bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors
Authors: Mifsud Karen R. , Kennedy Clare L. M. , Salatino Silvia , Sharma Eshita , Price Emily M. , Haque Samantha N. , Gialeli Andriana , Goss Hannah M. , Panchenko Polina E. , Broxholme John , Engledow Simon , Lockstone Helen , Cordero Llana Oscar , Reul Johannes M. H. M.
Published: August 2021

Glucocorticoid hormones (GCs) — acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) — are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.
MAIT cells regulate NK cell-mediated tumor immunity
Authors: Petley Emma V. , Koay Hui-Fern , Henderson Melissa A. , Sek Kevin , Todd Kirsten L. , Keam Simon P. , Lai Junyun , House Imran G. , Li Jasmine , Zethoven Magnus , Chen Amanda X. Y. , Oliver Amanda J. , Michie Jessica , Freeman Andrew J. , Giuffrida Lauren , Chan Jack D. , Pizzolla Angela , Mak Jeffrey Y. W. , McCulloch Timothy R. , Souza-Fonseca-Guimaraes Fernando , Kearney Conor J. , Millen Rosemary , Ramsay Robert G. , Huntington Nicholas D. , McCluskey James , Oliaro Jane , Fairlie David P. , Neeson Paul J. , Godfrey Dale I. , Beavis Paul A. , Darcy Phillip K.
Published: August 2021

The function of MR1-restricted mucosal-associated invariant T (MAIT) cells in tumor immunity is unclear. Here we show that MAIT cell-deficient mice have enhanced NK cell-dependent control of metastatic B16F10 tumor growth relative to control mice. Analyses of this interplay in human tumor samples reveal that high expression of a MAIT cell gene signature negatively impacts the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or activating MAIT cells in vivo, enhances anti-tumor immunity in B16F10 and E0771 mouse tumor models, including in the context of established metastasis. These effects are associated with enhanced NK cell responses and increased expression of both IFN-γ-dependent and inflammatory genes in NK cells. Importantly, activated human MAIT cells also promote the function of NK cells isolated from patient tumor samples. Our results thus describe an activation-dependent, MAIT cell-mediated regulation of NK cells, and suggest a potential therapeutic avenue for cancer treatment.
Genomic characterization of co-existing neoplasia and carcinoma lesions reveals distinct evolutionary paths of gallbladder cancer
Authors: Lin Jianzhen , Peng Xinxin , Dong Kun , Long Junyu , Guo Xuejiao , Li Hongyue , Bai Yi , Yang Xu , Wang Dongxu , Lu Xin , Mao Yilei , Sang Xinting , Ji Xuwo , Zhao Haitao , Liang Han
Published: August 2021

Gallbladder carcinoma is the most common cancer of the biliary tract with dismal survival largely due to delayed diagnosis. Biliary tract intraepithelial neoplasia (BilIN) is the common benign tumor that is suspected to be precancerous lesions. However, the genetic and evolutionary relationships between BilIN and carcinoma remain unclear. Here we perform whole-exome sequencing of coexisting low-grade BilIN (adenoma), high-grade BilIN, and carcinoma lesions, and normal tissues from the same patients. We identify aging as a major factor contributing to accumulated mutations and a critical role of CTNNB1 mutations in these tumors. We reveal two distinct carcinoma evolutionary paths: carcinoma can either diverge earlier and evolve more independently or form through the classic adenoma/dysplasia-carcinoma sequence model. Our analysis suggests that extensive loss-of-heterozygosity and mutation events in the initial stage tend to result in a cancerous niche, leading to the subsequent BilIN-independent path. These results reframes our understanding of tumor transformation and the evolutionary trajectory of carcinogenesis in the gallbladder, laying a foundation for the early diagnosis and effective treatment of gallbladder cancer.
Advancement in long-distance bird migration through individual plasticity in departure
Authors: Conklin Jesse R. , Lisovski Simeon , Battley Phil F.
Published: August 2021

Globally, bird migration is occurring earlier in the year, consistent with climate-related changes in breeding resources. Although often attributed to phenotypic plasticity, there is no clear demonstration of long-term population advancement in avian migration through individual plasticity. Using direct observations of bar-tailed godwits (Limosa lapponica) departing New Zealand on a 16,000-km journey to Alaska, we show that migration advanced by six days during 2008–2020, and that within-individual advancement was sufficient to explain this population-level change. However, in individuals tracked for the entire migration (50 total tracks of 36 individuals), earlier departure did not lead to earlier arrival or breeding in Alaska, due to prolonged stopovers in Asia. Moreover, changes in breeding-site phenology varied across Alaska, but were not reflected in within-population differences in advancement of migratory departure. We demonstrate that plastic responses can drive population-level changes in timing of long-distance migration, but also that behavioral and environmental constraints en route may yet limit adaptive responses to global change.
A squeezed quantum microcomb on a chip
Authors: Yang Zijiao , Jahanbozorgi Mandana , Jeong Dongin , Sun Shuman , Pfister Olivier , Lee Hansuek , Yi Xu
Published: August 2021

