bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Aurora Kinase B activity disrupts development and differentiation of salivary glands
Authors: Shaalan Abeer K. , Teshima Tathyane H. N. , Tucker Abigail S. , Proctor Gordon B.
Published: January 2021

Little is known about the key molecules that regulate cell division during organogenesis. Here we determine the role of the cell cycle promoter aurora kinase B (AURKB) during development, using embryonic salivary glands (E-SGs) as a model. AURKB is a serine/threonine kinase that regulates key events in mitosis, which makes it an attractive target for tailored anticancer therapy. Many reports have elaborated on the role of AURKB in neoplasia and cancer; however, no previous study has shown its role during organ development. Our previous experiments have highlighted the essential requirement for AURKB during adult exocrine regeneration. To investigate if AURKB is similarly required for progression during embryonic development, we pharmacologically inhibited AURKB in developing submandibular glands (SMGs) at embryonic day (E)13.5 and E16.5, using the highly potent and selective drug Barasertib. Inhibition of AURKB interfered with the expansion of the embryonic buds. Interestingly, this effect on SMG development was also seen when the mature explants (E16.5) were incubated for 24 h with another cell cycle inhibitor Aphidicolin. Barasertib prompted apoptosis, DNA damage and senescence, the markers of which (cleaved caspase 3, γH2AX, SA-βgal and p21, respectively), were predominantly seen in the developing buds. In addition to a reduction in cell cycling and proliferation of the epithelial cells in response to AURKB inhibition, Barasertib treatment led to an excessive generation of reactive oxygen species (ROS) that resulted in downregulation of the acinar differentiation marker Mist1. Importantly, inhibition of ROS was able to rescue this loss of identity, with Mist1 expression maintained despite loss of AURKB. Together, these data identify AURKB as a key molecule in supporting embryonic development and differentiation, while inhibiting senescence-inducing signals during organogenesis.
Pervasive distribution of polyester fibres in the Arctic Ocean is driven by Atlantic inputs
Authors: Ross Peter S. , Chastain Stephen , Vassilenko Ekaterina , Etemadifar Anahita , Zimmermann Sarah , Quesnel Sarah-Ann , Eert Jane , Solomon Eric , Patankar Shreyas , Posacka Anna M. , Williams Bill
Published: January 2021

Microplastics are increasingly recognized as ubiquitous global contaminants, but questions linger regarding their source, transport and fate. We document the widespread distribution of microplastics in near-surface seawater from 71 stations across the European and North American Arctic - including the North Pole. We also characterize samples to a depth of 1,015 m in the Beaufort Sea. Particle abundance correlated with longitude, with almost three times more particles in the eastern Arctic compared to the west. Polyester comprised 73% of total synthetic fibres, with an east-to-west shift in infra-red signatures pointing to a potential weathering of fibres away from source. Here we suggest that relatively fresh polyester fibres are delivered to the eastern Arctic Ocean, via Atlantic Ocean inputs and/or atmospheric transport from the South. This raises further questions about the global reach of textile fibres in domestic wastewater, with our findings pointing to their widespread distribution in this remote region of the world.
Insights into genome recoding from the mechanism of a classic +1-frameshifting tRNA
Authors: Gamper Howard , Li Haixing , Masuda Isao , Miklos Robkis D. , Christian Thomas , Conn Adam B. , Blaha Gregor , Petersson E. James , Gonzalez Ruben L. , Hou Ya-Ming
Published: January 2021

While genome recoding using quadruplet codons to incorporate non-proteinogenic amino acids is attractive for biotechnology and bioengineering purposes, the mechanism through which such codons are translated is poorly understood. Here we investigate translation of quadruplet codons by a +1-frameshifting tRNA, SufB2, that contains an extra nucleotide in its anticodon loop. Natural post-transcriptional modification of SufB2 in cells prevents it from frameshifting using a quadruplet-pairing mechanism such that it preferentially employs a triplet-slippage mechanism. We show that SufB2 uses triplet anticodon-codon pairing in the 0-frame to initially decode the quadruplet codon, but subsequently shifts to the +1-frame during tRNA-mRNA translocation. SufB2 frameshifting involves perturbation of an essential ribosome conformational change that facilitates tRNA-mRNA movements at a late stage of the translocation reaction. Our results provide a molecular mechanism for SufB2-induced +1 frameshifting and suggest that engineering of a specific ribosome conformational change can improve the efficiency of genome recoding.
Giant anomalous Hall effect from spin-chirality scattering in a chiral magnet
Authors: Fujishiro Yukako , Kanazawa Naoya , Kurihara Ryosuke , Ishizuka Hiroaki , Hori Tomohiro , Yasin Fehmi Sami , Yu Xiuzhen , Tsukazaki Atsushi , Ichikawa Masakazu , Kawasaki Masashi , Nagaosa Naoto , Tokunaga Masashi , Tokura Yoshinori
Published: January 2021

