bluuebunny/crossref_metadata_2025 huggingface dataset:
Varentropy of doubly truncated random variable
Authors: Sharma Akash , Kundu Chanchal
Published: July 2022

Recently, there is a growing interest to study the variability of uncertainty measure in information theory. For the sake of analyzing such interest, varentropy has been introduced and examined for one-sided truncated random variables. As the interval entropy measure is instrumental in summarizing various system and its components properties when it fails between two time points, exploring variability of such measure pronounces the extracted information. In this article, we introduce the concept of varentropy for doubly truncated random variable. A detailed study of theoretical results taking into account transformations, monotonicity and other conditions is proposed. A simulation study has been carried out to investigate the behavior of varentropy in shrinking interval for simulated and real-life data sets. Furthermore, applications related to the choice of most acceptable system and the first-passage times of an Ornstein–Uhlenbeck jump-diffusion process are illustrated.
Transmission of SARS-CoV-2 among children and staff in German daycare centres
Authors: Loss Julika , Wurm Juliane , Varnaccia Gianni , Schienkiewitz Anja , Iwanowski Helena , Loer Anne-Kathrin Mareike , Allen Jennifer , Wess Barbara , Schaffrath Rosario Angelika , Damerow Stefan , Kuttig Tim , Perlitz Hanna , Hornbacher Anselm , Finkel Bianca , Krause Carolin , Wormsbächer Jan , Sandoni Anna , Kubisch Ulrike , Eggers Kiara , Nitsche Andreas , Radonic Aleksandar , Trappe Kathrin , Drechsel Oliver , Klaper Kathleen , Franke Andrea , Hüther Antje , Buchholz Udo , Haas Walter , Wieler Lothar H. , Jordan Susanne
Published: July 2022

In daycare centres, the close contact of children with other children and employees favours the transmission of infections. The majority of children <6 years attend daycare programmes in Germany, but the role of daycare centres in the SARS-CoV-2 pandemic is unclear. We investigated the transmission risk in daycare centres and the spread of SARS-CoV-2 to associated households. 30 daycare groups with at least one recent laboratory-confirmed SARS-CoV-2 case were enrolled in the study (10/2020–06/2021). Close contact persons within daycare and households were examined over a 12-day period (repeated SARS-CoV-2 PCR tests, genetic sequencing of viruses, symptom diary). Households were interviewed to gain comprehensive information on each outbreak. We determined primary cases for all daycare groups. The number of secondary cases varied considerably between daycare groups. The pooled secondary attack rate (SAR) across all 30 daycare centres was 9.6%. The SAR tended to be higher when the Alpha variant was detected (15.9% vs. 5.1% with evidence of wild type). The household SAR was 53.3%. Exposed daycare children were less likely to get infected with SARS-CoV-2 than employees (7.7% vs. 15.5%). Containment measures in daycare programmes are critical to reduce SARS-CoV-2 transmission, especially to avoid spread to associated households.
A puzzling CHD: a late diagnosis of left atrial isomerism
Authors: Martins de Carvalho Miguel , Vasconcelos Mariana , Carvalho André , Cruz Cristina , Macedo Filipe
Published: July 2022

We present a case of a 41-year-old patient with an unknown complex cardiac anatomy, who was previously submitted to two cardiac surgeries. Using multimodality imaging, a retrospective diagnosis was established, revealing a heterotaxy syndrome (left isomerism).
Self-replicating probes are imminent – implications for SETI
Authors: Ellery Alex
Published: July 2022

In the early 1980s, the Sagan-Tipler debate raged regarding the interpretation of the Fermi paradox but no clear winner emerged. Sagan favoured the existence of ETI on the basis of the Copernican principle and Tipler favoured the non-existence of ETI on the basis of the Occam's razor principle. Tipler's stance was an expansion of the similar but earlier Hart declaration. However, crucial to the Tipler argument was the role played by self-replicating interstellar robot probes. Any technologically capable species will develop self-replication technology as the most economical means of exploring space and the Galaxy as a whole with minimal investment. There is no evidence of such probes in our solar system including the asteroid belt, ergo, ETI do not exist. This is a powerful and cogent argument. Counter-arguments have been weak including Sagan's sociological explanations. We present a Copernican argument that ETI do not exist – humans are developing self-replication technology today. We are developing the ability to 3D print entire robotic machines from extraterrestrial resources including electric motors and electronics as part of a general in-situ resource utilization (ISRU) capability. We have 3D-printed electric motors which can be potentially leveraged from extraterrestrial material that should be available in every star system. From a similar range of materials, we have identified a means to 3D print neural network circuitry. From our industrial ecology, self-replicating machines and indeed universal constructors are feasible. We describe in some detail how a self-replicating interstellar spacecraft may be constricted from asteroidal resources. We describe technological signatures of the processing of asteroidal material (which is expected to be common to most star systems), and the excess production of certain types of clay and other detritus materials. Self-replication technology is under development and imminent – if humans are pursuing self-replication technology, then by the Copernican principle, so would any technologically savvy species elsewhere. There is no evidence that they have.
Fostering the “Art of Forceful Speech”: Music in the Century Club of California, 1888–1920
Authors: Miller Leta E.
Published: July 2022

