bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response
Authors: Baldwin Louise A. , Bartonicek Nenad , Yang Jessica , Wu Sunny Z. , Deng Niantao , Roden Daniel L. , Chan Chia-Ling , Al-Eryani Ghamdan , Zanker Damien J. , Parker Belinda S. , Swarbrick Alexander , Junankar Simon
Published: November 2022

Cancers evade the immune system through the process of cancer immunoediting. While immune checkpoint inhibitors are effective for reactivating tumour immunity in some cancer types, many other solid cancers, including breast cancer, remain largely non-responsive. Understanding how non-responsive cancers evade immunity and whether this occurs at the clonal level will improve immunotherapeutic design. Here we use DNA barcoding to track murine mammary cancer cell clones during immunoediting and determine clonal transcriptional profiles that allow immune evasion following anti-PD1 plus anti-CTLA4 immunotherapy. Clonal diversity is significantly restricted by immunotherapy treatment in both primary tumours and metastases, demonstrating selection for pre-existing breast cancer cell populations and ongoing immunoediting during metastasis and treatment. Immunotherapy resistant clones express a common gene signature associated with poor survival of basal-like breast cancer patient cohorts. At least one of these genes has an existing small molecule that can potentially be used to improve immunotherapy response.
Differences in water and vapor transport through angstrom-scale pores in atomically thin membranes
Authors: Cheng Peifu , Fornasiero Francesco , Jue Melinda L. , Ko Wonhee , Li An-Ping , Idrobo Juan Carlos , Boutilier Michael S. H. , Kidambi Piran R.
Published: November 2022

The transport of water through nanoscale capillaries/pores plays a prominent role in biology, ionic/molecular separations, water treatment and protective applications. However, the mechanisms of water and vapor transport through nanoscale confinements remain to be fully understood. Angstrom-scale pores (~2.8–6.6 Å) introduced into the atomically thin graphene lattice represent ideal model systems to probe water transport at the molecular-length scale with short pores (aspect ratio ~1–1.9) i.e., pore diameters approach the pore length (~3.4 Å) at the theoretical limit of material thickness. Here, we report on orders of magnitude differences (~80×) between transport of water vapor (~44.2–52.4 g m−2 day−1 Pa−1) and liquid water (0.6–2 g m−2 day−1 Pa−1) through nanopores (~2.8–6.6 Å in diameter) in monolayer graphene and rationalize this difference via a flow resistance model in which liquid water permeation occurs near the continuum regime whereas water vapor transport occurs in the free molecular flow regime. We demonstrate centimeter-scale atomically thin graphene membranes with up to an order of magnitude higher water vapor transport rate (~5.4–6.1 × 104 g m−2 day−1) than most commercially available ultra-breathable protective materials while effectively blocking even sub-nanometer (>0.66 nm) model ions/molecules.
Circuit-guided population acclimation of a synthetic microbial consortium for improved biochemical production
Authors: Kang Chae Won , Lim Hyun Gyu , Won Jaehyuk , Cha Sanghak , Shin Giyoung , Yang Jae-Seong , Sung Jaeyoung , Jung Gyoo Yeol
Published: November 2022

Microbial consortia have been considered potential platforms for bioprocessing applications. However, the complexity in process control owing to the use of multiple strains necessitates the use of an efficient population control strategy. Herein, we report circuit-guided synthetic acclimation as a strategy to improve biochemical production by a microbial consortium. We designed a consortium comprising alginate-utilizing Vibrio sp. dhg and 3-hydroxypropionic acid (3-HP)-producing Escherichia coli strains for the direct conversion of alginate to 3-HP. We introduced a genetic circuit, named “Population guider”, in the E. coli strain, which degrades ampicillin only when 3-HP is produced. In the presence of ampicillin as a selection pressure, the consortium was successfully acclimated for increased 3-HP production by 4.3-fold compared to that by a simple co-culturing consortium during a 48-h fermentation. We believe this concept is a useful strategy for the development of robust consortium-based bioprocesses.
Hippocampal astrocytes modulate anxiety-like behavior
Authors: Cho Woo-Hyun , Noh Kyungchul , Lee Byung Hun , Barcelon Ellane , Jun Sang Beom , Park Hye Yoon , Lee Sung Joong
Published: November 2022

Astrocytes can affect animal behavior by regulating tripartite synaptic transmission, yet their influence on affective behavior remains largely unclear. Here we showed that hippocampal astrocyte calcium activity reflects mouse affective state during virtual elevated plus maze test using two-photon calcium imaging in vivo. Furthermore, optogenetic hippocampal astrocyte activation elevating intracellular calcium induced anxiolytic behaviors in astrocyte-specific channelrhodopsin 2 (ChR2) transgenic mice (hGFAP-ChR2 mice). As underlying mechanisms, we found ATP released from the activated hippocampal astrocytes increased excitatory synaptic transmission in dentate gyrus (DG) granule cells, which exerted anxiolytic effects. Our data uncover a role of hippocampal astrocytes in modulating mice anxiety-like behaviors by regulating ATP-mediated synaptic homeostasis in hippocampal DG granule cells. Thus, manipulating hippocampal astrocytes activity can be a therapeutic strategy to treat anxiety.
Structural basis of organic cation transporter-3 inhibition
Authors: Khanppnavar Basavraj , Maier Julian , Herborg Freja , Gradisch Ralph , Lazzarin Erika , Luethi Dino , Yang Jae-Won , Qi Chao , Holy Marion , Jäntsch Kathrin , Kudlacek Oliver , Schicker Klaus , Werge Thomas , Gether Ulrik , Stockner Thomas , Korkhov Volodymyr M. , Sitte Harald H.
Published: November 2022

Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.
Bayesian deep learning for error estimation in the analysis of anomalous diffusion
Authors: Seckler Henrik , Metzler Ralf
Published: November 2022

Modern single-particle-tracking techniques produce extensive time-series of diffusive motion in a wide variety of systems, from single-molecule motion in living-cells to movement ecology. The quest is to decipher the physical mechanisms encoded in the data and thus to better understand the probed systems. We here augment recently proposed machine-learning techniques for decoding anomalous-diffusion data to include an uncertainty estimate in addition to the predicted output. To avoid the Black-Box-Problem a Bayesian-Deep-Learning technique named Stochastic-Weight-Averaging-Gaussian is used to train models for both the classification of the diffusion model and the regression of the anomalous diffusion exponent of single-particle-trajectories. Evaluating their performance, we find that these models can achieve a well-calibrated error estimate while maintaining high prediction accuracies. In the analysis of the output uncertainty predictions we relate these to properties of the underlying diffusion models, thus providing insights into the learning process of the machine and the relevance of the output.
Gate-tunable Veselago interference in a bipolar graphene microcavity
Authors: Zhang Xi , Ren Wei , Bell Elliot , Zhu Ziyan , Tsai Kan-Ting , Luo Yujie , Watanabe Kenji , Taniguchi Takashi , Kaxiras Efthimios , Luskin Mitchell , Wang Ke
Published: November 2022

The relativistic charge carriers in monolayer graphene can be manipulated in manners akin to conventional optics. Klein tunneling and Veselago lensing have been previously demonstrated in ballistic graphene pn-junction devices, but collimation and focusing efficiency remains relatively low, preventing realization of advanced quantum devices and controlled quantum interference. Here, we present a graphene microcavity defined by carefully-engineered local strain and electrostatic fields. Electrons are manipulated to form an interference path inside the cavity at zero magnetic field via consecutive Veselago refractions. The observation of unique Veselago interference peaks via transport measurement and their magnetic field dependence agrees with the theoretical expectation. We further utilize Veselago interference to demonstrate localization of uncollimated electrons and thus improvement in collimation efficiency. Our work sheds new light on relativistic single-particle physics and provide a new device concept toward next-generation quantum devices based on manipulation of ballistic electron trajectory.
Structure of the IscB–ωRNA ribonucleoprotein complex, the likely ancestor of CRISPR-Cas9
Authors: Kato Kazuki , Okazaki Sae , Kannan Soumya , Altae-Tran Han , Esra Demircioglu F. , Isayama Yukari , Ishikawa Junichiro , Fukuda Masahiro , Macrae Rhiannon K. , Nishizawa Tomohiro , Makarova Kira S. , Koonin Eugene V. , Zhang Feng , Nishimasu Hiroshi
Published: November 2022

Transposon-encoded IscB family proteins are RNA-guided nucleases in the OMEGA (obligate mobile element-guided activity) system, and likely ancestors of the RNA-guided nuclease Cas9 in the type II CRISPR-Cas adaptive immune system. IscB associates with its cognate ωRNA to form a ribonucleoprotein complex that cleaves double-stranded DNA targets complementary to an ωRNA guide segment. Although IscB shares the RuvC and HNH endonuclease domains with Cas9, it is much smaller than Cas9, mainly due to the lack of the α-helical nucleic-acid recognition lobe. Here, we report the cryo-electron microscopy structure of an IscB protein from the human gut metagenome (OgeuIscB) in complex with its cognate ωRNA and a target DNA, at 2.6-Å resolution. This high-resolution structure reveals the detailed architecture of the IscB–ωRNA ribonucleoprotein complex, and shows how the small IscB protein assembles with the ωRNA and mediates RNA-guided DNA cleavage. The large ωRNA scaffold structurally and functionally compensates for the recognition lobe of Cas9, and participates in the recognition of the guide RNA–target DNA heteroduplex. These findings provide insights into the mechanism of the programmable DNA cleavage by the IscB–ωRNA complex and the evolution of the type II CRISPR-Cas9 effector complexes.
Regulome-based characterization of drug activity across the human diseasome
Authors: Iwata Michio , Kosai Keisuke , Ono Yuya , Oki Shinya , Mimori Koshi , Yamanishi Yoshihiro
Published: November 2022