The optical microresonator-based frequency comb (microcomb) provides a versatile platform for nonlinear physics studies and has wide applications ranging from metrology to spectroscopy. The deterministic quantum regime is an unexplored aspect of microcombs, in which unconditional entanglements among hundreds of equidistant frequency modes can serve as critical ingredients to scalable universal quantum computing and quantum networking. Here, we demonstrate a deterministic quantum microcomb in a silica microresonator on a silicon chip. 40 continuous-variable quantum modes, in the form of 20 simultaneously two-mode squeezed comb pairs, are observed within 1 THz optical span at telecommunication wavelengths. A maximum raw squeezing of 1.6 dB is attained. A high-resolution spectroscopy measurement is developed to characterize the frequency equidistance of quantum microcombs. Our demonstration offers the possibility to leverage deterministically generated, frequency multiplexed quantum states and integrated photonics to open up new avenues in fields of spectroscopy, quantum metrology, and scalable, continuous-variable-based quantum information processing.
Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis
Authors: Andres-Ejarque Rosa , Ale Hira Bahadur , Grys Katarzyna , Tosi Isabella , Solanky Shane , Ainali Chrysanthi , Catak Zeynep , Sreeneebus Hemawtee , Saklatvala Jake , Dand Nick , de Rinaldis Emanuele , Chapman Anna , Nestle Frank O. , Barnes Michael R. , Warren Richard B. , Reynolds Nick J. , Griffiths Christopher E. M. , Barker Jonathan N. , Smith Catherine H. , Di Meglio Paola ,   the PSORT Consortium, Di Meglio Paola , Emsley Richard , Evans Andrea , Payne Katherine , Stocken Deborah
Published: August 2021

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.
Large-scale computational discovery and analysis of virus-derived microbial nanocompartments
Authors: Andreas Michael P. , Giessen Tobias W.
Published: August 2021

Encapsulins are a class of microbial protein compartments defined by the viral HK97-fold of their capsid protein, self-assembly into icosahedral shells, and dedicated cargo loading mechanism for sequestering specific enzymes. Encapsulins are often misannotated and traditional sequence-based searches yield many false positive hits in the form of phage capsids. Here, we develop an integrated search strategy to carry out a large-scale computational analysis of prokaryotic genomes with the goal of discovering an exhaustive and curated set of all HK97-fold encapsulin-like systems. We find over 6,000 encapsulin-like systems in 31 bacterial and four archaeal phyla, including two novel encapsulin families. We formulate hypotheses about their potential biological functions and biomedical relevance, which range from natural product biosynthesis and stress resistance to carbon metabolism and anaerobic hydrogen production. An evolutionary analysis of encapsulins and related HK97-type virus families shows that they share a common ancestor, and we conclude that encapsulins likely evolved from HK97-type bacteriophages.
Structural dynamics of single SARS-CoV-2 pseudoknot molecules reveal topologically distinct conformers
Authors: Neupane Krishna , Zhao Meng , Lyons Aaron , Munshi Sneha , Ileperuma Sandaru M. , Ritchie Dustin B. , Hoffer Noel Q. , Narayan Abhishek , Woodside Michael T.
Published: August 2021

The RNA pseudoknot that stimulates programmed ribosomal frameshifting in SARS-CoV-2 is a possible drug target. To understand how it responds to mechanical tension applied by ribosomes, thought to play a key role during frameshifting, we probe its structural dynamics using optical tweezers. We find that it forms multiple structures: two pseudoknotted conformers with different stability and barriers, and alternative stem-loop structures. The pseudoknotted conformers have distinct topologies, one threading the 5′ end through a 3-helix junction to create a knot-like fold, the other with unthreaded 5′ end, consistent with structures observed via cryo-EM and simulations. Refolding of the pseudoknotted conformers starts with stem 1, followed by stem 3 and lastly stem 2; Mg2+ ions are not required, but increase pseudoknot mechanical rigidity and favor formation of the knot-like conformer. These results resolve the SARS-CoV-2 frameshift signal folding mechanism and highlight its conformational heterogeneity, with important implications for structure-based drug-discovery efforts.
Sc-compReg enables the comparison of gene regulatory networks between conditions using single-cell data
Authors: Duren Zhana , Lu Wenhui Sophia , Arthur Joseph G. , Shah Preyas , Xin Jingxue , Meschi Francesca , Li Miranda Lin , Nemec Corey M. , Yin Yifeng , Wong Wing Hung
Published: August 2021