The Century Club of California (CCC), founded in 1888, was San Francisco's most prestigious women's club in the early twentieth century. The club's aim was to promote intellectual growth and amplify female voices to help women enter the public domain with confidence. Weekly presentations featured renowned public figures and women who had achieved success in traditionally male fields. Rather than raising money for benevolent organizations, the CCC aimed to effect foundational social changes by informing women of the latest developments in all fields, thus empowering them to engage in political and social activism. Music played a critical role in furthering this ambitious goal; it had its own programming committee, which operated on an equal basis with those devoted to art, science, education, and current events. This article, based on the club's extensive collection of unpublished materials, looks at the CCC's first three decades, when the club promoted “the art of forceful speech” through modeling of successful women, providing opportunities for members to project their musical voices, elucidating new musical research, and supporting organizations such as the all-female Saturday Morning Orchestra. The CCC's activities underscore the significant role female musicians played in advancing the New Woman movement of the time.
Associations of maternal glucose markers in pregnancy with cord blood glucocorticoids and child hair cortisol levels
Authors: Cohen Nathan , Faleschini Sabrina , Rifas-Shiman Sheryl L. , Bouchard Luigi , Doyon Myriam , Simard Olivier , Arguin Melina , Fink Guy , Alman Amy C. , Kirby Russell , Chen Henian , Wilson Ronee , Fryer Kimberly , Perron Patrice , Oken Emily , Hivert Marie-France
Published: July 2022

Exposure to maternal hyperglycemia in utero has been associated with adverse metabolic outcomes in offspring. However, few studies have investigated the relationship between maternal hyperglycemia and offspring cortisol levels. We assessed associations of gestational diabetes mellitus (GDM) with cortisol biomarkers in two longitudinal prebirth cohorts: Project Viva included 928 mother–child pairs and Gen3G included 313 mother–child pairs. In Project Viva, GDM was diagnosed in N = 48 (5.2%) women using a two-step procedure (50 g glucose challenge test, if abnormal followed by 100 g oral glucose tolerance test [OGTT]), and in N = 29 (9.3%) women participating in Gen3G using one-step 75 g OGTT. In Project Viva, we measured cord blood glucocorticoids and child hair cortisol levels during mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In Gen3G, we measured hair cortisol at 5.4 (0.3) years. We used multivariable linear regression to examine associations of GDM with offspring cortisol, adjusting for child age and sex, maternal prepregnancy body mass index, education, and socioeconomic status. We additionally adjusted for child race/ethnicity in the cord blood analyses. In both Project Viva and Gen3G, we observed null associations of GDM and maternal glucose markers in pregnancy with cortisol biomarkers in cord blood at birth (β = 16.6 nmol/L, 95% CI −60.7, 94.0 in Project Viva) and in hair samples during childhood (β = −0.56 pg/mg, 95% CI −1.16, 0.04 in Project Viva; β = 0.09 pg/mg, 95% CI −0.38, 0.57 in Gen3G). Our findings do not support the hypothesis that maternal hyperglycemia is related to hypothalamic–pituitary–adrenal axis activity.
VA-ECMO and thrombus aspiration in a pulmonary embolism patient with	cardiac arrest and contraindications to thrombolytic therapy
Authors: Reisinger Alexander C. , Fandler-Höfler Simon , Kreuzer Philipp , Toth-Gayor Gabor , Schmidt Albrecht , Gary Thomas , Rief Peter , Eller Philipp , Brodmann Marianne
Published: July 2022