Drugs are expected to recover the cell system away from the impaired state to normalcy through disease treatment. However, the understanding of gene regulatory machinery underlying drug activity or disease pathogenesis is far from complete. Here, we perform large-scale regulome analysis for various diseases in terms of gene regulatory machinery. Transcriptome signatures were converted into regulome signatures of transcription factors by integrating publicly available ChIP-seq data. Regulome-based correlations between diseases and their approved drugs were much clearer than the transcriptome-based correlations. For example, an inverse correlation was observed for cancers, whereas a positive correlation was observed for immune system diseases. After demonstrating the usefulness of the regulome-based drug discovery method in terms of accuracy and applicability, we predicted new drugs for nonsmall cell lung cancer and validated the anticancer activity in vitro. The proposed method is useful for understanding disease–disease relationships and drug discovery.
Predicting vaccine effectiveness against invasive pneumococcal disease in children using immunogenicity data
Authors: Ryman Josiah , Weaver Jessica , Hu Tianyan , Weinberger Daniel M. , Yee Ka Lai , Sachs Jeffrey R.
Published: November 2022

The strength of the immune response, as measured by antibody concentrations, varies between pneumococcal conjugate vaccines (PCVs). Linking immunogenicity and effectiveness is necessary to assess whether changes in immune response from currently recommended PCVs to next-generation vaccines could impact effectiveness. Simulated reverse cumulative distribution curves were generated using published serotype-specific IgG concentrations with placebo or PCV7. This was combined with the published estimates of serotype-specific vaccine effectiveness of PCV7 against invasive pneumococcal disease to estimate the protective antibody concentration for each serotype in PCV7. Then, based on the published serotype-specific IgG concentrations in PCV13 recipients, reverse cumulative distribution curves were generated for the serotypes shared between PCV13 and PCV7. These estimated protective antibody concentration values were then used to predict the vaccine effectiveness of PCV13. The results were compared to published aggregate values for vaccine effectiveness. The aggregate median predicted vaccine effectiveness values were similar to previously reported observed values for the United Kingdom (93% versus 90%), Australia (71% versus 70%), and Germany (91% versus 90%). These results demonstrate that IgG concentrations of next-generation PCVs can be used to generate reliable estimates of vaccine effectiveness for serotypes shared with established PCVs.
Photoswitchable gating of non-equilibrium enzymatic feedback in chemically communicating polymersome nanoreactors
Authors: Rifaie-Graham Omar , Yeow Jonathan , Najer Adrian , Wang Richard , Sun Rujie , Zhou Kun , Dell Tristan N. , Adrianus Christopher , Thanapongpibul Chalaisorn , Chami Mohamed , Mann Stephen , de Alaniz Javier Read , Stevens Molly M.
Published: November 2022

The circadian rhythm generates out-of-equilibrium metabolite oscillations that are controlled by feedback loops under light/dark cycles. Here we describe a non-equilibrium nanosystem comprising a binary population of enzyme-containing polymersomes capable of light-gated chemical communication, controllable feedback and coupling to macroscopic oscillations. The populations consist of esterase-containing polymersomes functionalized with photo-responsive donor–acceptor Stenhouse adducts (DASA) and light-insensitive semipermeable urease-loaded polymersomes. The DASA–polymersome membrane becomes permeable under green light, switching on esterase activity and decreasing the pH, which in turn initiates the production of alkali in the urease-containing population. A pH-sensitive pigment that absorbs green light when protonated provides a negative feedback loop for deactivating the DASA–polymersomes. Simultaneously, increased alkali production deprotonates the pigment, reactivating esterase activity by opening the membrane gate. We utilize light-mediated fluctuations of pH to perform non-equilibrium communication between the nanoreactors and use the feedback loops to induce work as chemomechanical swelling/deswelling oscillations in a crosslinked hydrogel. We envision possible applications in artificial organelles, protocells and soft robotics.
On-surface synthesis of disilabenzene-bridged covalent organic frameworks
Authors: Sun Kewei , Silveira Orlando J. , Ma Yujing , Hasegawa Yuri , Matsumoto Michio , Kera Satoshi , Krejčí Ondřej , Foster Adam S. , Kawai Shigeki
Published: November 2022

Substituting carbon with silicon in organic molecules and materials has long been an attractive way to modify their electronic structure and properties. Silicon-doped graphene-based materials are known to exhibit exotic properties, yet conjugated organic materials with atomically precise Si substitution have remained difficult to prepare. Here we present the on-surface synthesis of one- and two-dimensional covalent organic frameworks whose backbones contain 1,4-disilabenzene (C4Si2) linkers. Silicon atoms were first deposited on a Au(111) surface, forming a AuSix film on annealing. The subsequent deposition and annealing of a bromo-substituted polyaromatic hydrocarbon precursor (triphenylene or pyrene) on this surface led to the formation of the C4Si2-bridged networks, which were characterized by a combination of high-resolution scanning tunnelling microscopy and photoelectron spectroscopy supported by density functional theory calculations. Each Si in a hexagonal C4Si2 ring was found to be covalently linked to one terminal Br atom. For the linear structure obtained with the pyrene-based precursor, the C4Si2 rings were converted into C4Si pentagonal siloles by further annealing.
Cellpose 2.0: how to train your own model
Authors: Pachitariu Marius , Stringer Carsen
Published: November 2022