The electrical Hall effect can be significantly enhanced through the interplay of the conduction electrons with magnetism, which is known as the anomalous Hall effect (AHE). Whereas the mechanism related to band topology has been intensively studied towards energy efficient electronics, those related to electron scattering have received limited attention. Here we report the observation of giant AHE of electron-scattering origin in a chiral magnet MnGe thin film. The Hall conductivity and Hall angle, respectively, reach $$40,000$$
40
,
000
 Ω−1 cm−1 and $$18$$
18
% in the ferromagnetic region, exceeding the conventional limits of AHE of intrinsic and extrinsic origins, respectively. A possible origin of the large AHE is attributed to a new type of skew-scattering via thermally excited spin-clusters with scalar spin chirality, which is corroborated by the temperature–magnetic-field profile of the AHE being sensitive to the film-thickness or magneto-crystalline anisotropy. Our results may open up a new platform to explore giant AHE responses in various systems, including frustrated magnets and thin-film heterostructures.
Pure non-local machine-learned density functional theory for electron correlation
Authors: Margraf Johannes T. , Reuter Karsten
Published: January 2021

Density-functional theory (DFT) is a rigorous and (in principle) exact framework for the description of the ground state properties of atoms, molecules and solids based on their electron density. While computationally efficient density-functional approximations (DFAs) have become essential tools in computational chemistry, their (semi-)local treatment of electron correlation has a number of well-known pathologies, e.g. related to electron self-interaction. Here, we present a type of machine-learning (ML) based DFA (termed Kernel Density Functional Approximation, KDFA) that is pure, non-local and transferable, and can be efficiently trained with fully quantitative reference methods. The functionals retain the mean-field computational cost of common DFAs and are shown to be applicable to non-covalent, ionic and covalent interactions, as well as across different system sizes. We demonstrate their remarkable possibilities by computing the free energy surface for the protonated water dimer at hitherto unfeasible gold-standard coupled cluster quality on a single commodity workstation.
Differential contribution of transcriptomic regulatory layers in the definition of neuronal identity
Authors: Ha Kevin C. H. , Sterne-Weiler Timothy , Morris Quaid , Weatheritt Robert J. , Blencowe Benjamin J.
Published: January 2021

Previous transcriptomic profiling studies have typically focused on separately analyzing mRNA expression, alternative splicing and alternative polyadenylation differences between cell and tissue types. However, the relative contribution of these three transcriptomic regulatory layers to cell type specification is poorly understood. This question is particularly relevant to neurons, given their extensive heterogeneity associated with brain location, morphology and function. In the present study, we generated profiles for the three regulatory layers from developmentally and regionally distinct subpopulations of neurons from the mouse hippocampus and broader nervous system. Multi-omics factor analyses revealed differing contributions of each transcriptomic layer in the discrimination of neurons based on their stage of development, region, and function. Importantly, profiles of differential alternative splicing and polyadenylation better discriminated specific neuronal subtype populations than gene expression patterns. These results provide evidence for differential relative contributions of coordinated gene regulatory layers in the specification of neuronal subtypes.
Structural basis for the multi-activity factor Rad5 in replication stress tolerance
Authors: Shen Miaomiao , Dhingra Nalini , Wang Quan , Cheng Chen , Zhu Songbiao , Tian Xiaolin , Yu Jun , Gong Xiaoxin , Li Xuzhichao , Zhang Hongwei , Xu Xin , Zhai Liting , Xie Min , Gao Ying , Deng Haiteng , He Yongning , Niu Hengyao , Zhao Xiaolan , Xiang Song
Published: January 2021

The yeast protein Rad5 and its orthologs in other eukaryotes promote replication stress tolerance and cell survival using their multiple activities, including ubiquitin ligase, replication fork remodeling and DNA lesion targeting activities. Here, we present the crystal structure of a nearly full-length Rad5 protein. The structure shows three distinct, but well-connected, domains required for Rad5’s activities. The spatial arrangement of these domains suggest that different domains can have autonomous activities but also undergo intrinsic coordination. Moreover, our structural, biochemical and cellular studies demonstrate that Rad5’s HIRAN domain mediates interactions with the DNA metabolism maestro factor PCNA and contributes to its poly-ubiquitination, binds to DNA and contributes to the Rad5-catalyzed replication fork regression, defining a new type of HIRAN domains with multiple activities. Our work provides a framework to understand how Rad5 integrates its various activities in replication stress tolerance.
Time-frequency super-resolution with superlets
Authors: Moca Vasile V. , Bârzan Harald , Nagy-Dăbâcan Adriana , Mureșan Raul C.
Published: January 2021

Due to the Heisenberg–Gabor uncertainty principle, finite oscillation transients are difficult to localize simultaneously in both time and frequency. Classical estimators, like the short-time Fourier transform or the continuous-wavelet transform optimize either temporal or frequency resolution, or find a suboptimal tradeoff. Here, we introduce a spectral estimator enabling time-frequency super-resolution, called superlet, that uses sets of wavelets with increasingly constrained bandwidth. These are combined geometrically in order to maintain the good temporal resolution of single wavelets and gain frequency resolution in upper bands. The normalization of wavelets in the set facilitates exploration of data with scale-free, fractal nature, containing oscillation packets that are self-similar across frequencies. Superlets perform well on synthetic data and brain signals recorded in humans and rodents, resolving high frequency bursts with excellent precision. Importantly, they can reveal fast transient oscillation events in single trials that may be hidden in the averaged time-frequency spectrum by other methods.
Functional cooperativity between the trigger factor chaperone and the ClpXP proteolytic complex
Authors: Rizzolo Kamran , Yu Angela Yeou Hsiung , Ologbenla Adedeji , Kim Sa Rang , Zhu Haojie , Ishimori Koichiro , Thibault Guillaume , Leung Elisa , Zhang Yi Wen , Teng Mona , Haniszewski Marta , Miah Noha , Phanse Sadhna , Minic Zoran , Lee Sukyeong , Caballero Julio Diaz , Babu Mohan , Tsai Francis T. F. , Saio Tomohide , Houry Walid A.
Published: January 2021

