bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids
Authors: de Vries Hilde D. , Palmiotti Anna , Li Rumei , Hovingh Milaine V. , Mulder Niels L. , Koehorst Martijn , Bloks Vincent W. , van Zutphen Tim , Kuipers Folkert , de Boer Jan Freark 
Published: September 2022

Abstract
Background
Cyp2c70-/- mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70-/- mice and reduces cholangiopathy development later in life.

Methods
Cyp2c70+/- males were crossed with Cyp2c70+/- females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70-/- and wild-type offspring at 3 and 8 weeks of age.

Results
Three-week-old Cyp2c70-/- pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70-/- pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70-/- pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment.

Conclusion
Perinatal exposure of Cyp2c70-/- mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70-/- mice has no long-lasting effects on liver pathophysiology.

Impact

This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70-/- mice.

Perinatal UDCA exposure of Cyp2c70-/- pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids.

Perinatal UDCA exposure of Cyp2c70-/- pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment.

The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.
Neurological examination at 32-weeks postmenstrual age predicts 12-month cognitive outcomes in very preterm-born infants
Authors: Huf Isabel U. , Baque Emmah , Colditz Paul B. , Chatfield Mark D. , Ware Robert S. , Boyd Roslyn N. , George Joanne M. 
Published: September 2022

Abstract
Background
To determine the diagnostic accuracy of Hammersmith Neonatal Neurological Examination (HNNE) at 30–32 weeks postmenstrual age (PMA, ‘Early’) and term equivalent age (TEA) in infants born <31 weeks PMA to predict cognitive outcomes at 12 months corrected age (CA).

Methods
Prospective cohort study of 119 infants (73 males; median 28.4 weeks gestational age at birth) who underwent Early and TEA HNNE. At 12 months CA, 104 participants completed Bayley Scales of Infant and Toddler Development, 3rd Edition, (Bayley-III). Optimum cut-off points for each HNNE subscale were determined to establish diagnostic accuracy for predicting adverse cognitive outcomes on the Bayley-III Cognitive Composite Scale (≤85).

Results
The best diagnostic accuracy for HNNE total score at 30–32 weeks PMA predicting cognitive impairment occurred at cut-off ≤16.7 (sensitivity (Se) = 71%, specificity (Sp) = 51%). The Abnormal Signs subscale demonstrated the best balance of sensitivity/specificity combination (Se = 71%, Sp = 71%; cut-off ≤1.5). For HNNE at TEA, the total score at cut-off ≤24.5 had Se = 71% and Sp = 47% for predicting cognitive impairment. The Tone Patterns subscale demonstrated the strongest diagnostic accuracy at TEA (Se = 71%, Sp = 63%; cut-off ≤3).

Conclusions
Early and TEA HNNE demonstrated moderate diagnostic accuracy for cognitive outcomes at 12-months CA in infants born <31 weeks gestational age.
Clinical Trial Registration: Australian New Zealand Clinical Trials Registry; Trial Registration Number: ACTRN12613000280707; web address of trial: http://www.ANZCTR.org.au/ACTRN12613000280707.aspx.

Impact

Early Hammersmith Neonatal Neurological Examination (HNNE) assessment at 30–32 weeks postmenstrual age has moderate diagnostic accuracy for cognitive outcomes at 12 months corrected age in infants born <31 weeks gestation.

Early HNNE at 30–32 weeks has stronger predictive validity than HNNE at term equivalent age.

Early HNNE may provide an early marker for risk-stratification to optimise the planning of post-discharge support and follow-up services for infants born preterm.
Structural and functional retinal alterations in patients with paranoid schizophrenia
Authors: Friedel Evelyn B. N. , Hahn Hannah-Tabea , Maier Simon , Küchlin Sebastian , Reich Michael , Runge Kimon , Bach Michael , Heinrich Sven P. , Kornmeier Jürgen , Endres Dominique , Ebert Dieter , Domschke Katharina , Tebartz van Elst Ludger , Nickel Kathrin 
Published: September 2022

