1068. Future sub-mm observation of radio-quiet AGNs with ALMA may allow to image the free–free emission of warm photoionized gas in AGNs down to the 30 mas scale, including highly absorbed AGNs.
A flexible subhalo abundance matching model for galaxy clustering in redshift space
Authors: Contreras S , Angulo R E , Zennaro M
Published: September 2021

We develop an extension of subhalo abundance matching (SHAM) capable of accurately reproducing the real and redshift-space clustering of galaxies in a state-of-the-art hydrodynamical simulation. Our method uses a low-resolution gravity-only simulation and it includes orphan and tidal disruption prescriptions for satellite galaxies, and a flexible amount of galaxy assembly bias. Furthermore, it includes recipes for star formation rate (SFR) based on the dark matter accretion rate. We test the accuracy of our model against catalogues of stellar-mass- and SFR-selected galaxies in the TNG300 hydrodynamic simulation. By fitting a small number of free parameters, our extended SHAM reproduces the projected correlation function and redshift-space multipoles for number densities $10^{-3} - 10^{-2}\, h^{3}{\rm Mpc}^{-3}$, at z = 1 and z = 0, and for scales r ∈ [0.3 − 20]h−1Mpc. Simultaneously, the SHAM results also retrieve the correct halo occupation distribution, the level of galaxy assembly bias, and higher order statistics present in the TNG300 galaxy catalogues. As an application, we show that our model simultaneously fits the projected correlation function of the SDSS in three disjoint stellar mass bins, with an accuracy similar to that of TNG300 galaxies. This SHAM extension can be used to get accurate clustering prediction even when using low and moderate-resolution simulations.
Conservation of radial actions in time-dependent spherical potentials
Authors: Burger Jan D , Peñarrubia Jorge , Zavala Jesús
Published: September 2021

In slowly evolving spherical potentials, Φ(r, t), radial actions are typically assumed to remain constant. Here, we construct dynamical invariants that allow us to derive the evolution of radial actions in spherical central potentials with an arbitrary time dependence. We show that to linear order, radial actions oscillate around a constant value with an amplitude $\propto \dot{\Phi }/\Phi \, P(E,L)$. Using this result, we develop a diffusion theory that describes the evolution of the radial action distributions of ensembles of tracer particles orbiting in generic time-dependent spherical potentials. Tests against restricted N-body simulations in a varying Kepler potential indicate that our linear theory is accurate in regions of phase-space in which the diffusion coefficient $\tilde {D}(J_r) \lt 0.01\, J_r^2$. For illustration, we apply our theory to two astrophysical processes. We show that the median mass accretion rate of a Milky Way (MW) dark matter (DM) halo leads to slow global time-variation of the gravitational potential, in which the evolution of radial actions is linear (i.e. either adiabatic or diffusive) for ∼84 per cent of the DM halo at redshift z = 0. This fraction grows considerably with look-back time, suggesting that diffusion may be relevant to the modelling of several Gyr old tidal streams in action-angle space. As a second application, we show that dynamical tracers in a dwarf-size self-interacting DM halo (with $\sigma /m_\chi = 1\, {\rm cm^2g^{-1}}$) have invariant radial actions during the formation of a cored density profile.
Extracting the astrophysics of reionization from the Lyα forest power spectrum: a first forecast
Authors: Montero-Camacho Paulo , Mao Yi
Published: September 2021