The comparison of gene regulatory networks between diseased versus healthy individuals or between two different treatments is an important scientific problem. Here, we propose sc-compReg as a method for the comparative analysis of gene expression regulatory networks between two conditions using single cell gene expression (scRNA-seq) and single cell chromatin accessibility data (scATAC-seq). Our software, sc-compReg, can be used as a stand-alone package that provides joint clustering and embedding of the cells from both scRNA-seq and scATAC-seq, and the construction of differential regulatory networks across two conditions. We apply the method to compare the gene regulatory networks of an individual with chronic lymphocytic leukemia (CLL) versus a healthy control. The analysis reveals a tumor-specific B cell subpopulation in the CLL patient and identifies TOX2 as a potential regulator of this subpopulation.
Efficient and large-area all vacuum-deposited perovskite light-emitting diodes via spatial confinement
Authors: Du Peipei , Li Jinghui , Wang Liang , Sun Liang , Wang Xi , Xu Xiang , Yang Longbo , Pang Jincong , Liang Wenxi , Luo Jiajun , Ma Ying , Tang Jiang
Published: August 2021

With rapid advances of perovskite light-emitting diodes (PeLEDs), the large-scale fabrication of patterned PeLEDs towards display panels is of increasing importance. However, most state-of-the-art PeLEDs are fabricated by solution-processed techniques, which are difficult to simultaneously achieve high-resolution pixels and large-scale production. To this end, we construct efficient CsPbBr3 PeLEDs employing a vacuum deposition technique, which has been demonstrated as the most successful route for commercial organic LED displays. By carefully controlling the strength of the spatial confinement in CsPbBr3 film, its radiative recombination is greatly enhanced while the nonradiative recombination is suppressed. As a result, the external quantum efficiency (EQE) of thermally evaporated PeLED reaches 8.0%, a record for vacuum processed PeLEDs. Benefitting from the excellent uniformity and scalability of the thermal evaporation, we demonstrate PeLED with a functional area up to 40.2 cm2 and a peak EQE of 7.1%, representing one of the most efficient large-area PeLEDs. We further achieve high-resolution patterned perovskite film with 100 μm pixels using fine metal masks, laying the foundation for potential display applications. We believe the strategy of confinement strength regulation in thermally evaporated perovskites provides an effective way to process high-efficiency and large-area PeLEDs towards commercial display panels.
Quasiadiabatic electron transport in room temperature nanoelectronic devices induced by hot-phonon bottleneck
Authors: Weng Qianchun , Yang Le , An Zhenghua , Chen Pingping , Tzalenchuk Alexander , Lu Wei , Komiyama Susumu
Published: August 2021

Since the invention of transistors, the flow of electrons has become controllable in solid-state electronics. The flow of energy, however, remains elusive, and energy is readily dissipated to lattice via electron-phonon interactions. Hence, minimizing the energy dissipation has long been sought by eliminating phonon-emission process. Here, we report a different scenario for facilitating energy transmission at room temperature that electrons exert diffusive but quasiadiabatic transport, free from substantial energy loss. Direct nanothermometric mapping of electrons and lattice in current-carrying GaAs/AlGaAs devices exhibit remarkable discrepancies, indicating unexpected thermal isolation between the two subsystems. This surprising effect arises from the overpopulated hot longitudinal-optical (LO) phonons generated through frequent emission by hot electrons, which induce equally frequent LO-phonon reabsorption (“hot-phonon bottleneck”) cancelling the net energy loss. Our work sheds light on energy manipulation in nanoelectronics and power-electronics and provides important hints to energy-harvesting in optoelectronics (such as hot-carrier solar-cells).
Atmospheric wavenumber-4 driven South Pacific marine heat waves and marine cool spells
Authors: Chiswell Stephen M.
Published: August 2021

Marine heat waves (MHW) and cool spells (MCS) can both positively and negatively impact marine ecosystems with potentially large societal and economic impacts. Here, I examine the global teleconnections of MHW/MCS in the southern hemisphere and Tasman Sea. When MHW/MCS are defined with respect to a linear warming trend, there is little evidence that MHW in the Tasman Sea are changing in either frequency or intensity but may be lasting longer. MCS may be becoming weaker and less frequent. I show that MHW/MCS in the Tasman Sea co-occur with corresponding events in the Atlantic, Indian, and eastern-Pacific Oceans, and these southern hemisphere events are likely driven by stalling of a global wavenumber-4 (W4) atmospheric wave, leading to anomalously weak north-easterly winds during MHW or strong south-westerly winds during MCS. Thus, the key to predicting MHW/MCS is in understanding what causes the atmospheric W4 wave to stall.
Demonstration of the effect of stirring on nucleation from experiments on the International Space Station using the ISS-EML facility
Authors: Gangopadhyay A. K. , Sellers M. E. , Bracker G. P. , Holland-Moritz D. , Van Hoesen D. C. , Koch S. , Galenko P. K. , Pauls A. K. , Hyers R. W. , Kelton K. F.
Published: August 2021