Pretrained neural network models for biological segmentation can provide good out-of-the-box results for many image types. However, such models do not allow users to adapt the segmentation style to their specific needs and can perform suboptimally for test images that are very different from the training images. Here we introduce Cellpose 2.0, a new package that includes an ensemble of diverse pretrained models as well as a human-in-the-loop pipeline for rapid prototyping of new custom models. We show that models pretrained on the Cellpose dataset can be fine-tuned with only 500–1,000 user-annotated regions of interest (ROI) to perform nearly as well as models trained on entire datasets with up to 200,000 ROI. A human-in-the-loop approach further reduced the required user annotation to 100–200 ROI, while maintaining high-quality segmentations. We provide software tools such as an annotation graphical user interface, a model zoo and a human-in-the-loop pipeline to facilitate the adoption of Cellpose 2.0.
In silico analysis of koranimine, a cyclic imine compound from Peribacillus frigoritolerans reveals potential nematicidal activity
Authors: Montecillo Jake Adolf V. , Bae Hanhong
Published: November 2022

Pine wilt disease (PWD) is a destructive vector-borne forest disease caused by the nematodeBursaphelenchus xylophilus. To date, several options are available for the management of pine wilt disease; however constant development and search for natural products with potential nematicidal activity are imperative to diversify management options and to cope with the possible future emergence of resistance in parasitic nematodes. Here, a combined metabolomics and genomics approach was employed to investigate the chemical repertoire and biosynthetic potential of the bacterial endophytePeribacillus frigoritoleransBE93, previously characterized to exhibit nematicidal activity againstB. xylophilus.Feature-based molecular networking revealed the presence of diverse secondary metabolites. A cyclic imine heptapeptide, koranimine, was found to be among the most abundant secondary metabolites produced. Genome mining displayed the presence of several putative biosynthetic gene clusters (BGCs), including a dedicated non-ribosomal peptide synthase (NRPS) BGC for koranimine. Given the non-ribosomal peptide nature of koranimine, in silico molecular docking analysis was conducted to investigate its potential nematicidal activity against the target receptor ivermectin-sensitive invertebrate α glutamate-gated chloride channel (GluCl). Results revealed the binding of koranimine at the allosteric site of the channel—the ivermectin binding site. Moreover, the ligand-receptor interactions observed were mostly shared between koranimine and ivermectin when bound to the α GluCl receptor thus, suggesting a possibly shared mechanism of potential nematicidal activity. This study highlights the efficiency of combined metabolomics and genomics approach in the identification of candidate compounds.
The excess volatility puzzle explained by financial noise amplification from endogenous feedbacks
Authors: Wehrli Alexander , Sornette Didier
Published: November 2022

The arguably most important paradox of financial economics—the excess volatility puzzle—first identified by Robert Shiller in 1981 states that asset prices fluctuate much more than information about their fundamental value. We show that this phenomenon is associated with an intrinsic propensity for financial markets to evolve towards instabilities. These properties, exemplified for two major financial markets, the foreign exchange and equity futures markets, can be expected to be generic in other complex systems where excess fluctuations result from the interplay between exogenous driving and endogenous feedback. Using an exact mapping of the key property (volatility/variance) of the price diffusion process onto that of a point process (arrival intensity of price changes), together with a self-excited epidemic model, we introduce a novel decomposition of the volatility of price fluctuations into an exogenous (i.e. efficient) component and an endogenous (i.e. inefficient) excess component. The endogenous excess volatility is found to be substantial, largely stable at longer time scales and thus provides a plausible explanation for the excess volatility puzzle. Our theory rationalises the remarkable fact that small stochastic exogenous fluctuations at the micro-scale of milliseconds to seconds are renormalised into long-term excess volatility with an amplification factor of around 5 for equity futures and 2 for exchange rates, in line with models including economic fundamentals explicitly.
MUC7 VNTR polymorphism and association with bronchial asthma in Egyptian children
Authors: Saad Entsar A. , Elsaid Afaf M. , Shoaib Rasha M. S. , Megahed Khaled F. , Elsharawy Amal N.
Published: November 2022