A functional association is uncovered between the ribosome-associated trigger factor (TF) chaperone and the ClpXP degradation complex. Bioinformatic analyses demonstrate conservation of the close proximity of tig, the gene coding for TF, and genes coding for ClpXP, suggesting a functional interaction. The effect of TF on ClpXP-dependent degradation varies based on the nature of substrate. While degradation of some substrates are slowed down or are unaffected by TF, surprisingly, TF increases the degradation rate of a third class of substrates. These include λ phage replication protein λO, master regulator of stationary phase RpoS, and SsrA-tagged proteins. Globally, TF acts to enhance the degradation of about 2% of newly synthesized proteins. TF is found to interact through multiple sites with ClpX in a highly dynamic fashion to promote protein degradation. This chaperone–protease cooperation constitutes a unique and likely ancestral aspect of cellular protein homeostasis in which TF acts as an adaptor for ClpXP.
Targeting adaptor protein SLP76 of RAGE as a therapeutic approach for lethal sepsis
Authors: Yan Zhengzheng , Luo Haihua , Xie Bingyao , Tian Tian , Li Shan , Chen Zhixia , Liu Jinghua , Zhao Xuwen , Zhang Liyong , Deng Yongqiang , Billiar Timothy R. , Jiang Yong
Published: January 2021

Accumulating evidence shows that RAGE has an important function in the pathogenesis of sepsis. However, the mechanisms by which RAGE transduces signals to downstream kinase cascades during septic shock are not clear. Here, we identify SLP76 as a binding partner for the cytosolic tail of RAGE both in vitro and in vivo and demonstrate that SLP76 binds RAGE through its sterile α motif (SAM) to mediate downstream signaling. Genetic deficiency of RAGE or SLP76 reduces AGE-induced phosphorylation of p38 MAPK, ERK1/2 and IKKα/β, as well as cytokine release. Delivery of the SAM domain into macrophages via the TAT cell-penetrating peptide blocks proinflammatory cytokine production. Furthermore, administration of TAT-SAM attenuates inflammatory cytokine release and tissue damage in mice subjected to cecal ligation and puncture (CLP) and protects these mice from the lethality of sepsis. These findings reveal an important function for SLP76 in RAGE-mediated pro-inflammatory signaling and shed light on the development of SLP76-targeted therapeutics for sepsis.
Metal-free atom transfer radical polymerization with ppm catalyst loading under sunlight
Authors: Ma Qiang , Song Jinshuai , Zhang Xun , Jiang Yu , Ji Li , Liao Saihu
Published: January 2021

Organocatalytic atom transfer radical polymerization (O-ATRP) is recently emerging as an appealing method for the synthesis of metal-free polymer materials with well-defined microstructures and architectures. However, the development of highly effective catalysts that can be employed at a practical low loading are still a challenging task. Herein, we introduce a catalyst design logic based on heteroatom-doping of polycyclic arenes, which leads to the discovery of oxygen-doped anthanthrene (ODA) as highly effective organic photoredox catalysts for O-ATRP. In comparison with known organocatalysts, ODAs feature strong visible-light absorption together with high molar extinction coefficient (ε455nm up to 23,950 M–1 cm–1), which allow for the establishment of a controlled polymerization under sunlight at low ppm levels of catalyst loading.
DsbA-L deficiency in T cells promotes diet-induced thermogenesis through suppressing IFN-γ production
Authors: Zhou Haiyan , Peng Xinyi , Hu Jie , Wang Liwen , Luo Hairong , Zhang Junyan , Zhang Yacheng , Li Guobao , Ji Yujiao , Zhang Jingjing , Bai Juli , Liu Meilian , Zhou Zhiguang , Liu Feng
Published: January 2021

Adipose tissue-resident T cells have been recognized as a critical regulator of thermogenesis and energy expenditure, yet the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding greatly suppresses the expression of disulfide-bond A oxidoreductase-like protein (DsbA-L), a mitochondria-localized chaperone protein, in adipose-resident T cells, which correlates with reduced T cell mitochondrial function. T cell-specific knockout of DsbA-L enhances diet-induced thermogenesis in brown adipose tissue (BAT) and protects mice from HFD-induced obesity, hepatosteatosis, and insulin resistance. Mechanistically, DsbA-L deficiency in T cells reduces IFN-γ production and activates protein kinase A by reducing phosphodiesterase-4D expression, leading to increased BAT thermogenesis. Taken together, our study uncovers a mechanism by which T cells communicate with brown adipocytes to regulate BAT thermogenesis and whole-body energy homeostasis. Our findings highlight a therapeutic potential of targeting T cells for the treatment of over nutrition-induced obesity and its associated metabolic diseases.
Selective hydrogenolysis of catechyl lignin into propenylcatechol over an atomically dispersed ruthenium catalyst
Authors: Wang Shuizhong , Zhang Kaili , Li Helong , Xiao Ling-Ping , Song Guoyong
Published: January 2021