The effect of fluid flow on crystal nucleation in supercooled liquids is not well understood. The variable density and temperature gradients in the liquid make it difficult to study this under terrestrial gravity conditions. Nucleation experiments were therefore made in a microgravity environment using the Electromagnetic Levitation Facility on the International Space Station on a bulk glass-forming Zr57Cu15.4Ni12.6Al10Nb5 (Vit106), as well as Cu50Zr50 and the quasicrystal-forming Ti39.5Zr39.5Ni21 liquids. The maximum supercooling temperatures for each alloy were measured as a function of controlled stirring by applying various combinations of radio-frequency positioner and heater voltages to the water-cooled copper coils. The flow patterns were simulated from the known parameters for the coil and the levitated samples. The maximum nucleation temperatures increased systematically with increased fluid flow in the liquids for Vit106, but stayed nearly unchanged for the other two. These results are consistent with the predictions from the Coupled-Flux model for nucleation.
Swimming, flying, and diving behaviors from a unified 2D potential model
Authors: Jung Sunghwan
Published: August 2021

Animals swim in water, fly in air, or dive into water to find mates, chase prey, or escape from predators. Even though these locomotion modes are phenomenologically distinct, we can rationalize the underlying hydrodynamic forces using a unified fluid potential model. First, we review the previously known complex potential of a moving thin plate to describe circulation and pressure around the body. Then, the impact force in diving or thrust force in swimming and flying are evaluated from the potential flow model. For the impact force, we show that the slamming or impact force of various ellipsoid-shaped bodies of animals increases with animal weight, however, the impact pressure does not vary much. For fliers, birds and bats follow a linear correlation between thrust lift force and animal weight. For swimming animals, we present a scaling of swimming speed as a balance of thrust force with drag, which is verified with biological data. Under this framework, three distinct animal behaviors (i.e., swimming, flying, and diving) are similar in that a thin appendage displaces and pressurizes a fluid, but different in regards to the surroundings, being either fully immersed in a fluid or at a fluid interface.
Human beta defensin levels and vaginal microbiome composition in post-menopausal women diagnosed with lichen sclerosus
Authors: Brunner Alexandra , Medvecz Márta , Makra Nóra , Sárdy Miklós , Komka Kinga , Gugolya Máté , Szabó Dóra , Gajdács Márió , Ostorházi Eszter
Published: August 2021

Human beta defensins (hBDs) may play an important role in the progression of lichen sclerosus (LS), due to their ability to induce excessive stimulation of extracellular matrix synthesis and fibroblast activation. The genetic ability of the individual to produce defensins, the presence of microbes influencing defensin production, and the sensitivity of microbes to defensins together regulate the formation of an ever-changing balance between defensin levels and microbiome composition. We investigated the potential differences in postmenopausal vaginal microbiome composition and vaginal hBD levels in LS patients compared to non-LS controls. LS patients exhibited significantly lower levels of hBD1 (p = 0.0003), and significantly higher levels of hBD2 (p = 0.0359) and hBD3 (p = 0.0002), compared to the control group. The microbiome of the LS patients was dominated by possibly harmful bacteria including Lactobacillus iners, Streptococcus anginosus or Gardnerella vaginalis known to initiate direct or indirect damage by increasing defensin level production. Our observations highlight that correcting the composition of the microbiome may be applicable in supplementary LS therapy by targeting the restoration of the beneficial flora that does not increase hBD2-3 production.
Examining the interplay between face mask usage, asymptomatic transmission, and social distancing on the spread of COVID-19
Authors: Catching Adam , Capponi Sara , Yeh Ming Te , Bianco Simone , Andino Raul
Published: August 2021

COVID-19’s high virus transmission rates have caused a pandemic that is exacerbated by the high rates of asymptomatic and presymptomatic infections. These factors suggest that face masks and social distance could be paramount in containing the pandemic. We examined the efficacy of each measure and the combination of both measures using an agent-based model within a closed space that approximated real-life interactions. By explicitly considering different fractions of asymptomatic individuals, as well as a realistic hypothesis of face masks protection during inhaling and exhaling, our simulations demonstrate that a synergistic use of face masks and social distancing is the most effective intervention to curb the infection spread. To control the pandemic, our models suggest that high adherence to social distance is necessary to curb the spread of the disease, and that wearing face masks provides optimal protection even if only a small portion of the population comply with social distance. Finally, the face mask effectiveness in curbing the viral spread is not reduced if a large fraction of population is asymptomatic. Our findings have important implications for policies that dictate the reopening of social gatherings.
Tautomeric equilibrium, proton affinity and mass spectrometry fragmentation of flexible hydrogen-bonded precursors and rigid $$\hbox {N}\longrightarrow \hbox {BF}_2$$ fluorescent dyes
Authors: Kaczorowska Małgorzata A. , Kaczmarek-Kędziera Anna , Ośmiałowski Borys
Published: August 2021