AbstractOphthalmological methods have increasingly raised the interest of neuropsychiatric specialists. While the integrity of the retinal cell functions can be evaluated with the electroretinogram (ERG), optical coherence tomography (OCT) allows a structural investigation of retinal layer thicknesses. Previous studies indicate possible functional and structural retinal alterations in patients with schizophrenia. Twenty-five patients with paranoid schizophrenia and 25 healthy controls (HC) matched for age, sex, and smoking status participated in this study. Both, ERG and OCT were applied to obtain further insights into functional and structural retinal alterations. A significantly reduced a-wave amplitude and thickness of the corresponding para- and perifoveal outer nuclear layer (ONL) was detected in patients with paranoid schizophrenia with a positive correlation between both measurement parameters. Amplitude and peak time of the photopic negative response (PhNR) and thickness of the parafoveal ganglion cell layer (GCL) were decreased in patients with schizophrenia compared to HC. Our results show both structural and functional retinal differences between patients with paranoid schizophrenia and HC. We therefore recommend the comprehensive assessment of the visual system of patients with schizophrenia, especially to further investigate the effect of antipsychotic medication, the duration of illness, or other factors such as inflammatory or neurodegenerative processes. Moreover, longitudinal studies are required to investigate whether the functional alterations precede the structural changes.
Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals with pharmacological significance
Authors: Greco Laura A. , Reay William R. , Dayas Christopher V. , Cairns Murray J. 
Published: September 2022

AbstractAlmost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.368, SE = 0.076,P = 1.61 × 10−6), cannabis use disorder (rg = 0.309, SE = 0.033,P = 1.97 × 10−20) and nicotine (rg = 0.117, SE = 0.043,P = 7.0 × 10−3), as well as drinks per week (rg = 0.087, SE = 0.021,P = 6.36 × 10−5), cigarettes per day (rg = 0.11, SE = 0.024,P = 4.93 × 10−6) and life-time cannabis use (rg = 0.234, SE = 0.029,P = 3.74 × 10−15). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22,P = 1.6 × 10−3). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders (SUDs), we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. The results from this study further supports the existence of underlying shared biology that drives the overlap in substance dependence in schizophrenia, including specific biological systems related to metabolism and neuronal function.
Accumulation of mutations in antibody and CD8 T cell epitopes in a B cell depleted lymphoma patient with chronic SARS-CoV-2 infection
Authors: Khatamzas Elham , Antwerpen Markus H. , Rehn Alexandra , Graf Alexander , Hellmuth Johannes Christian , Hollaus Alexandra , Mohr Anne-Wiebe , Gaitzsch Erik , Weiglein Tobias , Georgi Enrico , Scherer Clemens , Stecher Stephanie-Susanne , Gruetzner Stefanie , Blum Helmut , Krebs Stefan , Reischer Anna , Leutbecher Alexandra , Subklewe Marion , Dick Andrea , Zange Sabine , Girl Philipp , Müller Katharina , Weigert Oliver , Hopfner Karl-Peter , Stemmler Hans-Joachim , von Bergwelt-Baildon Michael , Keppler Oliver T. , Wölfel Roman , Muenchhoff Maximilian , Moosmann Andreas 
Published: September 2022

AbstractAntibodies against the spike protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can drive adaptive evolution in immunocompromised patients with chronic infection. Here we longitudinally analyze SARS-CoV-2 sequences in a B cell-depleted, lymphoma patient with chronic, ultimately fatal infection, and identify three mutations in the spike protein that dampen convalescent plasma-mediated neutralization of SARS-CoV-2. Additionally, four mutations emerge in non-spike regions encoding three CD8 T cell epitopes, including one nucleoprotein epitope affected by two mutations. Recognition of each mutant peptide by CD8 T cells from convalescent donors is reduced compared to its ancestral peptide, with additive effects resulting from double mutations. Querying public SARS-CoV-2 sequences shows that these mutations have independently emerged as homoplasies in circulating lineages. Our data thus suggest that potential impacts of CD8 T cells on SARS-CoV-2 mutations, at least in those with humoral immunodeficiency, warrant further investigation to inform on vaccine design.
Using multiple sampling strategies to estimate SARS-CoV-2 epidemiological parameters from genomic sequencing data
Authors: Inward Rhys P. D. , Parag Kris V. , Faria Nuno R. 
Published: September 2022

AbstractThe choice of viral sequences used in genetic and epidemiological analysis is important as it can induce biases that detract from the value of these rich datasets. This raises questions about how a set of sequences should be chosen for analysis. We provide insights on these largely understudied problems using SARS-CoV-2 genomic sequences from Hong Kong, China, and the Amazonas State, Brazil. We consider multiple sampling schemes which were used to estimate Rt and rt as well as related R0 and date of origin parameters. We find that both Rt and rt are sensitive to changes in sampling whilst R0 and the date of origin are relatively robust. Moreover, we find that analysis using unsampled datasets result in the most biased Rt and rt estimates for both our Hong Kong and Amazonas case studies. We highlight that sampling strategy choices may be an influential yet neglected component of sequencing analysis pipelines.
Hardware implementation of Bayesian network based on two-dimensional memtransistors
Authors: Zheng Yikai , Ravichandran Harikrishnan , Schranghamer Thomas F. , Trainor Nicholas , Redwing Joan M. , Das Saptarshi 
Published: September 2022