C-lignin is a homo-biopolymer, being made up of caffeyl alcohol exclusively. There is significant interest in developing efficient and selective catalyst for depolymerization of C-lignin, as it represents an ideal feedstock for producing catechol derivatives. Here we report an atomically dispersed Ru catalyst, which can serve as an efficient catalyst for the hydrogenolysis of C-lignin via the cleavage of C−O bonds in benzodioxane linkages, giving catechols in high yields with TONs up to 345. A unique selectivity to propenylcatechol (77%) is obtained, which is otherwise hard to achieve, because this catalyst is capable of hydrogenolysis rather than hydrogenation. This catalyst also demonstrates good reusability in C-lignin depolymerization. Detailed investigations by model compounds concluded that the pathways involving dehydration and/or dehydrogenation reactions are incompatible routes; we deduced that caffeyl alcohol generated via concurrent C−O bonds cleavage of benzodioxane unit may act as an intermediate in the C-lignin hydrogenolysis. Current demonstration validates that atomically dispersed metals can not only catalyze small molecules reactions, but also drive the transformation of abundant and renewable biopolymer.
Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease
Authors: Garcia-Gomez Antonio , Li Tianlu , de la Calle-Fabregat Carlos , Rodríguez-Ubreva Javier , Ciudad Laura , Català-Moll Francesc , Godoy-Tena Gerard , Martín-Sánchez Montserrat , San-Segundo Laura , Muntión Sandra , Morales Xabier , Ortiz-de-Solórzano Carlos , Oyarzabal Julen , San José-Enériz Edurne , Esteller Manel , Agirre Xabier , Prosper Felipe , Garayoa Mercedes , Ballestar Esteban
Published: January 2021

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.
Modelling the global burden of drug-resistant tuberculosis avertable by a post-exposure vaccine
Authors: Fu Han , Lewnard Joseph A. , Frost Isabel , Laxminarayan Ramanan , Arinaminpathy Nimalan
Published: January 2021

There have been notable advances in the development of vaccines against active tuberculosis (TB) disease for adults and adolescents. Using mathematical models, we seek to estimate the potential impact of a post-exposure TB vaccine, having 50% efficacy in reducing active disease, on global rifampicin-resistant (RR-) TB burden. In 30 countries that together accounted for 90% of global RR-TB incidence in 2018, a future TB vaccine could avert 10% (95% credible interval: 9.7–11%) of RR-TB cases and 7.3% (6.6–8.1%) of deaths over 2020–2035, with India, China, Indonesia, Pakistan, and the Russian Federation having the greatest contribution. This impact would increase to 14% (12–16%) and 31% (29–33%) respectively, when combined with improvements in RR-TB diagnosis and treatment relative to a scenario of no vaccine and no such improvements. A future TB vaccine could have important implications for the global control of RR-TB, especially if implemented alongside enhancements in management of drug resistance.
Epitope-specific immunity against Staphylococcus aureus coproporphyrinogen III oxidase
Authors: Klimka Alexander , Mertins Sonja , Nicolai Anne Kristin , Rummler Liza Marie , Higgins Paul G. , Günther Saskia Diana , Tosetti Bettina , Krut Oleg , Krönke Martin
Published: January 2021

Staphylococcus aureus represents a serious infectious threat to global public health and a vaccine against S. aureus represents an unmet medical need. We here characterise two S. aureus vaccine candidates, coproporphyrinogen III oxidase (CgoX) and triose phosphate isomerase (TPI), which fulfil essential housekeeping functions in heme synthesis and glycolysis, respectively. Immunisation with rCgoX and rTPI elicited protective immunity against S. aureus bacteremia. Two monoclonal antibodies (mAb), CgoX-D3 and TPI-H8, raised against CgoX and TPI, efficiently provided protection against S. aureus infection. MAb-CgoX-D3 recognised a linear epitope spanning 12 amino acids (aa), whereas TPI-H8 recognised a larger discontinuous epitope. The CgoX-D3 epitope conjugated to BSA elicited a strong, protective immune response against S. aureus infection. The CgoX-D3 epitope is highly conserved in clinical S. aureus isolates, indicating its potential wide usability against S. aureus infection. These data suggest that immunofocusing through epitope-based immunisation constitutes a strategy for the development of a S. aureus vaccine with greater efficacy and better safety profile.
Identification of a neutralizing epitope within minor repeat region of Plasmodium falciparum CS protein
Authors: Calvo-Calle J. Mauricio , Mitchell Robert , Altszuler Rita , Othoro Caroline , Nardin Elizabeth
Published: January 2021