Summary: A 57-year-old male patient with a history of proximal deep vein thrombosis on vitamin K antagonist therapy, suffered a recent hypertensive intracranial hemorrhage without significant neurological deficit. Three weeks later he presented with bilateral central pulmonary embolism. He had witnessed cardiac arrest and was put on veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Endovascular thrombectomy with an Aspirex device led to a significant improvement of hemodynamics. VA-ECMO was terminated after one day, an IVC filter was inserted, and he was discharged from ICU after 15 days. In conclusion, VA-ECMO and endovascular therapy are rescue strategies in patients with contraindications for thrombolysis.
Impact of Vertical Mixing on Summertime Net Community Production in Canadian Arctic and Subarctic Waters: Insights From In Situ Measurements and Numerical Simulations
Authors: Izett Robert W. , Castro de la Guardia Laura , Chanona Melanie , Myers Paul G. , Waterman Stephanie , Tortell Philippe D.
Published: July 2022

We present ΔO2/Ar‐based estimates of mixed layer net community production (NCP) from three summer cruises in the North American Arctic and Subarctic oceans. Coupling shipboard underway and discrete observations with output from an ocean circulation model, we correct the NCP estimates for vertical mixing fluxes impacting the surface O2 budget. Large positive mixing fluxes, exceeding 100 mmol O2 m−2 d−1, were derived in regions of strong wind‐driven mixing, such as the Labrador Sea (LS), and in the physically‐dynamic Canadian Arctic Archipelago. In contrast, flux corrections were small (<10 mmol O2 m−2 d−1, on average) in the density‐stratified Baffin Bay, where mixing was low, and parts of the well‐mixed Hudson Strait (HS), where vertical O2 gradients were weak. The distribution of corrected NCP was highly heterogenous across the study region, reflecting varying contributions of nutrient supply, freshwater input and sea ice dynamics. Elevated NCP was apparent in the LS, HS, and nearshore regions influenced by glacial meltwater and recent ice retreat. Low NCP and localized net heterotrophy occurred in Baffin Bay, and near strong freshwater and organic matter sources in Hudson Bay and the Queen Maud Gulf. A multiple linear regression model developed using available oceanographic data explained ∼58% of the observed NCP variability. Our work demonstrates the spatially explicit influence of vertical mixing on ΔO2/Ar‐based NCP calculations across varied hydrographic conditions, and presents a novel approach to account for this process. This study contributes new knowledge of biological productivity distributions in under‐sampled, rapidly changing, high‐latitude waters.
On the Considerations of Using Near Real Time Data for Space Weather Hazard Forecasting
Authors: Smith A. W. , Forsyth C. , Rae I. J. , Garton T. M. , Jackman C. M. , Bakrania M. , Shore R. M. , Richardson G. S. , Beggan C. D. , Heyns M. J. , Eastwood J. P. , Thomson A. W. P. , Johnson J. M.
Published: July 2022

Space weather represents a severe threat to ground‐based infrastructure, satellites and communications. Accurately forecasting when such threats are likely (e.g., when we may see large induced currents) will help to mitigate the societal and financial costs. In recent years computational models have been created that can forecast hazardous intervals, however they generally use post‐processed “science” solar wind data from upstream of the Earth. In this work we investigate the quality and continuity of the data that are available in Near‐Real‐Time (NRT) from the Advanced Composition Explorer and Deep Space Climate Observatory (DSCOVR) spacecraft. In general, the data available in NRT corresponds well with post‐processed data, however there are three main areas of concern: greater short‐term variability in the NRT data, occasional anomalous values and frequent data gaps. Some space weather models are able to compensate for these issues if they are also present in the data used to fit (or train) the model, while others will require extra checks to be implemented in order to produce high quality forecasts. We find that the DSCOVR NRT data are generally more continuous, though they have been available for small fraction of a solar cycle and therefore DSCOVR has experienced a limited range of solar wind conditions. We find that short gaps are the most common, and are most frequently found in the plasma data. To maximize forecast availability we suggest the implementation of limited interpolation if possible, for example, for gaps of 5 min or less, which could increase the fraction of valid input data considerably.
Coherent modulation of chiral nonlinear optics with crystal symmetry
Authors: Zhang Yi , Bai Xueyin , Arias Muñoz Juan , Dai Yunyun , Das Susobhan , Wang Yadong , Sun Zhipei
Published: July 2022