The impact of cosmic reionization on the Lyα forest power spectrum has recently been shown to be significant even at low redshifts (z ∼ 2). This memory of reionization survives cosmological time-scales because high-entropy mean-density gas is heated to ∼3 × 104 K by reionization, which is inhomogeneous, and subsequent shocks from denser regions. In the near future, the first measurements of the Lyα forest 3D power spectrum will be very likely achieved by upcoming observational efforts such as the Dark Energy Spectroscopic Instrument (DESI). In addition to abundant cosmological information, these observations have the potential to extract the astrophysics of reionization from the Lyα forest. We forecast, for the first time, the accuracy with which the measurements of Lyα forest 3D power spectrum can place constraints on the reionization parameters with DESI. Specifically, we demonstrate that the constraints on the ionization efficiency, ζ, and the threshold mass for haloes that host ionizing sources, mturn, will have the 1σ error at the level of ζ = 25.0 ± 11.6 and $\log _{10} (m_{\rm turn}/{\rm M}_\odot) = 8.7^{+0.36}_{-0.70}$, respectively. The Lyα forest 3D power spectrum will thus provide an independent probe of reionization, probably even earlier in detection with DESI, with a sensitivity only slightly worse than the upcoming 21-cm power spectrum measurement with the Hydrogen Epoch of Reionization Array (HERA), i.e. σDESI/σHERA ≈ 1.5 for ζ and σDESI/σHERA ≈ 2.0 for log10(mturn/M⊙). Nevertheless, the Lyα forest constraint will be improved about three times tighter than the current constraint from reionization observations with high-z galaxy priors, i.e. σDESI/σcurrent ≈ 1/3 for ζ.
Comparative Genomics Sheds Light on the Convergent Evolution of Miniaturized Wasps
Authors: Xu Hongxing , Ye Xinhai , Yang Yajun , Yang Yi , Sun Yu H , Mei Yang , Xiong Shijiao , He Kang , Xu Le , Fang Qi , Li Fei , Ye Gongyin , Lu Zhongxian
Published: September 2021

Miniaturization has occurred in many animal lineages, including insects and vertebrates, as a widespread trend during animal evolution. Among Hymenoptera, miniaturization has taken place in some parasitoid wasp lineages independently, and may have contributed to the diversity of species. However, the genomic basis of miniaturization is little understood. Diverged approximately 200 Ma, Telenomus wasps (Platygastroidea) and Trichogramma wasps (Chalcidoidea) have both evolved to a highly reduced body size independently, representing a paradigmatic example of convergent evolution. Here, we report a high-quality chromosomal genome of Telenomus remus, a promising candidate for controlling Spodoptera frugiperda, a notorious pest that has recently caused severe crop damage. The T. remus genome (129 Mb) is characterized by a low density of repetitive sequence and a reduction of intron length, resulting in the shrinkage of genome size. We show that hundreds of genes evolved faster in two miniaturized parasitoids Trichogramma pretiosum and T. remus. Among them, 38 genes exhibit extremely accelerated evolutionary rates in these miniaturized wasps, possessing diverse functions in eye and wing development as well as cell size control. These genes also highlight potential roles in body size regulation. In sum, our analyses uncover a set of genes with accelerated evolutionary rates in Tri. pretiosum and T. remus, which might be responsible for their convergent adaptations to miniaturization, and thus expand our understanding on the evolutionary basis of miniaturization. Additionally, the genome of T. remus represents the first genome resource of superfamily Platygastroidea, and will facilitate future studies of Hymenoptera evolution and pest control.
High resolution copy number inference in cancer using short-molecule nanopore sequencing
Authors: Baslan Timour , Kovaka Sam , Sedlazeck Fritz J , Zhang Yanming , Wappel Robert , Tian Sha , Lowe Scott W , Goodwin Sara , Schatz Michael C
Published: September 2021

Genome copy number is an important source of genetic variation in health and disease. In cancer, Copy Number Alterations (CNAs) can be inferred from short-read sequencing data, enabling genomics-based precision oncology. Emerging Nanopore sequencing technologies offer the potential for broader clinical utility, for example in smaller hospitals, due to lower instrument cost, higher portability, and ease of use. Nonetheless, Nanopore sequencing devices are limited in the number of retrievable sequencing reads/molecules compared to short-read sequencing platforms, limiting CNA inference accuracy. To address this limitation, we targeted the sequencing of short-length DNA molecules loaded at optimized concentration in an effort to increase sequence read/molecule yield from a single nanopore run. We show that short-molecule nanopore sequencing reproducibly returns high read counts and allows high quality CNA inference. We demonstrate the clinical relevance of this approach by accurately inferring CNAs in acute myeloid leukemia samples. The data shows that, compared to traditional approaches such as chromosome analysis/cytogenetics, short molecule nanopore sequencing returns more sensitive, accurate copy number information in a cost effective and expeditious manner, including for multiplex samples. Our results provide a framework for short-molecule nanopore sequencing with applications in research and medicine, which includes but is not limited to, CNAs.
CSCD2: an integrated interactional database of cancer-specific circular RNAs
Authors: Feng Jing , Chen Wenbo , Dong Xin , Wang Jun , Mei Xiangfei , Deng Jin , Yang Siqi , Zhuo Chenjian , Huang Xiaoyu , Shao Lin , Zhang Rongyu , Guo Jing , Ma Ronghui , Liu Juan , Li Feng , Wu Ying , Han Leng , He Chunjiang
Published: September 2021