Malaria remains a major cause of morbidity and mortality worldwide with 219 million infections and 435,000 deaths predominantly in Africa. The infectivePlasmodiumsporozoite is the target of a potent humoral immune response that can protect murine, simian and human hosts against challenge by malaria-infected mosquitoes. Early murine studies demonstrated that sporozoites or subunit vaccines based on the sporozoite major surface antigen, the circumsporozoite (CS) protein, elicit antibodies that primarily target the central repeat region of the CS protein. In the current murine studies, using monoclonal antibodies and polyclonal sera obtained following immunization withP. falciparumsporozoites or synthetic repeat peptides, we demonstrate differences in the ability of these antibodies to recognize the major and minor repeats contained in the central repeat region. The biological relevance of these differences in fine specificity was explored using a transgenicP. bergheirodent parasite expressing theP. falciparumCS repeat region. In these in vitro and in vivo studies, we demonstrate that the minor repeat region, comprised of three copies of alternating NANP and NVDP tetramer repeats, contains an epitope recognized by sporozoite-neutralizing antibodies. In contrast, murine monoclonal antibodies specific for the major CS repeats (NANP)ncould be isolated from peptide-immunized mice that had limited or no sporozoite-neutralizing activity. These studies highlight the importance of assessing the fine specificity and functions of antirepeat antibodies elicited byP. falciparumCS-based vaccines and suggest that the design of immunogens to increase antibody responses to minor CS repeats may enhance vaccine efficacy.
Giant lungfish genome elucidates the conquest of land by vertebrates
Authors: Meyer Axel , Schloissnig Siegfried , Franchini Paolo , Du Kang , Woltering Joost M. , Irisarri Iker , Wong Wai Yee , Nowoshilow Sergej , Kneitz Susanne , Kawaguchi Akane , Fabrizius Andrej , Xiong Peiwen , Dechaud Corentin , Spaink Herman P. , Volff Jean-Nicolas , Simakov Oleg , Burmester Thorsten , Tanaka Elly M. , Schartl Manfred
Published: January 2021

Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, ‘conquered’ the land and ultimately gave rise to all land vertebrates, including humans1–3. Here we determine the chromosome-quality genome of the Australian lungfish (Neoceratodus forsteri), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14× larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods4,5, underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution.
High energy implementation of coil-target scheme for guided re-acceleration of laser-driven protons
Authors: Ahmed Hamad , Hadjisolomou Prokopis , Naughton Kealan , Alejo Aaron , Brauckmann Stephanie , Cantono Giada , Ferguson Simon , Cerchez Mirela , Doria Domenico , Green James , Gwynne Deborah , Hodge Thomas , Kumar Deepak , Macchi Andrea , Prasad Rajendra , Willi Oswald , Borghesi Marco , Kar Satyabrata
Published: January 2021

Developing compact ion accelerators using intense lasers is a very active area of research, motivated by a strong applicative potential in science, industry and healthcare. However, proposed applications in medical therapy, as well as in nuclear and particle physics demand a strict control of ion energy, as well as of the angular and spectral distribution of ion beam, beyond the intrinsic limitations of the several acceleration mechanisms explored so far. Here we report on the production of highly collimated ($$\sim 0.2^{\circ }$$

∼
0
.

2
∘

half angle divergence), high-charge (10s of pC) and quasi-monoenergetic proton beams up to $$\sim$$
∼
50 MeV, using a recently developed method based on helical coil targetry. In this concept, ions accelerated from a laser-irradiated foil are post-accelerated and conditioned in a helical structure positioned at the rear of the foil. The pencil beam of protons was produced by guided post-acceleration at a rate of $$\sim$$
∼
2 GeV/m, without sacrificing the excellent beam emittance of the laser-driven proton beams. 3D particle tracing simulations indicate the possibility of sustaining high acceleration gradients over extended helical coil lengths, thus maximising the gain from such miniature accelerating modules.
Optimal pulse length of insonification for Piezo1 activation and intracellular calcium response
Authors: Liao Defei , Hsiao Ming-Yen , Xiang Gaoming , Zhong Pei
Published: January 2021

Ultrasound (US) neuromodulation, especially sonogenetics, has been demonstrated with potential applications in noninvasive and targeted treatment of various neurological disorders. Despite the growing interest, the mechanism for US neuromodulation remains elusive, and the optimal condition for eliciting a neural response with minimal adverse effect has not been identified. Here, we investigate the Piezo1 activation and intracellular calcium response elicited by acoustical streaming induced shear stress under various US exposure conditions. We find that Piezo1 activation and resultant intracellular calcium response depend critically on shear stress amplitude and pulse length of the stimulation. Under the same insonification acoustic energy, we further identify an optical pulse length that leads to maximum cell deformation, Piezo1 activation, and calcium response with minimal injury, confirmed by numerical modeling of Piezo1 channel gating dynamics. Our results provide insight into the mechanism of ultrasonic activation of Piezo1 and highlight the importance of optimizing US exposure conditions in sonogenetics applications.
A comprehensive analysis of the phylogenetic signal in ramp sequences in 211 vertebrates
Authors: McKinnon Lauren M. , Miller Justin B. , Whiting Michael F. , Kauwe John S. K. , Ridge Perry G.
Published: January 2021