Overproduction of mucins in the airways donates largely to airway blockage in asthma patients. Glycoprotein MUC7 plays a role in the clearance of bacteria and has anti-candidacidal criteria. Our goal was to investigate the association between the MUC7 variable number of tandem repeats (VNTR) polymorphism and bronchial asthma among Egyptian children. The MUC7 VNTR polymorphism was investigated among 100 children with bronchial asthma and 100 healthy controls using polymerase chain reaction (PCR) method. Serum levels of immunoglobulin E (IgE), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta1 (TGF-β1) were assessed by enzyme-linked immunosorbent assay (ELISA) technique. The frequencies of 6*5 genotype, 5*5 genotype, (6*5 + 5*5) genotypes, and MUC7*5 allele of the MUC7 VNTR variant were significantly lower among asthmatic patients than controls (p < 0.015, OR = 0.39, 95% CI = 0.19–0.81; p = 0.03, OR = 0.18, 95% CI = 0.04–0.86; p < 0.001, OR = 0.29, 95% CI = 0.15–0.58; p < 0.001, OR = 0.3, 95% CI = 0.17–0.55, respectively). The (6*5 + 5*5) genotypes of the MUC7 VNTR variant were not associated with the clinical manifestations and serum levels of IgE, TNF-α, and TGF-β1 among asthmatic patients (p ˃ 0.05). In conclusion, the (6*5 + 5*5) genotypes of the MUC7 VNTR variant may have a protective role for bronchial asthma in Egyptian children.
Association studies between chromosomal regions 1q21.3, 5q21.3, 14q21.2 and 17q21.31 and numbers of children in Poland
Authors: Clark Jeremy S. C. , van de Wetering Thierry , Marciniak Błażej , Żądzińska Elżbieta , Ciechanowicz Andrzej , Kaczmarczyk Mariusz , Boroń Agnieszka , Rydzewska Kamila , Posiadło Konrad , Strapagiel Dominik
Published: November 2022

Number of children is an important human trait and studies have indicated associations with single-nucleotide polymorphisms (SNPs). Aim: to give further evidence for four associations using a large sample of Polish subjects. Data from the POPULOUS genetic database was provided from anonymous, healthy, unrelated, Polish volunteers of both sexes (N = 5760). SNPs (n = 173) studied: (a) 69 from the chromosome 17 H1/H2 inversion; (b) six from 1q21.3, 5q21.3 and 14q21.2; and (c) 98 random negative controls. Zero-inflated negative-binomial regression (z.i.) was performed (0–3 numbers of children per individual (NCI) set as non-events; adjustors: year of birth, sex). Significance level p = 0.05 with Bonferroni correction. Statistically-significant differences (with data from both sexes combined) were obtained from highly-linked inversion SNPs: representative rs12373123 gave means: homozygotes TT: 2.31 NCI (n = 1418); heterozygotes CT: 2.35 NCI (n = 554); homozygotes CC: 2.44 NCI (n = 43) (genotype p = 0.01; TTvs.CC p = 0.004; CTvs.CC p = 0.009). (Male data alone gave similar results.) Recessive modeling indicated that H2-homozygotes had 0.118 more children than H1-homozygotes + heterozygotes (z.i.-count estimates ± standard errors: CT, − 0.508 ± 0.194; TT, − 0.557 ± 0.191). The non-over-dispersed count model detected no interactions: of importance there was no significant interaction with age. No positive results were obtained from negative-control SNPs or (b). Conclusions: association between the H1/H2 inversion and numbers of children (previously reported in Iceland) has been confirmed, albeit using a different statistical model. One limitation is the small amount of data, despite initially ~ 6000 subjects. Causal studies require further investigation.
The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer
Authors: Quaglia Fabio , Krishn Shiv Ram , Sossey-Alaoui Khalid , Rana Priyanka Shailendra , Pluskota Elzbieta , Park Pyung Hun , Shields Christopher D. , Lin Stephen , McCue Peter , Kossenkov Andrew V. , Wang Yanqing , Goodrich David W. , Ku Sheng-Yu , Beltran Himisha , Kelly William K. , Corey Eva , Klose Maja , Bandtlow Christine , Liu Qin , Altieri Dario C. , Plow Edward F. , Languino Lucia R.
Published: November 2022

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype.
Milk proteins as a feed restriction signature indicating the metabolic adaptation of dairy cows
Authors: Leduc A. , Le Guillou S. , Bianchi L. , Correia L. Oliveira , Gelé M. , Pires J. , Martin P. , Leroux C. , Le Provost F. , Boutinaud M.
Published: November 2022

Milk production in dairy cows is affected by numerous factors, including diet. Feed restriction is known to have little impact on milk total protein content but its effect on the fine protein composition is still poorly documented. The objective of this study was to describe the effects of two feed restriction trials of different intensities on the milk protein composition of Holstein cows. One restriction trial was of high intensity (H: 8 mid-lactation Holstein cows) and the second of moderate intensity (M: 19 peak lactation Holstein cows). Feed restriction decreased the milk protein yield for caseins under the M trial and of all six major milk proteins under the H trial. These decreased yields lead to lower concentrations of αs1-, αs2- and β-caseins during the H trial. The milk proteome, analyzed on 32 milk samples, was affected as a function of restriction intensity. Among the 345 proteins identified eight varied under the M trial and 160 under the H trial. Ontology analyses revealed their implication in carbohydrate, lipid and protein metabolisms as well as in the immune system. These proteins reflected adaptations of the animal and mammary gland physiology to feed restriction and constituted a signature of this change.
The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families
Authors: Al-Kasbi Ghalia , Al-Murshedi Fathiya , Al-Kindi Adila , Al-Hashimi Nadia , Al-Thihli Khalid , Al-Saegh Abeer , Al-Futaisi Amna , Al-Mamari Watfa , Al-Asmi Abdullah , Bruwer Zandre , Al-Kharusi Khalsa , Al-Rashdi Samiya , Zadjali Fahad , Al-Yahyaee Said , Al-Maawali Almundher
Published: November 2022

Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.
A game-based approach for designing a collaborative evolution mechanism for unmanned swarms on community networks
Authors: Wu Zhonghong , Pan Li , Yu Minggang , Liu Jintao , Mei Dan
Published: November 2022

Intelligent and coordinated unmanned aerial vehicle (UAV) swarm combat will be the main mode of warfare in the future, and mechanistic design of autonomous cooperation within swarms is the key to enhancing combat effectiveness. Exploration of the essential features and patterns of autonomous collaboration in unmanned swarms has become the focus of scientific research and technological applications, in keeping with the evolving conceptions of the military theatre. However, given the unique attributes of the military and the novelty of the warfare mode of unmanned swarms, few achievements have been reported in the existing research. In this study, we analysed the military requirements of unmanned swarm operations and proposed an analytic framework for autonomous collaboration. Then, a literature review addressing swarm evolution dynamics, game-based swarm collaboration, and collaborative evolution on complex networks was conducted. Next, on the basis of the above work, we designed a community network for unmanned swarm cooperation and constructed a collaborative evolution model based on the multiplayer public goods game (PGG). Furthermore, according to the “network” and “model”, the dynamic evolution process of swarm collaboration was formally deduced. Finally, a simulation was conducted to analyse the influence of relevant parameters (i.e., swarm size, degree distribution, cost, multiplication factor) on the collaborative behaviour of unmanned swarms. According to the simulation results, some reasonable suggestions for collaborative management and control in swarm operation are given, which can provide theoretical reference and decision-making support for the design of coordination mechanisms and improved combat effectiveness in unmanned swarm operation.
Molecular co-localization of multiple drugs in a nanoscopic delivery vehicle for potential synergistic remediation of multi-drug resistant bacteria
Authors: Banerjee Amrita , Mukherjee Dipanjan , Bera Arpan , Ghosh Ria , Mondal Susmita , Mukhopadhyay Subhadipta , Das Ranjan , Altass Hatem M. , Natto Sameer. S. A. , Moussa Ziad , Ahmed Saleh A. , Chattopadhyay Arpita , Pal Samir Kumar
Published: November 2022

Anti-microbial resistant infection is predicted to be alarming in upcoming years. In the present study, we proposed co-localization of two model drugs viz., rifampicin and benzothiazole used in anti-tuberculosis and anti-fungal agents respectively in a nanoscopic cationic micelle (cetyl triethyl ammonium bromide) with hydrodynamic diameter of 2.69 nm. Sterilization effect of the co-localized micellar formulation against a model multi-drug resistant bacterial strain viz., Methicillin resistant Staphylococcus aureus was also investigated. 99.88% decrease of bacterial growth in terms of colony forming unit was observed using the developed formulation. While Dynamic Light Scattering and Forsters Resonance Energy Transfer between benzothiazole and rifampicin show co-localization of the drugs in the nanoscopic micellar environment, analysis of time-resolved fluorescence decays by Infelta-Tachiya model and the probability distribution of the donor–acceptor distance fluctuations for 5 μM,10 μM and 15 μM acceptor concentrations confirm efficacy of the co-localization. Energy transfer efficiency and the donor acceptor distance are found to be 46% and 20.9 Å respectively. We have also used a detailed computational biology framework to rationalize the sterilization effect of our indigenous formulation. It has to be noted that the drugs used in our studies are not being used for their conventional indication. Rather the co-localization of the drugs in the micellar environment shows a completely different indication of their use in the remediation of multi-drug resistant bacteria revealing the re-purposing of the drugs for potential use in hospital-born multi-drug resistant bacterial infection.
Spurious oscillations reduction in transient diffusion and wave propagation problems discretized with the Finite Element Method
Authors: Neto Augusto Badke , Mansur Webe João , Ferreira Walnório Graça
Published: November 2022

This work presents a new method, the SOR_FEM, spurious oscillation reduction-FEM, that uses analytical solutions of simple problems to find numerical solutions of more complex problems to reduce the spurious oscillations that occur due to solution discontinuity. With the proposed method it is possible to find numerical solutions without spurious oscillations of problems submitted to impulsive point sources without using any approximation for the Dirac delta function. To validate the proposed method, linear problems of heat diffusion and wave propagation in homogeneous and heterogeneous media are solved with the Finite Element Method (FEM).
Impact of body mass index on in-hospital mortality for six acute cardiovascular diseases in Japan
Authors: Yoshida Naofumi , Ogawa Masato , Nakai Michikazu , Kanaoka Koshiro , Sumita Yoko , Emoto Takuo , Saito Yoshihiro , Yamamoto Hiroyuki , Izawa Kazuhiro P. , Sakai Yoshitada , Hirota Yushi , Ogawa Wataru , Iwanaga Yoshitaka , Miyamoto Yoshihiro , Yamashita Tomoya , Hirata Ken-ichi
Published: November 2022