The significant function of circRNAs in cancer was recognized in recent work, so a well-organized resource is required for characterizing the interactions between circRNAs and other functional molecules (such as microRNA and RNA-binding protein) in cancer. We previously developed cancer-specific circRNA database (CSCD), a comprehensive database for cancer-specific circRNAs, which is widely used in circRNA research. Here, we updated CSCD to CSCD2 (http://geneyun.net/CSCD2 or http://gb.whu.edu.cn/CSCD2), which includes significantly more cancer-specific circRNAs identified from a large number of human cancer and normal tissues/cell lines. CSCD2 contains >1000 samples (825 tissues and 288 cell lines) and identifies a large number of circRNAs: 1 013 461 cancer-specific circRNAs, 1 533 704 circRNAs from only normal samples and 354 422 circRNAs from both cancer and normal samples. In addition, CSCD2 predicts potential miRNA–circRNA and RBP–circRNA interactions using binding motifs from >200 RBPs and 2000 microRNAs. Furthermore, the potential full-length and open reading frame sequence of these circRNAs were also predicted. Collectively, CSCD2 provides a significantly enhanced resource for exploring the function and regulation of circRNAs in cancer.
ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD
Authors: Park Jumin , Lee Jongbo , Kim Ji-hyung , Lee Jongbin , Park Heeju , Lim Chunghun
Published: September 2021

C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD.
CPT1A and fatty acid β-oxidation are essential for tumor cell growth and survival in hormone receptor-positive breast cancer
Authors: Jariwala Nidhi , Mehta Gaurav A , Bhatt Vrushank , Hussein Shaimaa , Parker Kimberly A , Yunus Neha , Parker Joel S , Guo Jessie Yanxiang , Gatza Michael L
Published: September 2021

Chromosome 11q13-14 amplification is a defining feature of high-risk hormone receptor-positive (HR+) breast cancer; however, the mechanism(s) by which this amplicon contributes to breast tumorigenesis remains unclear. In the current study, proteogenomic analyses of >3000 breast tumors from the TCGA, METABRIC and CPTAC studies demonstrated that carnitine palmitoyltransferase 1A (CPT1A), which is localized to this amplicon, is overexpressed at the mRNA and protein level in aggressive luminal tumors, strongly associated with indicators of tumor proliferation and a predictor of poor prognosis. In vitro genetic studies demonstrated that CPT1A is required for and can promote luminal breast cancer proliferation, survival, as well as colony and mammosphere formation. Since CPT1A is the rate-limiting enzyme during fatty acid oxidation (FAO), our data indicate that FAO may be essential for these tumors. Pharmacologic inhibition of FAO prevented in vitro and in vivo tumor growth and cell proliferation as well as promoted apoptosis in luminal breast cancer cells and orthotopic xenograft tumor models. Collectively, our data establish an oncogenic role for CPT1A and FAO in HR+ luminal tumors and provide preclinical evidence and rationale supporting further investigation of FAO as a potential therapeutic opportunity for the treatment of HR+ breast cancer.
SCISSOR™: a single-cell inferred site-specific omics resource for tumor microenvironment association study
Authors: Cui Xiang , Qin Fei , Yu Xuanxuan , Xiao Feifei , Cai Guoshuai
Published: September 2021