The stability of two groups of conformationally locked molecules, similar in topology, but differing only by the type of the bridge rigidifying their structure, is studied. The series of the less-rigid 2-phenacylheterocyclic compounds and their stiff difluoroboranyl derivatives are investigated for the determination of the effect of$$\hbox {NCH}_3$$NCH3/S/O replacement in a five-membered heterocyclic ring and the presence of a strong electron-donating group on the tautomeric equilibrium, protonation affinity, and fragmentation pattern observed in the structural elucidation by means of mass spectrometry technique. The results of the$$\omega $$ωB97X-D/6-311++G(d,p) calculations, the topological analysis of electron density as well as the experimental MS measurements show the importance of the number of heteroatoms, their properties, and location in the molecule for the rational design of the systems of desired stable tautomers or the favorable protonation sites. The obtained data allow for the understanding of the fundamentals of the novel highly fluorescent difluoroborates fragmentation behavior, vital for their structural elucidation with the application of high-resolution tandem mass spectrometry methods.
Inhibition of CSF1R, a receptor involved in microglia viability, alters behavioral and molecular changes induced by cocaine
Authors: da Silva Maria Carolina Machado , Gomes Giovanni Freitas , de Barros Fernandes Heliana , da Silva Aristóbolo Mendes , Teixeira Antônio Lúcio , Moreira Fabrício A. , de Miranda Aline Silva , de Oliveira Antônio Carlos Pinheiro
Published: August 2021

Different data suggest that microglia may participate in the drug addiction process as these cells respond to neurochemical changes induced by the administration of these substances. In order to study the role of microglia in drug abuse, Swiss mice aged 8–9 weeks were treated with the CSF1R inhibitor PLX3397 (40 mg/kg, p.o.) and submitted to behavioral sensitization or conditioned place preference (CPP) induced by cocaine (15 mg/kg, i.p.). Thereafter, brains were used to evaluate the effects of CSF1R inhibition and cocaine administration on morphological, biochemical and molecular changes. CSF1R inhibition attenuated behavioral sensitization, reduced the number of Iba-1+ cells and increased ramification and lengths of the branches in the remaining microglia. Additionally, both cocaine and PLX3397 increased the cell body to total cell size ratio of Iba-1+ cells, as well as CD68+ and GFAP+ stained areas, suggesting an activated pattern of the glial cells. Besides, CSF1R inhibition increased CX3CL1 levels in the striatum, prefrontal cortex and hippocampus, as well as reduced CX3CR1 expression in the hippocampus. In this region, cocaine also reduced BDNF levels, an effect that was enhanced by CSF1R inhibition. In summary, our results suggest that microglia participate in the behavioral and molecular changes induced by cocaine. This study contributes to the understanding of the role of microglia in cocaine addiction.
Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
Authors: Sayyab Shumaila , Lundmark Anders , Larsson Malin , Ringnér Markus , Nystedt Sara , Marincevic-Zuniga Yanara , Tamm Katja Pokrovskaja , Abrahamsson Jonas , Fogelstrand Linda , Heyman Mats , Norén-Nyström Ulrika , Lönnerholm Gudmar , Harila-Saari Arja , Berglund Eva C. , Nordlund Jessica , Syvänen Ann-Christine
Published: August 2021

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.
Elimination of glutamatergic transmission from Hb9 interneurons does not impact treadmill locomotion
Authors: Koronfel Lina M. , Kanning Kevin C. , Alcos Angelita , Henderson Christopher E. , Brownstone Robert M.
Published: August 2021

The spinal cord contains neural circuits that can produce the rhythm and pattern of locomotor activity. It has previously been postulated that a population of glutamatergic neurons, termed Hb9 interneurons, contributes to locomotor rhythmogenesis. These neurons were identified by their expression of the homeobox gene, Hb9, which is also expressed in motor neurons. We developed a mouse line in which Cre recombinase activity is inducible in neurons expressing Hb9. We then used this line to eliminate vesicular glutamate transporter 2 from Hb9 interneurons, and found that there were no deficits in treadmill locomotion. We conclude that glutamatergic neurotransmission by Hb9 interneurons is not required for locomotor behaviour. The role of these neurons in neural circuits remains elusive.
Understanding nutrient imbalances in maize (Zea mays L.) using the diagnosis and recommendation integrated system (DRIS) approach in the Maize belt of Nigeria
Authors: Aliyu Kamaluddin T. , Huising Jeroen , Kamara Alpha Y. , Jibrin Jibrin M. , Mohammed Ibrahim B. , Nziguheba Generose , Adam Adam M. , Vanlauwe Bernard
Published: August 2021

Low nutrient use efficiency in maize as a result of imbalanced nutrition has been reported to drastically reduce yield. We implemented a nutrient omission experiment to assess the effect of nutrient application on maize yield and nutritional balance. Maize ear leaves were analyzed for nutrients, to identify nutrient balance status using the Diagnostic and Recommendation Integrated System (DRIS) approach. Results indicated that omission of N or P resulted in highly imbalanced DRIS indices respectively, and significantly lower grain yield. A strong inverse relationship between K ear leaf content with DRIS index suggests that K application negatively increases K imbalance in many situations. Imbalances of Mg, Ca and Cu were more associated with higher yielding treatments. A Which-Won-Where result show that nutrient imbalances in the diagnosis were systematically frequent when N was omitted. All the diagnosed nutrients were imbalanced even under the highest yielding NPKZn treatment; indicating further opportunity for yield increase with more balanced nutrition. Balanced nutrition of maize in the maize belt of Nigeria should target application of varying rates of N, P, K, Mg, S and Zn, depending on the soil conditions. But, because of complexities of nutrient interactions during uptake, it is hardly possible to realize a balanced nutrition. However, differentiating the application of antagonistic nutrients into foliar or soil-based methods is recommended for a more balanced maize nutrition.
Aflatoxins are natural scavengers of reactive oxygen species
Authors: Finotti E. , Parroni A. , Zaccaria M. , Domin M. , Momeni B. , Fanelli C. , Reverberi M.
Published: August 2021