Ramp sequences increase translational speed and accuracy when rare, slowly-translated codons are found at the beginnings of genes. Here, the results of the first analysis of ramp sequences in a phylogenetic construct are presented. Ramp sequences were compared from 247 vertebrates (114 Mammalian and 133 non-mammalian), where the presence and absence of ramp sequences was analyzed as a binary character in a parsimony and maximum likelihood framework. Additionally, ramp sequences were mapped to the Open Tree of Life synthetic tree to determine the number of parallelisms and reversals that occurred, and those results were compared to random permutations. Parsimony and maximum likelihood analyses of the presence and absence of ramp sequences recovered phylogenies that are highly congruent with established phylogenies. Additionally, 81% of vertebrate mammalian ramps and 81.2% of other vertebrate ramps had less parallelisms and reversals than the mean from 1000 randomly permuted trees. A chi-square analysis of completely orthologous ramp sequences resulted in a p-value < 0.001 as compared to random chance. Ramp sequences recover comparable phylogenies as other phylogenomic methods. Although not all ramp sequences appear to have a phylogenetic signal, more ramp sequences track speciation than expected by random chance. Therefore, ramp sequences may be used in conjunction with other phylogenomic approaches if many orthologs are taken into account. However, phylogenomic methods utilizing few orthologs should be cautious in incorporating ramp sequences because individual ramp sequences may provide conflicting signals.
Role of physical activity and fitness on sleep in sedentary middle-aged adults: the FIT-AGEING study
Authors: Mochón-Benguigui Sol , Carneiro-Barrera Almudena , Castillo Manuel J. , Amaro-Gahete Francisco J.
Published: January 2021

The association of physical activity and fitness with sleep still remains unclear since there is a lack of studies in this field of research using objective measurements of these variables. This study aimed to investigate the association of objectively-measured sedentariness, physical activity levels, and physical fitness with sleep quantity and quality in sedentary middle-aged adults. A total of 74 volunteers (52.7% women; aged 53.7 ± 5.1) were recruited for the present study. Cardiorespiratory fitness was measured through a maximal treadmill test, and muscular strength by extension and flexion peak torque, and by the hand grip test. Physical activity and objective sleep parameters were determined through accelerometry, and subjective sleep by the Pittsburgh Sleep Quality Index (PSQI). Reduced levels of sedentariness, greater VO2max, and greater muscular strength were positively related to improved objective sleep quantity and quality (all P ≤ 0.05). Furthermore, higher levels of overall physical activity, VO2max, and muscular strength were related to better subjective sleep quantity and quality (all P ≤ 0.05). Reduced sedentariness and increased physical activity and fitness may be a potential prevention and/or treatment pathway to reduce sleep disturbances and, in general, to improve patients physical and psychological health for a successful aging process.
Molecular analyses identifies new domains and structural differences among Streptococcus pneumoniae immune evasion proteins PspC and Hic
Authors: Du Shanshan , Vilhena Cláudia , King Samantha , Sahagún-Ruiz Alfredo , Hammerschmidt Sven , Skerka Christine , Zipfel Peter F.
Published: January 2021

The PspC and Hic proteins of Streptococcuspneumoniae are some of the most variable microbial immune evasion proteins identified to date. Due to structural similarities and conserved binding profiles, it was assumed for a long time that these pneumococcal surface proteins represent a protein family comprised of eleven subgroups. Recently, however, the evaluation of more proteins revealed a greater diversity of individual proteins. In contrast to previous assumptions a pattern evaluation of six PspC and five Hic variants, each representing one of the previously defined subgroups, revealed distinct structural and likely functionally regions of the proteins, and identified nine new domains and new domain alternates. Several domains are unique to PspC and Hic variants, while other domains are also present in other virulence factors encoded by pneumococci and other bacterial pathogens. This knowledge improved pattern evaluation at the level of full-length proteins, allowed a sequence comparison at the domain level and identified domains with a modular composition. This novel strategy increased understanding of individual proteins variability and modular domain composition, enabled a structural and functional characterization at the domain level and furthermore revealed substantial structural differences between PspC and Hic proteins. Given the exceptional genomic diversity of the multifunctional PspC and Hic proteins a detailed structural and functional evaluation need to be performed at the strain level. Such knowledge will also be useful for molecular strain typing and characterizing PspC and Hic proteins from new clinical S. pneumoniae strains.
Nutritional status and anxious and depressive symptoms in anorexia nervosa: a prospective study
Authors: Pleplé A. , Lalanne C. , Huas C. , Mattar L. , Hanachi M. , Flament M. F. , Carchon I. , Jouen F. , Berthoz S. , Godart N.
Published: January 2021

The interweaving of malnutrition and symptoms of anxiety and depression in anorexia Nervosa (AN) is mentioned without any consensus regarding the course of anxious-depressive symptoms in relation to nutritional status in the course of treatment of patients with AN. The objectives of the current study in a large sample of AN inpatients were to assess the relationships between anxiety and depression symptoms and nutritional status both over the course of inpatient treatment and at discharge. 222 consecutive inpatients with AN (DSM-IV TR) were assessed (entrance and discharge) for duration of illness, psychiatric treatments, sociodemographic data and with psychometric scales for different psychopathological symptoms [depressive (BDI), anxiety and depressive (HAD scale), obsessive–compulsive (MOCI) and social phobia (LSAS fear score)]. Nutritional status was assessed with Body Mass Index (BMI) and body composition by bioelectrical impedance. The Fat free mass index [FFMI = FFM (kg)/height (m2)] was considered for the analysis. Two models were developed where the dependent variables were each psychopathological score at discharge (BDI, HAD anxiety, MOCI, and LSAS fear) in the cross-sectional model, and their variation in the longitudinal model (where a positive score reflected symptom decrease at discharge). A fixed set of predictors, defined on presumed clinical and statistical relevance (FFMI in the cross-sectional model and Variation of FFMI in the longitudinal model), were considered in each model, without any model selection procedure. This is the first study to confirm a positive relationship between the course of eating disorder symptoms and that of anxious-depressive symptoms during inpatient treatment of AN even after adjustment on a vast array of possibly confounding factors.
Modelling normal age-related changes in individual retinal layers using location-specific OCT analysis
Authors: Trinh Matt , Khou Vincent , Zangerl Barbara , Kalloniatis Michael , Nivison-Smith Lisa
Published: January 2021