Light modulation is of paramount importance for photonics and optoelectronics. Here we report all-optical coherent modulation of third-harmonic generation (THG) with chiral light via the symmetry enabled polarization selectivity. The concept is experimentally validated in monolayer materials (MoS2) with modulation depth approaching ~100%, ultra-fast modulation speed (<~130 fs), and wavelength-independence features. Moreover, the power and polarization of the incident optical beams can be used to tune the output chirality and modulation performance. Major performance of our demonstration reaches the fundamental limits of optical modulation: near-unity modulation depth, instantaneous speed (ultra-fast coherent interaction), compact footprint (atomic thickness), and unlimited operation bandwidth, which hold an ideal optical modulation solution for emerging and future nonlinear optical applications (e.g., interconnection, imaging, computing, and quantum technologies).
Moisture-resistant, stretchable NOx gas sensors based on laser-induced graphene for environmental monitoring and breath analysis
Authors: Yang Li , Zheng Guanghao , Cao Yaoqian , Meng Chuizhou , Li Yuhang , Ji Huadong , Chen Xue , Niu Guangyu , Yan Jiayi , Xue Ye , Cheng Huanyu
Published: July 2022

The accurate, continuous analysis of healthcare-relevant gases such as nitrogen oxides (NOx) in a humid environment remains elusive for low-cost, stretchable gas sensing devices. This study presents the design and demonstration of a moisture-resistant, stretchable NOx gas sensor based on laser-induced graphene (LIG). Sandwiched between a soft elastomeric substrate and a moisture-resistant semipermeable encapsulant, the LIG sensing and electrode layer is first optimized by tuning laser processing parameters such as power, image density, and defocus distance. The gas sensor, using a needlelike LIG prepared with optimal laser processing parameters, exhibits a large response of 4.18‰ ppm−1 to NO and 6.66‰ ppm−1 to NO2, an ultralow detection limit of 8.3 ppb to NO and 4.0 ppb to NO2, fast response/recovery, and excellent selectivity. The design of a stretchable serpentine structure in the LIG electrode and strain isolation from the stiff island allows the gas sensor to be stretched by 30%. Combined with a moisture-resistant property against a relative humidity of 90%, the reported gas sensor has further been demonstrated to monitor the personal local environment during different times of the day and analyze human breath samples to classify patients with respiratory diseases from healthy volunteers. Moisture-resistant, stretchable NOx gas sensors can expand the capability of wearable devices to detect biomarkers from humans and exposed environments for early disease diagnostics.
High levels of NRF2 sensitize temozolomide-resistant glioblastoma cells to ferroptosis via ABCC1/MRP1 upregulation
Authors: de Souza I. , Monteiro L. K. S. , Guedes C. B. , Silva M. M. , Andrade-Tomaz M. , Contieri B. , Latancia M. T. , Mendes D. , Porchia B. F. M. M. , Lazarini M. , Gomes L. R. , Rocha C. R. R.
Published: July 2022

Glioblastoma patients have a poor prognosis mainly due to temozolomide (TMZ) resistance. NRF2 is an important transcript factor involved in chemotherapy resistance due to its protective role in the transcription of genes involved in cellular detoxification and prevention of cell death processes, such as ferroptosis. However, the relation between NRF2 and iron-dependent cell death in glioma is still poorly understood. Therefore, in this study, we analyzed the role of NRF2 in ferroptosis modulation in glioblastoma cells. Two human glioblastoma cell lines (U251MG and T98G) were examined after treatment with TMZ, ferroptosis inducers (Erastin, RSL3), and ferroptosis inhibitor (Ferrostatin-1). Our results demonstrated that T98G was more resistant to chemotherapy compared to U251MG and showed elevated levels of NRF2 expression. Interestingly, T98G revealed higher sensitivity to ferroptosis, and significant GSH depletion upon system xc− blockage. NRF2 silencing in T98G cells (T98G-shNRF2) significantly reduced the viability upon TMZ treatment. On the other hand, T98G-shNRF2 was resistant to ferroptosis and reverted intracellular GSH levels, indicating that NRF2 plays a key role in ferroptosis induction through GSH modulation. Moreover, silencing of ABCC1, a well-known NRF2 target that diminishes GSH levels, has demonstrated a similar collateral sensitivity. T98G-siABCC1 cells were more sensitive to TMZ and resistant to Erastin. Furthermore, we found that NRF2 positively correlates with ABCC1 expression in tumor tissues of glioma patients, which can be associated with tumor aggressiveness, drug resistance, and poor overall survival. Altogether, our data indicate that high levels of NRF2 result in collateral sensitivity on glioblastoma via the expression of its pro-ferroptotic target ABCC1, which contributes to GSH depletion when the system xc− is blocked by Erastin. Thus, ferroptosis induction could be an important therapeutic strategy to reverse drug resistance in gliomas with high NRF2 and ABCC1 expression.
Temperature elevations can induce switches to homoclinic action potentials that alter neural encoding and synchronization
Authors: Hesse Janina , Schleimer Jan-Hendrik , Maier Nikolaus , Schmitz Dietmar , Schreiber Susanne
Published: July 2022