The role of aflatoxins (AFs) in the biology of producing strains, Aspergillus sect. Flavi, is still a matter of debate. Over recent years, research has pointed to how environmental factors altering the redox balance in the fungal cell can switch on the synthesis of AF. Notably, it has been known for decades that oxidants promote AF synthesis. More recent evidence has indicated that AF synthesis is controlled at the transcriptional level: reactive species that accumulate in fungal cells in the stationary growth phase modulate the expression of aflR, the main regulator of AF synthesis—through the oxidative stress related transcription factor AP-1. Thus, AFs are largely synthesized and secreted when (i) the fungus has exploited most nutritional resources; (ii) the hyphal density is high; and (iii) reactive species are abundant in the environment. In this study, we show that AFs efficiently scavenge peroxides and extend the lifespan of E. coli grown under oxidative stress conditions. We hypothesize a novel role for AF as an antioxidant and suggest its biological purpose is to extend the lifespan of AFs-producing strains of Aspergillus sect. Flavi under highly oxidizing conditions such as when substrate resources are depleted, or within a host.
Suppression of top-down influence decreases neuronal excitability and contrast sensitivity in the V1 cortex of cat
Authors: Ding Jian , Hu Xiangmei , Xu Fei , Yu Hao , Ye Zheng , Zhang Shen , Pan Huijun , Pan Deng , Tu Yanni , Zhang Qiuyu , Sun Qingyan , Hua Tianmiao
Published: August 2021

How top-down influence affects neuronal activity and information encoding in the primary visual cortex (V1) remains elusive. This study examined changes of neuronal excitability and contrast sensitivity in cat V1 cortex after top-down influence of area 7 (A7) was modulated by transcranial direct current stimulation (tDCS). The neuronal excitability in V1 cortex was evaluated by visually evoked field potentials (VEPs), and contrast sensitivity (CS) was assessed by the inverse of threshold contrast of neurons in response to visual stimuli at different performance accuracy. We found that the amplitude of VEPs in V1 cortex lowered after top-down influence suppression with cathode-tDCS in A7, whereas VEPs in V1 did not change after sham-tDCS in A7 and nonvisual cortical area 5 (A5) or cathode-tDCS in A5 and lesioned A7. Moreover, the mean CS of V1 neurons decreased after cathode-tDCS but not sham-tDCS in A7, which could recover after tDCS effect vanished. Comparisons of neuronal contrast-response functions showed that cathode-tDCS increased the stimulus contrast required to generate the half-maximum response, with a weakly-correlated reduction in maximum response but not baseline response. Therefore, top-down influence of A7 enhanced neuronal excitability in V1 cortex and improved neuronal contrast sensitivity by both contrast gain and response gain.
Development of robust isothermal RNA amplification assay for lab-free testing of RNA viruses
Authors: Biyani Radhika , Sharma Kirti , Kojima Kenji , Biyani Madhu , Sharma Vishnu , Kumawat Tarun , Juma Kevin Maafu , Yanagihara Itaru , Fujiwara Shinsuke , Kodama Eiichi , Takamura Yuzuru , Takagi Masahiro , Yasukawa Kiyoshi , Biyani Manish
Published: August 2021

Simple tests of infectiousness that return results in minutes and directly from samples even with low viral loads could be a potential game-changer in the fight against COVID-19. Here, we describe an improved isothermal nucleic acid amplification assay, termed the RICCA (RNAIsothermalCo-assisted andCoupledAmplification) reaction, that consists of a simple one-pot format of ‘sample-in and result-out’ with a primary focus on the detection of low copy numbers of RNA virus directly from saliva without the need for laboratory processing. We demonstrate our assay by detecting 16S rRNA directly fromE. colicells with a sensitivity as low as 8 CFU/μL and RNA fragments from a synthetic template of SARS-CoV-2 with a sensitivity as low as 1740 copies/μL. We further demonstrate the applicability of our assay for real-time testing at the point of care by designing a closed format for paper-based lateral flow assay and detecting heat-inactivated SARS-COV-2 virus in human saliva at concentrations ranging from 28,000 to 2.8 copies/μL with a total assay time of 15–30 min.
Fully-automated root image analysis (faRIA)
Authors: Narisetti Narendra , Henke Michael , Seiler Christiane , Junker Astrid , Ostermann Jörn , Altmann Thomas , Gladilin Evgeny
Published: August 2021