Body mass index (BMI) distribution and its impact on cardiovascular disease (CVD) vary between Asian and western populations. The study aimed to reveal time-related trends in the prevalence of obesity and underweight and safe ranges of BMI in Japanese patients with CVD. We analyzed 5,020,464 records from the national Japanese Registry of All Cardiac and Vascular Diseases—Diagnosis Procedure Combination dataset over time (2012–2019) and evaluated BMI trends and the impact on in-hospital mortality for six acute CVDs: acute heart failure (AHF), acute myocardial infarction (AMI), acute aortic dissection (AAD), ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Patients were categorized into five groups using the WHO Asian-BMI criteria: underweight (< 18.5 kg/m2), normal (18.5–22.9 kg/m2), overweight at risk (23.0–24.9 kg/m2), obese I (25.0–29.9 kg/m2), and obese II (≥ 30.0 kg/m2). Age was significantly and inversely related to high BMI for all diseases (P < 0.001). The proportion of BMI categories significantly altered over time; annual BMI trends showed a significant and gradual increase, except AAD. In adjusted mixed models, underweight was significantly associated with a high risk of in-hospital mortality in all CVD patients (AHF, OR 1.41, 95% CI 1.35–1.48, P < 0.001; AMI, OR 1.27, 95% CI 1.20–1.35, P < 0.001; AAD, OR 1.23, 95% CI 1.16–1.32, P < 0.001; IS, OR 1.45, 95% CI 1.41–1.50, P < 0.001; ICH, OR 1.18, 95% CI 1.13–1.22, P < 0.001; SAH, OR 1.17, 95% CI 1.10–1.26, P < 0.001). Moreover, obese I and II groups were significantly associated with a higher incidence of in-hospital mortality, except AHF and IS. Age was associated with in-hospital mortality for all BMI categories in six CVD patients. BMI increased annually in patients with six types of CVDs. Although underweight BMI was associated with high mortality rates, the impact of obesity on in-hospital mortality differs among CVD types.
Synthesis of unequally-spaced arrays using the fractional Fourier series
Authors: Boozari Mahdi , Khalaj-Amirhosseini Mohammad
Published: November 2022

This paper introduces an algebraic method to synthesize the radiation pattern of unequally-spaced arrays. In this method, first, the characteristic matrix, containing the sampled data of the desired pattern, is established. Then, the fractional Fourier series is calculated using the distinct eigenvalues and eigenvectors of the characteristic matrix. In the following, the location of the array elements is estimated using the eigenvalues by considering the mutual coupling effect. The magnitude and phase of the excitation currents are computed using the least square method. Also, it is proved that the number of elements can be reduced using the eigenvalue decomposition and differential spectrum method. Several important patterns are investigated to verify the performance of the proposed method, and then a comprehensive discussion is expressed for all cases. It is shown that using the proposed method, a greater average spacing is achieved which allows bettering mitigate the phenomenon of mutual coupling. Furthermore, the various results show that the proposed method offers a better approximation of the desired array factor especially for beam-shaped patterns. This method also has a noble ability to reduce the number of array elements compared to a generic reference array, while still retaining a good ability to approximate the desired pattern fairly faithfully.
Research On Maize Disease Identification Methods In Complex Environments Based On Cascade Networks And Two-Stage Transfer Learning
Authors: Liu Hongxin , Lv Haichen , Li Jiajun , Liu Yongshuo , Deng Limiao
Published: November 2022

Achieving accurate and reliable maize disease identification in complex environments is a huge challenge. This is because disease images obtained from natural environments are often in complex contexts that may contain elements similar to disease characteristics or symptoms. Based on cascade network and two-stage transformation learning, the new method is proposed in this paper and applied the improved method to the task of identification and classification of four maize leaf types in a complex environment. The proposed method has a cascade structure which consists of a Faster R-CNN leaf detector (denoted as LS-RCNN) and a CNN disease classifier, named CENet(Complex Environment Network). The LS-RCNN detector with an attention mechanism was used to detect maize leaves from the image, and the CENet model further classified the leaf images detected in the first stage into four categories: Cercospora leaf spot, Common rust, Northern Leaf Blight, and Healthy, which allowed image features to be extracted more efficiently. The subsequent use of a two-stage transfer learning strategy to train CENet models of disease images in complex contexts allows for faster training of the models while ensuring accuracy. The experimental results show that the proposed method is used to identify four types of maize leaves with an F1-score of 99.70%, which is better than some popular CNN models and others' methods, and has a more obvious advantage in terms of training speed. The model proposed in this experiment has a positive significance for exploring other Crop variety identification and classification under complex backgrounds.
Effect of FXR agonist GW4064 in the treatment of hilar cholangiocarcinoma in rats
Authors: Wang Jie-ping , Zhang Meng-yu , Luo Ming , Qin Shu , Xia Xian-ming
Published: November 2022