Almost seventy years after the discovery of the mechanisms of action potential generation, some aspects of their computational consequences are still not fully understood. Based on mathematical modeling, we here explore a type of action potential dynamics – arising from a saddle-node homoclinic orbit bifurcation - that so far has received little attention. We show that this type of dynamics is to be expected by specific changes in common physiological parameters, like an elevation of temperature. Moreover, we demonstrate that it favours synchronization patterns in networks – a feature that becomes particularly prominent when system parameters change such that homoclinic spiking is induced. Supported by in-vitro hallmarks for homoclinic spikes in the rodent brain, we hypothesize that the prevalence of homoclinic spikes in the brain may be underestimated and provide a missing link between the impact of biophysical parameters on abrupt transitions between asynchronous and synchronous states of electrical activity in the brain.
Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
Authors: Schneider Kai Markus , Mohs Antje , Gui Wenfang , Galvez Eric J. C. , Candels Lena Susanna , Hoenicke Lisa , Muthukumarasamy Uthayakumar , Holland Christian H. , Elfers Carsten , Kilic Konrad , Schneider Carolin Victoria , Schierwagen Robert , Strnad Pavel , Wirtz Theresa H. , Marschall Hanns-Ulrich , Latz Eicke , Lelouvier Benjamin , Saez-Rodriguez Julio , de Vos Willem , Strowig Till , Trebicka Jonel , Trautwein Christian
Published: July 2022

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced HCC are limited. Here, we observe that intestinal dysbiosis affects antitumor immune surveillance and drives liver disease progression towards cancer. Dysbiotic microbiota, as seen in Nlrp6−/− mice, induces a Toll-like receptor 4 dependent expansion of hepatic monocytic myeloid-derived suppressor cells (mMDSC) and suppression of T-cell abundance. This phenotype is transmissible via fecal microbiota transfer and reversible upon antibiotic treatment, pointing to the high plasticity of the tumor microenvironment. While loss of Akkermansia muciniphila correlates with mMDSC abundance, its reintroduction restores intestinal barrier function and strongly reduces liver inflammation and fibrosis. Cirrhosis patients display increased bacterial abundance in hepatic tissue, which induces pronounced transcriptional changes, including activation of fibro-inflammatory pathways as well as circuits mediating cancer immunosuppression. This study demonstrates that gut microbiota closely shapes the hepatic inflammatory microenvironment opening approaches for cancer prevention and therapy.
Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Authors: Robinson Philip S. , Thomas Laura E. , Abascal Federico , Jung Hyunchul , Harvey Luke M. R. , West Hannah D. , Olafsson Sigurgeir , Lee Bernard C. H. , Coorens Tim H. H. , Lee-Six Henry , Butlin Laura , Lander Nicola , Truscott Rebekah , Sanders Mathijs A. , Lensing Stefanie V. , Buczacki Simon J. A. , ten Hoopen Rogier , Coleman Nicholas , Brunton-Sim Roxanne , Rushbrook Simon , Saeb-Parsy Kourosh , Lalloo Fiona , Campbell Peter J. , Martincorena Iñigo , Sampson Julian R. , Stratton Michael R.
Published: July 2022

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.
The effect of COVID certificates on vaccine uptake, health outcomes, and the economy
Authors: Oliu-Barton Miquel , Pradelski Bary S. R. , Woloszko Nicolas , Guetta-Jeanrenaud Lionel , Aghion Philippe , Artus Patrick , Fontanet Arnaud , Martin Philippe , Wolff Guntram B.
Published: July 2022

In the COVID-19 pandemic many countries required COVID certificates, proving vaccination, recovery, or a recent negative test, to access public and private venues. We estimate their effect on vaccine uptake for France, Germany, and Italy using counterfactuals constructed via innovation diffusion theory. The announcement of COVID certificates during summer 2021 were associated – although causality cannot be directly inferred – with increased vaccine uptake in France of 13.0 (95% CI 9.7–14.9) percentage points (p.p.) of the total population until the end of the year, in Germany 6.2 (2.6–6.9) p.p., and in Italy 9.7 (5.4–12.3) p.p. Based on these estimates, an additional 3979 (3453–4298) deaths in France, 1133 (−312–1358) in Germany, and 1331 (502–1794) in Italy were averted; and gross domestic product (GDP) losses of €6.0 (5.9–6.1) billion in France, €1.4 (1.3–1.5) billion in Germany, and €2.1 (2.0–2.2) billion in Italy were prevented. Notably, in France, the application of COVID certificates averted high intensive care unit occupancy levels where prior lockdowns were instated.
Expanding chemical space by para-C−H arylation of arenes
Authors: Maiti Sudip , Li Yingzi , Sasmal Sheuli , Guin Srimanta , Bhattacharya Trisha , Lahiri Goutam Kumar , Paton Robert S. , Maiti Debabrata
Published: July 2022