AbstractBayesian networks (BNs) find widespread application in many real-world probabilistic problems including diagnostics, forecasting, computer vision, etc. The basic computing primitive for BNs is a stochastic bit (s-bit) generator that can control the probability of obtaining ‘1’ in a binary bit-stream. While silicon-based complementary metal-oxide-semiconductor (CMOS) technology can be used for hardware implementation of BNs, the lack of inherent stochasticity makes it area and energy inefficient. On the other hand, memristors and spintronic devices offer inherent stochasticity but lack computing ability beyond simple vector matrix multiplication due to their two-terminal nature and rely on extensive CMOS peripherals for BN implementation, which limits area and energy efficiency. Here, we circumvent these challenges by introducing a hardware platform based on 2D memtransistors. First, we experimentally demonstrate a low-power and compact s-bit generator circuit that exploits cycle-to-cycle fluctuation in the post-programmed conductance state of 2D memtransistors. Next, the s-bit generators are monolithically integrated with 2D memtransistor-based logic gates to implement BNs. Our findings highlight the potential for 2D memtransistor-based integrated circuits for non-von Neumann computing applications.
Activation of stably silenced genes by recruitment of a synthetic de-methylating module
Authors: Chan Wing Fuk , Coughlan Hannah D. , Chen Yunshun , Keenan Christine R. , Smyth Gordon K. , Perkins Andrew C. , Johanson Timothy M. , Allan Rhys S. 
Published: September 2022

AbstractStably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show that TETact demethylation-coupled activation is able to induce transcription of suppressed genes, both individually and simultaneously in cells, and has utility across a number of cell types. Furthermore, we show that TETact can effectively reactivate embryonic haemoglobin genes in non-erythroid cells. We anticipate that TETact will expand the existing CRISPR toolbox and be valuable for functional studies, genetic screens and potential therapeutics.
A fungal tolerance trait and selective inhibitors proffer HMG-CoA reductase as a herbicide mode-of-action
Authors: Haywood Joel , Breese Karen J. , Zhang Jingjing , Waters Mark T. , Bond Charles S. , Stubbs Keith A. , Mylne Joshua S. 
Published: September 2022

AbstractDecades of intense herbicide use has led to resistance in weeds. Without innovative weed management practices and new herbicidal modes of action, the unabated rise of herbicide resistance will undoubtedly place further stress upon food security. HMGR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is the rate limiting enzyme of the eukaryotic mevalonate pathway successfully targeted by statins to treat hypercholesterolemia in humans. As HMGR inhibitors have been shown to be herbicidal, HMGR could represent a mode of action target for the development of herbicides. Here, we present the crystal structure of a HMGR fromArabidopsis thaliana(AtHMG1) which exhibits a wider active site than previously determined structures from different species. This plant conserved feature enables the rational design of specific HMGR inhibitors and we develop a tolerance trait through sequence analysis of fungal gene clusters. These results suggest HMGR to be a viable herbicide target modifiable to provide a tolerance trait.
Noise-resilient and high-speed deep learning with coherent silicon photonics
Authors: Mourgias-Alexandris G. , Moralis-Pegios M. , Tsakyridis A. , Simos S. , Dabos G. , Totovic A. , Passalis N. , Kirtas M. , Rutirawut T. , Gardes F. Y. , Tefas A. , Pleros N. 
Published: September 2022

AbstractThe explosive growth of deep learning applications has triggered a new era in computing hardware, targeting the efficient deployment of multiply-and-accumulate operations. In this realm, integrated photonics have come to the foreground as a promising energy efficient deep learning technology platform for enabling ultra-high compute rates. However, despite integrated photonic neural network layouts have already penetrated successfully the deep learning era, their compute rate and noise-related characteristics are still far beyond their promise for high-speed photonic engines. Herein, we demonstrate experimentally a noise-resilient deep learning coherent photonic neural network layout that operates at 10GMAC/sec/axon compute rates and follows a noise-resilient training model. The coherent photonic neural network has been fabricated as a silicon photonic chip and its MNIST classification performance was experimentally evaluated to support accuracy values of >99% and >98% at 5 and 10GMAC/sec/axon, respectively, offering 6× higher on-chip compute rates and >7% accuracy improvement over state-of-the-art coherent implementations.
Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism
Authors: Diot Cédric , García-González Aurian P. , Vieira Andre F. , Walker Melissa , Honeywell Megan , Doyle Hailey , Ponomarova Olga , Rivera Yomari , Na Huimin , Zhang Hefei , Lee Michael , Olsen Carissa P. , Walhout Albertha J. M. 
Published: September 2022

AbstractTamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.
Cytoplasmic organization promotes protein diffusion in Xenopus extracts
Authors: Huang William Y. C. , Cheng Xianrui , Ferrell James E. 
Published: September 2022

AbstractThe cytoplasm is highly organized. However, the extent to which this organization influences the dynamics of cytoplasmic proteins is not well understood. Here, we use Xenopus laevis egg extracts as a model system to study diffusion dynamics in organized versus disorganized cytoplasm. Such extracts are initially homogenized and disorganized, and self-organize into cell-like units over the course of tens of minutes. Using fluorescence correlation spectroscopy, we observe that as the cytoplasm organizes, protein diffusion speeds up by about a factor of two over a length scale of a few hundred nanometers, eventually approaching the diffusion time measured in organelle-depleted cytosol. Even though the ordered cytoplasm contained organelles and cytoskeletal elements that might interfere with diffusion, the convergence of protein diffusion in the cytoplasm toward that in organelle-depleted cytosol suggests that subcellular organization maximizes protein diffusivity. The effect of organization on diffusion varies with molecular size, with the effects being largest for protein-sized molecules, and with the time scale of the measurement. These results show that cytoplasmic organization promotes the efficient diffusion of protein molecules in a densely packed environment.
Tunable two-dimensional superconductivity and spin-orbit coupling at the EuO/KTaO3(110) interface
Authors: Hua Xiangyu , Meng Fanbao , Huang Zongyao , Li Zhaohang , Wang Shuai , Ge Binghui , Xiang Ziji , Chen Xianhui 
Published: September 2022

AbstractUnconventional quantum states, most notably the two-dimensional (2D) superconductivity, have been realized at the interfaces of oxide heterostructures where they can be effectively tuned by the gate voltage (VG). Here we report that the interface between high-quality EuO (111) thin film and KTaO3 (KTO) (110) substrate shows superconductivity with onset transition temperature $$T_{{{\mathrm{c}}}}^{{{{\mathrm{onset}}}}}$$

T

c

onset

= 1.35 K. The 2D nature of superconductivity is verified by the large anisotropy of the upper critical field and the characteristics of a Berezinskii–Kosterlitz-Thouless transition. By applying VG, $$T_{{{\mathrm{c}}}}^{{{{\mathrm{onset}}}}}$$

T

c

onset

can be tuned from ~1 to 1.7 K; such an enhancement can be possibly associated with a boosted spin-orbit energy $$\varepsilon _{{{{\mathrm{so}}}}} = \hbar /\tau _{{{{\mathrm{so}}}}}$$

ε

so

=
ħ
/

τ

so

, where τso is the spin-orbit relaxation time. Further analysis of τso based on the upper critical field (Hc2) and magnetoconductance reveals complex nature of spin-orbit coupling (SOC) at the EuO/KTO(110) interface with different mechanisms dominating the influence of SOC effects on the superconductivity and the magnetotransport in the normal state. Our results demonstrate that the SOC should be considered an important factor in determining the 2D superconductivity at oxide interfaces.
Inactivated rabies-vectored SARS-CoV-2 vaccine provides long-term immune response unaffected by vector immunity
Authors: Yankowski Catherine , Wirblich Christoph , Kurup Drishya , Schnell Matthias J. 
Published: September 2022

AbstractThe objective of this study is to further analyze recombinant rabies virus-vectored SARS-CoV-2 vaccine, CORAVAX, as an effective COVID-19 vaccine strategy. CORAVAX has proven immunogenic and protective against SARS-CoV-2 in animal models. Here, we have screened adjuvants for the highest quality antibody titers, negated the concern of pre-existing rabies-vector immunity, and established its potential as a long-term COVID-19 vaccine. We have tested toll-like receptor 4 (TLR4) agonists, inflammasome activators, and alum adjuvants in CORAVAX and found TLR4-activating MPLA-AddaVax to have the greatest potential. We followed the humoral immune response to CORAVAX in mice with pre-existing rabies virus immunity and saw no significant differences compared to naive mice. We then followed the immune response to CORAVAX over several months and 1-year post-immunization. Mice maintained high antigen-specific serum antibody titers as well as long-lived antibody-secreting cells in the spleen and bone marrow. We believe this rabies-vector strategy combats the problem of waning immunity of other COVID-19 vaccines. These results together support CORAVAX’s potential during the ongoing COVID-19 pandemic.