Current descriptions of retinal thickness across normal age cohorts are mostly limited to global analyses, thus overlooking spatial variation across the retina and limiting spatial analyses of retinal and optic nerve disease. This retrospective cross-sectional study uses location-specific cluster analysis of 8 × 8 macular average grid-wise thicknesses to quantify topographical patterns and rates of normal, age-related changes in all individual retinal layers of 253 eyes of 253 participants across various age cohorts (n = 23–69 eyes per decade). Most retinal layers had concentric spatial cluster patterns except the retinal nerve fibre layer (RNFL) which displayed a nasal, asymmetric radial pattern. Age-related thickness decline mostly occurred after the late 4th decade, described by quadratic regression models. The ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), and outer nuclear layer + Henle’s fibre layer (ONL+HFL) were significantly associated with age (p < 0.0001 to < 0.05), demonstrating similar rates of thickness decline (mean pooled slope =  − 0.07 µm/year), while the IS/OS had lesser mean pooled thickness slopes for all clusters (− 0.04 µm/year). The RNFL, OPL, and RPE exhibited no significant age-related thickness change, and the RNFL were significantly associated with sex. Analysis using spatial clusters compared to the ETDRS sectors revealed more extensive spatial definition and less variability in the former method. These spatially defined, clustered normative data and age-correction functions provide an accessible method of retinal thickness analysis with more spatial detail and less variability than the ETDRS sectors, potentially aiding the diagnosis and monitoring of retinal and optic nerve disease.
Human ex vivo lung perfusion: a novel model to study human lung diseases
Authors: Cárdenes Nayra , Sembrat John , Noda Kentaro , Lovelace Tyler , Álvarez Diana , Bittar Humberto E. Trejo , Philips Brian J. , Nouraie Mehdi , Benos Panayiotis V. , Sánchez Pablo G. , Rojas Mauricio
Published: January 2021

Experimental animal models to predict physiological responses to injury and stress in humans have inherent limitations. Therefore, the development of preclinical human models is of paramount importance. Ex vivo lung perfusion (EVLP) has typically been used to recondition donor lungs before transplantation. However, this technique has recently advanced into a model to emulate lung mechanics and physiology during injury. In the present study, we propose that the EVLP of diseased human lungs is a well-suited preclinical model for translational research on chronic lung diseases. Throughout this paper, we demonstrate this technique's feasibility in pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), emphysema, and non-disease donor lungs not suitable for transplantation. In this study, we aimed to perfuse the lungs for 6 h with the EVLP system. This facilitated a robust and continuous assessment of airway mechanics, pulmonary hemodynamics, gas exchange, and biochemical parameters. We then collected at different time points tissue biopsies of lung parenchyma to isolate RNA and DNA to identify each disease's unique gene expression. Thus, demonstrating that EVLP could successfully serve as a clinically relevant experimental model to derive essential insights into pulmonary pathophysiology and various human lung diseases.
Temperature dependence for high electrical performance of Mn-doped high surface area activated carbon (HSAC) as additives for hybrid capacitor
Authors: Otgonbayar Zambaga , Fatema Kamrun Nahar , Yang Sunhye , Kim Ick-Jun , Kim Minchul , Shim Sang Eun , Oh Won-Chun
Published: January 2021

Herein, we manufactured the positive and negative electrodes for the hybrid capacitor. The Mn-doped High surface area of Activated carbon composite used for the positive electrode and as-prepared composite was calcined at 600 °C and 800 °C. The morphological structures and pore-size distributions of MnYP-600HTT and MnYP-800HTT were characterized by means of XRD, SEM, EDAX, TEM, and BET. According to the BET specific surface-area evaluation, MnYP-600HTT and MnYP-800HTT were 1272.6 and 1388.1 m2/g, respectively. Total pore volumes were 0.627 and 0.687 cm3/g, which is beneficial for forming ion-transport channels in electrochemical reactions. The MnYP-600HTT electrode had a high specific capacity of 177.2 mAh/g at 20C, and the capacity retention was 64.8%. During the entire cycling, MnYP-600HTT had excellent cyclic stability in 500 cycles along with high efficiency. The robust design of the MnYP-600HTT and MnYP-800HTT cathode materials introduced in this work pave the way for designing next-generation supercapacitors operating at ultra-high C rates. The Mn-doped high surface of activated carbon had stable energy density and superior cycling stability that were demonstrated in supercapacitor systems.
Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes
Authors: Chou Ya-Ching , Chen Ming-Jer , Chen Pi-Hua , Chang Ching-Wen , Yu Mu-Hsien , Chen Yi-Jen , Tsai Eing-Mei , Tsai Shih-Feng , Kuo Wun-Syuan , Tzeng Chii-Ruey
Published: January 2021