Tumor tissues are heterogeneous with different cell types in tumor microenvironment, which play an important role in tumorigenesis and tumor progression. Several computational algorithms and tools have been developed to infer the cell composition from bulk transcriptome profiles. However, they ignore the tissue specificity and thus a new resource for tissue-specific cell transcriptomic reference is needed for inferring cell composition in tumor microenvironment and exploring their association with clinical outcomes and tumor omics. In this study, we developed SCISSOR™ (https://thecailab.com/scissor/), an online open resource to fulfill that demand by integrating five orthogonal omics data of >6031 large-scale bulk samples, patient clinical outcomes and 451 917 high-granularity tissue-specific single-cell transcriptomic profiles of 16 cancer types. SCISSOR™ provides five major analysis modules that enable flexible modeling with adjustable parameters and dynamic visualization approaches. SCISSOR™ is valuable as a new resource for promoting tumor heterogeneity and tumor–tumor microenvironment cell interaction research, by delineating cells in the tissue-specific tumor microenvironment and characterizing their associations with tumor omics and clinical outcomes.
KS01.4.A NK cells as key orchestrators in mediating the anti-tumour response to immune checkpoint blockade in melanoma brain metastases
Authors: Fife C M , Williams J , Brownlie R , Andreou T , Sunderland A , McKimmie C , Salmond R , Lorger M
Published: September 2021

BACKGROUND

Brain metastases (BrM) are an unmet clinical need with poor prognosis. 60% of melanoma patients develop BrM. BrM are strongly understudied due to frequent exclusion from clinical trials, and hence treatment options commonly lag behind. Antibodies targeting the immune-inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have demonstrated efficacy against melanoma BrM. Despite this, therapeutic responses are highly variable, and it is unknown why therapy fails in a high proportion of patients. Improved therapeutic strategies require a thorough understanding of potentially exploitable mechanisms of therapeutic efficacy. Our data previously implicated different immune cells, foremost CD8+ T cells, but also NK cells, in the intracranial efficacy and enhanced survival benefit of immune checkpoint blockade (ICB). Our aim here is to investigate the role of NK cells in mediating the response to ICB in melanoma BrM.

MATERIAL AND METHODS

To study the role of NK cells in the response to ICB in melanoma BrM, a tumour transplantation model of B16 melanoma with simultaneous extracranial (i.e., flank) and brain tumours in C57BL/6 mice was utilised. NK cells were depleted through administration of anti-asialo-GM1 NK cell-depleting antibodies. Confirmation of NK cell depletion and quantification of intratumoral immune cell populations was performed using flow cytometry. Intratumoral gene expression of key chemokines and immune mediator genes was assessed using RT-qPCR and mRNA-seq.

RESULTS

Highly variable response to ICB with respect to intratumoral accumulation of CD8+ T cells allowed separation of mice into responders and non-responders and revealed genes and pathways associated with response to ICB. NK cell depletion reversed the ICB-mediated increase in the accumulation of CD8+ T cells and significantly reduced the expression of genes associated with response in intracranial and extracranial tumours. The ICB-mediated significant increase in gene expression of various chemokines (i.e., Cxcl9/10) and immune mediators (i.e., Ifng, Prf1 and Gzmb) was significantly abrogated upon NK cell depletion.

CONCLUSION

NK cells play a critical role in the underlying mechanisms of ICB efficacy through their modulation of the tumour microenvironment and enhancement of CD8+ T cell accumulation in intracranial tumours. Targeting of NK cells may allow potentiation of ICB therapy in the brain, as well as at extracranial sites.
KS02.4.A Olaparib in Recurrent IDH-mutant High-Grade Glioma (OLAGLI)
Authors: Ducray F , Sanson M , Chinot O , Fontanilles M , Rivoirard R , Thomas-Maisonneuve L , Cartalat S , Tabouret E , Bonneville-Levard A , Darlix A , Ameli R , Meyronet D , Gueyffier F , Remontet L , Maucort-Boulch D , Dehais C , Honnorat J
Published: September 2021

BACKGROUND

There is a need to develop new treatments in IDH-mutant high-grade gliomas recurring after radiotherapy and chemotherapy. Based on preclinical studies showing that IDH-mutant tumors could be vulnerable to PARP inhibition we launched a phase II study to test the efficacy of olaparib (Lynparza) monotherapy in this population.