The study objective was to observe the treatment effect of the farnesoid X receptor (FXR) agonist GW4064 in a rat model of hilar cholangiocarcinoma to explore a new therapeutic target for gene therapy for hilar cholangiocarcinoma. Eighty male Wistar rats were randomly divided into four groups (treatment group, model group, control group and sham operation group, 20 rats in each group). The four groups were fed a standard diet. The treatment group and the model group were injected with a suspension of cholangiocarcinoma QBC939 cells into the hilar bile duct with a microsyringe, the control group was injected with normal saline, and the sham operation group was not injected with anything. A modified tail suspension test (TST) was used to evaluate the vitality of the rats. At 4 weeks, one rat in the treatment group and model group was euthanized, and the changes in the hilar bile duct were recorded. The procedure was repeated at 6 weeks. After 6 weeks, hilar cholangiocarcinoma occurred in the treatment group and model group. Then, the treatment group was injected with GW4064 intraperitoneally at a dose of 50 mg/kg/day. One week after injection, the rats in the four groups were euthanized. Pathological examination confirmed that tumours had formed, and hilar bile duct tissues were taken from the four groups. FXR, Bsep, Ntcp and NF-κB expression in the hilar bile duct was detected by real-time polymerase chain reaction (RT–PCR) and immunohistochemistry. After three weeks, the rats in the treatment group and model group ate less, and their weight was significantly reduced. Six weeks later, hilar cholangiocarcinoma was detected in the treatment group and model group. After treatment with GW4064, the ratios of FXR/GAPDH mRNA, Bsep/GAPDH mRNA, Ntcp/GAPDH mRNA and NF-κBp65/GAPDH mRNA were significantly different among the four groups. Under a light microscope, FXR protein reacted with anti-FXR antibody, Bsep protein reacted with anti-Bsep antibody, Ntcp protein reacted with anti-Ntcp antibody and NF-κBp65 protein reacted with anti-NF-κBp65 antibody, and they showed granular expression. Every pathological section included 4,800 cells, and there were different numbers of positive cells in each group. FXR expression in the hilar cholangiocarcinoma of rats was significantly lower than that in normal hilar bile duct tissues. GW4064 increased the expression of FXR in tumour tissues. These findings suggest that FXR may be a new therapeutic target and that GW4064 may be helpful in the treatment of hilar cholangiocarcinoma.
Impact of elevated body mass index on cumulative live birth rate and obstetric safety in women undergoing assisted reproductive technology
Authors: Hu Dan , Huang Bo , Xiong Min , Yao Junning , Yang Shulin , Wu Ruxing , Zhang Hanwang , Zhao Yiqing
Published: November 2022

This study evaluated the impact of elevated body mass index (BMI) on short- and long-term outcomes of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatments. A total of 7229 patients undergoing IVF/ICSI fresh cycles and subsequent frozen embryo transfer cycles from 2014 to 2020 were divided into normal (18.5–24.9 kg/m2) and high BMI (≥ 25 kg/m2) groups. Ovarian response, pregnancy outcomes, and safety of both mother and fetus were the main outcome measures. Furthermore, multivariate analysis was used to determine whether BMI was associated with cumulative live birth rate (CLBR). Results showed that for younger women (< 38 year), CLBR was significantly reduced in the high BMI group compared with the normal BMI control and was accompanied by fewer retrieved oocytes and available embryos. Additionally, the incidence of hypertensive disorders of pregnancy, fetal macrosomia, and cleft lip and palate birth defects resulting from cumulative live births was significantly higher compared with the normal BMI group. No differences were observed among older women (≥ 38 year). Multivariate analysis revealed that high BMI was a risk factor for CLBR. Our study suggested that elevated BMI has a greater adverse impact on younger women.
Integrated genomics and proteomics analysis of Paenibacillus peoriae IBSD35 and insights into its antimicrobial characteristics
Authors: Ngashangva Ng , Mukherjee Pulok K. , Sharma Chandradev , Kalita Mohan C. , Sarangthem Indira
Published: November 2022

Antimicrobial resistance has been developing fast and incurring a loss of human life, and there is a need for new antimicrobial agents. Naturally occurring antimicrobial peptides offer the characteristics to counter AMR because the resistance development is low or no resistance. Antimicrobial peptides from Paenibacillus peoriae IBSD35 cell-free supernatant were salted out and purified using chromatography and characterized with liquid chromatography–tandem-mass spectrometry. The extract has shown a high and broad spectrum of antimicrobial activity. Combining the strain IBSD35 genome sequence with its proteomic data enabled the prediction of biosynthetic gene clusters by connecting the peptide from LC–MS/MS data to the gene that encode. Antimicrobial peptide databases offered a platform for the effective search, prediction, and design of AMPs and expanded the studies on their isolation, structure elucidation, biological evaluation, and pathway engineering. The genome-based taxonomy and comparisons have shown that P. peoriae IBSD35 is closely related to Paenibacillus peoriae FSL J3-0120. P. peoriae IBSD35 harbored endophytic trait genes and nonribosomal peptide synthases biosynthetic gene clusters. The comparative genomics revealed evolutionary insights and facilitated the discovery of novel SMs using proteomics from the extract of P. peoriae IBSD35. It will increase the potential to find novel bio-molecules to counter AMR.