Biaryl scaffolds are privileged templates used in the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets. Biaryls are found in the structures of therapeutics, including antibiotics, anti-inflammatory, analgesic, neurological and antihypertensive drugs. However, existing synthetic routes to biphenyls rely on traditional coupling approaches that require both arenes to be prefunctionalized with halides or pseudohalides with the desired regiochemistry. Therefore, the coupling of drug fragments may be challenging via conventional approaches. As an attractive alternative, directed C−H activation has the potential to be a versatile tool to form para-substituted biphenyl motifs selectively. However, existing C–H arylation protocols are not suitable for drug entities as they are hindered by catalyst deactivation by polar and delicate functionalities present alongside the instability of macrocyclic intermediates required for para-C−H activation. To address this challenge, we have developed a robust catalytic system that displays unique efficacy towards para-arylation of highly functionalized substrates such as drug entities, giving access to structurally diversified biaryl scaffolds. This diversification process provides access to an expanded chemical space for further exploration in drug discovery. Further, the applicability of the transformation is realized through the synthesis of drug molecules bearing a biphenyl fragment. Computational and experimental mechanistic studies further provide insight into the catalytic cycle operative in this versatile C−H arylation protocol.
PRMT5 activates AKT via methylation to promote tumor metastasis
Authors: Huang Lei , Zhang Xiao-Ou , Rozen Esteban J. , Sun Xiaomei , Sallis Benjamin , Verdejo-Torres Odette , Wigglesworth Kim , Moon Daniel , Huang Tingting , Cavaretta John P. , Wang Gang , Zhang Lei , Shohet Jason M. , Lee Mary M. , Wu Qiong
Published: July 2022

Protein arginine methyltransferase 5 (PRMT5) is the primary methyltransferase generating symmetric-dimethyl-arginine marks on histone and non-histone proteins. PRMT5 dysregulation is implicated in multiple oncogenic processes. Here, we report that PRMT5-mediated methylation of protein kinase B (AKT) is required for its subsequent phosphorylation at Thr308 and Ser473. Moreover, pharmacologic or genetic inhibition of PRMT5 abolishes AKT1 arginine 15 methylation, thereby preventing AKT1 translocation to the plasma membrane and subsequent recruitment of its upstream activating kinases PDK1 and mTOR2. We show that PRMT5/AKT signaling controls the expression of the epithelial-mesenchymal-transition transcription factors ZEB1, SNAIL, and TWIST1. PRMT5 inhibition significantly attenuates primary tumor growth and broadly blocks metastasis in multiple organs in xenograft tumor models of high-risk neuroblastoma. Collectively, our results suggest that PRMT5 inhibition augments anti-AKT or other downstream targeted therapeutics in high-risk metastatic cancers.
Optimal acceleration voltage for near-atomic resolution imaging of layer-stacked 2D polymer thin films
Authors: Liang Baokun , Zhang Yingying , Leist Christopher , Ou Zhaowei , Položij Miroslav , Wang Zhiyong , Mücke David , Dong Renhao , Zheng Zhikun , Heine Thomas , Feng Xinliang , Kaiser Ute , Qi Haoyuan
Published: July 2022