High-throughput root phenotyping in the soil became an indispensable quantitative tool for the assessment of effects of climatic factors and molecular perturbation on plant root morphology, development and function. To efficiently analyse a large amount of structurally complex soil-root images advanced methods for automated image segmentation are required. Due to often unavoidable overlap between the intensity of fore- and background regions simple thresholding methods are, generally, not suitable for the segmentation of root regions. Higher-level cognitive models such as convolutional neural networks (CNN) provide capabilities for segmenting roots from heterogeneous and noisy background structures, however, they require a representative set of manually segmented (ground truth) images. Here, we present a GUI-based tool for fully automated quantitative analysis of root images using a pre-trained CNN model, which relies on an extension of the U-Net architecture. The developed CNN framework was designed to efficiently segment root structures of different size, shape and optical contrast using low budget hardware systems. The CNN model was trained on a set of 6465 masks derived from 182 manually segmented near-infrared (NIR) maize root images. Our experimental results show that the proposed approach achieves a Dice coefficient of 0.87 and outperforms existing tools (e.g., SegRoot) with Dice coefficient of 0.67 by application not only to NIR but also to other imaging modalities and plant species such as barley and arabidopsis soil-root images from LED-rhizotron and UV imaging systems, respectively. In summary, the developed software framework enables users to efficiently analyse soil-root images in an automated manner (i.e. without manual interaction with data and/or parameter tuning) providing quantitative plant scientists with a powerful analytical tool.
Mortality and risk factors associated with pulmonary embolism in coronavirus disease 2019 patients: a systematic review and meta-analysis
Authors: Gómez Carlos Andrés , Sun Cheuk-Kwan , Tsai I-Ting , Chang Yang-Pei , Lin Ming-Chung , Hung I-Yin , Chang Ying-Jen , Wang Li-Kai , Lin Yao-Tsung , Hung Kuo-Chuan
Published: August 2021

To determine, in patients with coronavirus disease 2019 (COVID-19) infection, the associations of pulmonary embolism (PE) with mortality and risk factors for PE as well as the therapeutic benefit of anticoagulant prophylaxis. Embase, PubMed, Cochrane controlled trials register, and Web of Science databases were searched from inception to October 10, 2020. We included all published trials on PE in patients diagnosed with COVID-19 with eligibility of the trials assessed following the PRISMA guidelines. Sixteen clinical trials with 5826 patients were eligible. There were significant associations of PE with the male gender [odd ratio (OR) = 1.59, 95% CI 1.28–1.97], mechanical ventilation (OR = 3.71, 95% CI 2.57–5.36), intensive care unit admission (OR = 2.99, 95% CI 2.11–4.23), circulating D-dimer [mean difference (MD) = 5.04 µg/mL, 95% CI 3.67–6.42) and CRP (MD = 1.97 mg/dL, 95% CI 0.58– 3.35) concentrations without significant correlation between PE and mortality (OR = 1.31, 95% CI 0.82–2.08) as well as other parameters or comorbidities. After omitting one trial with strict patient selection criteria for anticoagulant prophylaxis, significant prophylactic benefit was noted (OR = 0.31, 95% CI 0.1–0.91). Our findings identified the risk factors associated with PE in COVID-19 patients and supported the therapeutic benefit of anticoagulant prophylaxis against PE in this patient population.
Support vector machine and deep-learning object detection for localisation of hard exudates
Authors: Kurilová Veronika , Goga Jozef , Oravec Miloš , Pavlovičová Jarmila , Kajan Slavomír
Published: August 2021

Hard exudates are one of the main clinical findings in the retinal images of patients with diabetic retinopathy. Detecting them early significantly impacts the treatment of underlying diseases; therefore, there is a need for automated systems with high reliability. We propose a novel method for identifying and localising hard exudates in retinal images. To achieve fast image pre-scanning, a support vector machine (SVM) classifier was combined with a faster region-based convolutional neural network (faster R-CNN) object detector for the localisation of exudates. Rapid pre-scanning filtered out exudate-free samples using a feature vector extracted from the pre-trained ResNet-50 network. Subsequently, the remaining samples were processed using a faster R-CNN detector for detailed analysis. When evaluating all the exudates as individual objects, the SVM classifier reduced the false positive rate by 29.7% and marginally increased the false negative rate by 16.2%. When evaluating all the images, we recorded a 50% reduction in the false positive rate, without any decrease in the number of false negatives. The interim results suggested that pre-scanning the samples using the SVM prior to implementing the deep-network object detector could simultaneously improve and speed up the current hard exudates detection method, especially when there is paucity of training data.
Effect of saliva fluid properties on pathogen transmissibility
Authors: Reyes Jonathan , Fontes Douglas , Bazzi Alexander , Otero Michelle , Ahmed Kareem , Kinzel Michael
Published: August 2021