To determine whether genetic predisposition to endometriosis varies depending on ethnicity and in association with expression quantitative trait loci (eQTL) in a Taiwanese population. We conducted a genome-wide association study (GWAS) and replicated it in 259 individuals with laparoscopy-confirmed stage III or IV endometriosis (cases) and 171 women without endometriosis (controls). Their genomic DNA was extracted from blood and evaluated by the GWAS of Taiwan Biobank Array. Novel genetic variants that predispose individuals to endometriosis were identified using GWAS and replication, including rs10739199 (P = 6.75 × 10−5) and rs2025392 (P = 8.01 × 10−5) at chromosome 9, rs1998998 (P = 6.5 × 10−6) at chromosome 14, and rs6576560 (P = 9.7 × 10−6) at chromosome 15. After imputation, strong signals were exhibited by rs10822312 (P = 1.80 × 10−7) at chromosome 10, rs58991632 (P = 1.92 × 10−6) and rs2273422 (P = 2.42 × 10−6) at chromosome 20, and rs12566078 (P = 2.5 × 10−6) at chromosome 1. We used the Genotype-Tissue Expression (GTEx) database to observe eQTL. Among these SNPs, the cis-eQTL rs13126673 of inturned planar cell polarity protein (INTU) showed significant association with INTU expression (P = 5.1 × 10–33). Moreover, the eQTL analysis was performed on endometriotic tissues from women with endometriosis. The expression of INTU in 78 endometriotic tissue of women with endometriosis is associated with rs13126673 genotype (P = 0.034). To our knowledge, this is the first GWAS to link endometriosis and eQTL in a Taiwanese population.
Evaluation of wavelength ranges and tissue depth probed by diffuse reflectance spectroscopy for colorectal cancer detection
Authors: Nogueira Marcelo Saito , Maryam Siddra , Amissah Michael , Lu Huihui , Lynch Noel , Killeen Shane , O’Riordain Micheal , Andersson-Engels Stefan
Published: January 2021

Colorectal cancer (CRC) is the third most common type of cancer worldwide and the second most deadly. Recent research efforts have focused on developing non-invasive techniques for CRC detection. In this study, we evaluated the diagnostic capabilities of diffuse reflectance spectroscopy (DRS) for CRC detection by building 6 classification models based on support vector machines (SVMs). Our dataset consists of 2889 diffuse reflectance spectra collected from freshly excised ex vivo tissues of 47 patients over wavelengths ranging from 350 and 1919 nm with source-detector distances of 630-µm and 2500-µm to probe different depths. Quadratic SVMs were used and performance was evaluated using twofold cross-validation on 10 iterations of randomized training and test sets. We achieved (93.5 ± 2.4)% sensitivity, (94.0 ± 1.7)% specificity AUC by probing the superficial colorectal tissue and (96.1 ± 1.8)% sensitivity, (95.7 ± 0.6)% specificity AUC by sampling deeper tissue layers. To the best of our knowledge, this is the first DRS study to investigate the potential of probing deeper tissue layers using larger SDD probes for CRC detection in the luminal wall. The data analysis showed that using a broader spectrum and longer near-infrared wavelengths can improve the diagnostic accuracy of CRC as well as probing deeper tissue layers.
Intraocular toxicity caused by MEROCTANE perfluorocarbon liquid
Authors: Coco-Martin Rosa M. , Andrés-Iglesias Cristina , Srivastava Girish K. , Lagos-Rodriguez Javier , Ruiz-Tevah Miguel , Díaz-Cárdenas Mario R. , Fernandez-Bueno Ivan , García-Serna Juan , García-Gutierrez María T. , García-Layana Alfredo , Pastor J. Carlos
Published: January 2021

Serious intraocular toxicity cases have been reported worldwide after the use of different perfluorocarbon liquids. The current study reports for the first-time the clinical pictures of cases of acute intraocular toxicity caused by MEROCTANE, a perfluoro-octane commercialized by a Turkish company and distributed in many countries. A series of 18 cases from Chile and Spain was retrospectively analysed. To evaluate the impurity profile, a suspicious MEROCTANE sample (lot OCT.01.2013) was analysed by gas chromatography mass spectrometry and compared with a non-suspicious sample of the same commercial perfluoro-octane (lot OCT 722011). Cytotoxicity was tested following a direct-contact method, taking into consideration the high volatility and hydrophobicity of perfluoro-octane and following the ISO 10993 guideline. Cytotoxicity test showed clear cytotoxic effects of the analysed batch (less than 9% of cell viability). Moreover, chemical analysis demonstrated the presence of many contaminants, some highly toxic (acids and alcohols). Perfluorocarbon liquids are useful tools for intraocular surgery but companies and Agencies of Medical Devices must implement measures that guarantee the safety of these products based on both chemical and cytotoxicity analysis for every batch. Medical staff should be encouraged to report any suspected case to their respective National Agencies.