Despite superb instrumental resolution in modern transmission electron microscopes (TEM), high-resolution imaging of organic two-dimensional (2D) materials is a formidable task. Here, we present that the appropriate selection of the incident electron energy plays a crucial role in reducing the gap between achievable resolution in the image and the instrumental limit. Among a broad range of electron acceleration voltages (300 kV, 200 kV, 120 kV, and 80 kV) tested, we found that the highest resolution in the HRTEM image is achieved at 120 kV, which is 1.9 Å. In two imine-based 2D polymer thin films, unexpected molecular interstitial defects were unraveled. Their structural nature is identified with the aid of quantum mechanical calculations. Furthermore, the increased image resolution and enhanced image contrast at 120 kV enabled the detection of functional groups at the pore interfaces. The experimental setup has also been employed for an amorphous organic 2D material.
A third vaccination with a single T cell epitope confers protection in a murine model of SARS-CoV-2 infection
Authors: Pardieck Iris N. , van der Sluis Tetje C. , van der Gracht Esmé T. I. , Veerkamp Dominique M. B. , Behr Felix M. , van Duikeren Suzanne , Beyrend Guillaume , Rip Jasper , Nadafi Reza , Beyranvand Nejad Elham , Mülling Nils , Brasem Dena J. , Camps Marcel G. M. , Myeni Sebenzile K. , Bredenbeek Peter J. , Kikkert Marjolein , Kim Yeonsu , Cicin-Sain Luka , Abdelaal Tamim , van Gisbergen Klaas P. J. M. , Franken Kees L. M. C. , Drijfhout Jan Wouter , Melief Cornelis J. M. , Zondag Gerben C. M. , Ossendorp Ferry , Arens Ramon
Published: July 2022

Understanding the mechanisms and impact of booster vaccinations are essential in the design and delivery of vaccination programs. Here we show that a three dose regimen of a synthetic peptide vaccine elicits an accruing CD8+ T cell response against one SARS-CoV-2 Spike epitope. We see protection against lethal SARS-CoV-2 infection in the K18-hACE2 transgenic mouse model in the absence of neutralizing antibodies, but two dose approaches are insufficient to confer protection. The third vaccine dose of the single T cell epitope peptide results in superior generation of effector-memory T cells and tissue-resident memory T cells, and these tertiary vaccine-specific CD8+ T cells are characterized by enhanced polyfunctional cytokine production. Moreover, fate mapping shows that a substantial fraction of the tertiary CD8+ effector-memory T cells develop from re-migrated tissue-resident memory T cells. Thus, repeated booster vaccinations quantitatively and qualitatively improve the CD8+ T cell response leading to protection against otherwise lethal SARS-CoV-2 infection.
Diurnal modulation of subthalamic beta oscillatory power in Parkinson’s disease patients during deep brain stimulation
Authors: van Rheede Joram J. , Feldmann Lucia K. , Busch Johannes L. , Fleming John E. , Mathiopoulou Varvara , Denison Timothy , Sharott Andrew , Kühn Andrea A.
Published: July 2022

Beta-band activity in the subthalamic local field potential (LFP) is correlated with Parkinson’s disease (PD) symptom severity and is the therapeutic target of deep brain stimulation (DBS). While beta fluctuations in PD patients are well characterized on shorter timescales, it is not known how beta activity evolves around the diurnal cycle, outside a clinical setting. Here, we obtained chronic recordings (34 ± 13 days) of subthalamic beta power in PD patients implanted with the Percept DBS device during high-frequency DBS and analysed their diurnal properties as well as sensitivity to artifacts. Time of day explained 41 ± 9% of the variance in beta power (p < 0.001 in all patients), with increased beta during the day and reduced beta at night. Certain movements affected LFP quality, which may have contributed to diurnal patterns in some patients. Future DBS algorithms may benefit from taking such diurnal and artifactual fluctuations in beta power into account.
CovidPubGraph: A FAIR Knowledge Graph of COVID-19 Publications
Authors: Pestryakova Svetlana , Vollmers Daniel , Sherif Mohamed Ahmed , Heindorf Stefan , Saleem Muhammad , Moussallem Diego , Ngomo Axel-Cyrille Ngonga
Published: July 2022

The rapid generation of large amounts of information about the coronavirus SARS-CoV-2 and the disease COVID-19 makes it increasingly difficult to gain a comprehensive overview of current insights related to the disease. With this work, we aim to support the rapid access to a comprehensive data source on COVID-19 targeted especially at researchers. Our knowledge graph, CovidPubGraph, an RDF knowledge graph of scientific publications, abides by the Linked Data and FAIR principles. The base dataset for the extraction is CORD-19, a dataset of COVID-19-related publications, which is updated regularly. Consequently, CovidPubGraph is updated biweekly. Our generation pipeline applies named entity recognition, entity linking and link discovery approaches to the original data. The current version of CovidPubGraph contains 268,108,670 triples and is linked to 9 other datasets by over 1 million links. In our use case studies, we demonstrate the usefulness of our knowledge graph for different applications. CovidPubGraph is publicly available under the Creative Commons Attribution 4.0 International license.
Predicting the impacts of land management for sustainable development on depression risk in a Ugandan case study
Authors: Pienkowski Thomas , Keane Aidan , Kinyanda Eugene , Asiimwe Caroline , Milner-Gulland E. J.
Published: July 2022