With an increasing body of evidence that SARS-CoV-2 is an airborne pathogen, droplet character formed during speech, coughs, and sneezes are important. Larger droplets tend to fall faster and are less prone to drive the airborne transmission pathway. Alternatively, small droplets (aerosols) can remain suspended for long time periods. The small size of SARS-CoV-2 enables it to be encapsulated in these aerosols, thereby increasing the pathogen’s ability to be transmitted via airborne paths. Droplet formation during human respiratory events relates to airspeed (speech, cough, sneeze), fluid properties of the saliva/mucus, and the fluid content itself. In this work, we study the fluidic drivers (fluid properties and content) and their influence on factors relating to transmissibility. We explore the relationship between saliva fluid properties and droplet airborne transmission paths. Interestingly, the natural human response appears to potentially work with these drivers to mitigate pathogen transmission. In this work, the saliva is varied using two approaches: (1) modifying the saliva with colloids that increase the viscosity/surface tension, and (2) stimulating the saliva content to increased/decreased levels. Through modern experimental and numerical flow diagnostic methods, the character, content, and exposure to droplets and aerosols are all evaluated. The results indicate that altering the saliva properties can significantly impact the droplet size distribution, the formation of aerosols, the trajectory of the bulk of the droplet plume, and the exposure (or transmissibility) to droplets. High-fidelity numerical methods used and verify that increased droplet size character enhances droplet fallout. In the context of natural saliva response, we find previous studies indicating natural human responses of increased saliva viscosity from stress and reduced saliva content from either stress or illness. These responses both favorably correspond to reduced transmissibility. Such a finding also relates to potential control methods, hence, we compared results to a surgical mask. In general, we find that saliva alteration can produce fewer and larger droplets with less content and aerosols. Such results indicate a novel approach to alter SARS-CoV-2’s transmission path and may act as a way to control the COVID-19 pandemic, as well as influenza and the common cold.
Genotypic identification of Panicum spp. in New South Wales, Australia using DNA barcoding
Authors: Chen Yuchi , Zhu Xiaocheng , Loukopoulos Panayiotis , Weston Leslie A. , Albrecht David E. , Quinn Jane C.
Published: August 2021

Australia has over 30 Panicum spp. (panic grass) including several non-native species that cause crop and pasture loss and hepatogenous photosensitisation in livestock. It is critical to correctly identify them at the species level to facilitate the development of appropriate management strategies for efficacious control of Panicum grasses in crops, fallows and pastures. Currently, identification of Panicum spp. relies on morphological examination of the reproductive structures, but this approach is only useful for flowering specimens and requires significant taxonomic expertise. To overcome this limitation, we used multi-locus DNA barcoding for the identification of ten selected Panicum spp. found in Australia. With the exception of P. buncei, other native Australian Panicum were genetically separated at the species level and distinguished from non-native species. One nuclear (ITS) and two chloroplast regions (matK and trnL intron-trnF) were identified with varying facility for DNA barcode separation of the Panicum species. Concatenation of sequences from ITS, matK and trnL intron-trnF regions provided clear separation of eight regionally collected species, with a maximum intraspecific distance of 0.22% and minimum interspecific distance of 0.33%. Two of three non-native Panicum species exhibited a smaller genome size compared to native species evaluated, and we speculate that this may be associated with biological advantages impacting invasion of non-native Panicum species in novel locations. We conclude that multi-locus DNA barcoding, in combination with traditional taxonomic identification, provides an accurate and cost-effective adjunctive tool for further distinguishing Panicum spp. at the species level.
Structural network topology and microstructural alterations of the anterior insula associate with cognitive and affective impairment in Parkinson’s disease
Authors: Jonkman L. E. , Fathy Y. Y. , Berendse H. W. , Schoonheim M. M. , van de Berg W. D. J.
Published: August 2021

The aim of the current study was to assess the structural centrality and microstructural integrity of the cortical hubs of the salience network, the anterior insular cortex (AIC) subregions and anterior cingulate cortex (ACC), and their relationship to cognitive and affective impairment in PD. MRI of 53 PD patients and 15 age-matched controls included 3D-T1 for anatomical registration, and diffusion tensor imaging for probabilistic tractography. Network topological measures of eigenvector and betweenness centrality were calculated for ventral (vAI) and dorsal (dAI) AIC. Microstructural tract integrity between vAI, dAI and the ACC was quantified with fractional anisotrophy (FA) and mean diffusivity (MD). Structural integrity and connectivity were related to cognitive and affective scores. The dAI had significantly higher eigenvector centrality in PD than controls (p < 0.01), associated with higher depression scores (left dAI only, rs = 0.28, p < 0.05). Tracts between dAI and ACC showed lower FA and higher MD in PD (p < 0.05), and associated with lower semantic fluency, working memory and executive functioning, and higher anxiety scores (range 0.002 < p < 0.05). This study provides evidence for clinically relevant structural damage to the cortical hubs of the salience network in PD, possibly due to extensive local neuropathology and loss of interconnecting AIC-ACC tracts.