METHODS

Adults with recurrent high-grade IDH-mutant gliomas after radiotherapy and at least one line of alkylating chemotherapy (PCV or TMZ), KPS > 60, normal organ function were enrolled. The primary endpoint was 6 months PFS according to RANO criteria. Patients were treated with olaparib 300 mg twice daily. We used a single-stage Fleming design with p0 = 30%, p1 = 50%, a type I unilateral error rate of 5% and a power of 80%.

RESULTS

35 patients with recurrent IDH-mutant gliomas (IDH1R132H-mutant n = 32, other IDH mutation n = 3, 1p/19 codeleted n = 16, 1p/19q non-codeleted n = 14) were enrolled (malignantly transformed low-grade gliomas n = 21, anaplastic gliomas n = 8, glioblastomas n = 6). Median time since diagnosis was 7.4 years (1–22 years), median time since radiotherapy was 2.8 years (0.6–18 years), median number of previous chemotherapy lines was 2 (1–5). With a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression and 2 patients were still on treatment 16 to 18 months after treatment start. At 6 months, 11/35 patients were progression-free (31 %). According to RANO criteria, based on local investigator analysis, 2 patients (5%) had a partial response and 14 patients a stable disease (37%) with a median duration of response of 9 months (4–18+). Median PFS and OS were 2.3 and 15.9 months and were similar in 1p/19q codeleted and non-codeleted patients. A grade 3 olaparib-related adverse event was observed in 5 patients (14%, lymphopenia n = 3, fatigue n = 2, diarrhea n = 1) and a grade 2 in 15 patients (43%), most frequently consisting in fatigue (23%), gastrointestinal disorders (20%) and lymphopenia (20%). No patient definitively stopped olaparib due to side effects.

CONCLUSIONS

In this heavily pre-treated population of recurrent IDH-mutant gliomas, olaparib monotherapy was well tolerated and resulted in some activity supporting its evaluation in association with alkylating chemotherapy in recurrent IDH-mutant gliomas in future studies.
OS05.8.A A Phase 0/1 ‘Trigger’ Trial of Ribociclib Plus Everolimus in Recurrent High-Grade Glioma
Authors: Sanai N , Tien A , Jiang J , Chang Y , Pennington-Krygier C , DeSantis A , Fujita Y , Kim S , Li J , Mehta S
Published: September 2021

BACKGROUND

The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients.

MATERIAL AND METHODS

Eligible patients had recurrent HGG with (1) intact RB expression, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of presurgical ribociclib (400mg QD) plus everolimus (2.5mg QD) and then underwent tumor resection at 2, 8 or 24 hours following the last dose. Five subsequent dose-escalation cohorts each enrolled three additional patients, reaching a maximum dose-level of ribociclib (600mg QD) plus everolimus (60mg QW). Tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects, including RB and S6 phosphorylation, were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC50) and a PD ‘trigger’ (>30% decrease in both pRB and pS6) were set for each drug. Gd-nonenhancing tissue exhibiting both PK and PD effects in excess of these thresholds qualified patients for postoperative combination therapy.

RESULTS

21 patients with WHO Grade III (n=2) and WHO Grade IV (n=19) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM (i.e., > 5-fold biochemical IC50 for CDK4/6 inhibition), whereas the unbound everolimus tumor concentrations in all patients were below the lower limit of quantitation (i.e., < 0.2 nM). The median total concentrations of everolimus in tumors at dose-levels 0 to 5 were 2.9, 8.8, 10.3, 5.0, 15.7, and 13.7 nM, respectively. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients.

CONCLUSION

In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor, consistent with the observed tumor PD effects. Everolimus exhibits very limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.