Agricultural intensification and expanding protected areas are proposed sustainable development approaches. But, their consequences for mental health are poorly understood. This study aims to predict how forest conservation and contract farming may alter resource access and depression risk in rural Uganda. Residents (N = 695) in 11 communities in Masindi District were asked about their expectations under land management scenarios using scenario-based interviews, household characteristics and depression symptoms. Over 80% of respondents presented with a ‘business-as-usual forest access’ scenario expected reduced access to forest income and food over the next decade; this number climbed above 90% among ‘restricted forest access’ scenario respondents. Over 99% of those presented with two land access scenarios (‘business-as-usual land access’ and ‘sugarcane expansion land access’) expected wealthy households to gain land but poorer families to lose it, threatening to increase poverty and food insecurity among small-scale farmers. Bayesian structural equation modelling suggested that depression severity was positively associated with food insecurity (0.20, 95% CI = 0.12–0.28) and economic poverty (0.11, 95% CI 0.02–0.19). Decision-makers should evaluate the mental health impacts of conservation and agricultural approaches that restrict access to livelihood resources. Future research could explore opportunities to support mental health through sustainable use of nature.
A novel prognostic model for malignant patients with Gram-negative bacteremia based on real-world research
Authors: Ni Sujiao , Xu Pingyao , Zhang Kaijiong , Zou Haiming , Luo Huaichao , Liu Chang , Li Yuping , Li Yan , Wang Dongsheng , Zhang Renfei , Zu Ruiling
Published: July 2022

Gram-negative bacteremia (GNB) is a common complication in malignant patients. Identifying risk factors and developing a prognostic model for GNB might improve the survival rate. In this observational and real-world study, we retrospectively analyzed the risk factors and outcomes of GNB in malignant patients. Multivariable regression was used to identify risk factors for the incidence of GNB, while Cox regression analysis was performed to identify significant prognostic factors. A prognostic model was constructed based on Cox regression analysis and presented on a nomogram. ROC curves, calibration plots, and Kaplan–Meier analysis were used to estimate the model. It comprised 1004 malignant patients with Bloodstream infection (BSI) in the study cohort, 65.7% (N = 660) acquired GNB. Multivariate analysis showed gynecologic cancer, hepatobiliary cancer, and genitourinary cancer were independent risk factors related to the incidence of GNB. Cox regression analysis raised that shock, admission to ICU before infection, pulmonary infection, higher lymphocyte counts, and lower platelet counts were independent risk factors for overall survival (OS). The OS was significantly different between the two groups classified by optimal cut-off value (log-rank, p < 0.001). Above all, a nomogram was created based on the prognostic model, which was presented on a website freely. This real-world study was concentrated on the malignant patients with GNB and proved that shock, admission to ICU before infection, pulmonary infection, higher lymphocyte counts, and lower platelet counts were related to the death of these patients. And a prognostic model was constructed to estimate the risk score of mortality, further to reduce the risk of death.
CyberSco.Py an open-source software for event-based, conditional microscopy
Authors: Chiron Lionel , Le Bec Matthias , Cordier Céline , Pouzet Sylvain , Milunov Dimitrije , Banderas Alvaro , Di Meglio Jean-Marc , Sorre Benoit , Hersen Pascal
Published: July 2022

Timelapse fluorescence microscopy imaging is routinely used in quantitative cell biology. However, microscopes could become much more powerful investigation systems if they were endowed with simple unsupervised decision-making algorithms to transform them into fully responsive and automated measurement devices. Here, we report CyberSco.Py, Python software for advanced automated timelapse experiments. We provide proof-of-principle of a user-friendly framework that increases the tunability and flexibility when setting up and running fluorescence timelapse microscopy experiments. Importantly, CyberSco.Py combines real-time image analysis with automation capability, which allows users to create conditional, event-based experiments in which the imaging acquisition parameters and the status of various devices can be changed automatically based on the image analysis. We exemplify the relevance of CyberSco.Py to cell biology using several use case experiments with budding yeast. We anticipate that CyberSco.Py could be used to address the growing need for smart microscopy systems to implement more informative quantitative cell biology experiments.
Temporal quality degradation in AI models
Authors: Vela Daniel , Sharp Andrew , Zhang Richard , Nguyen Trang , Hoang An , Pianykh Oleg S.
Published: July 2022

As AI models continue to advance into many real-life applications, their ability to maintain reliable quality over time becomes increasingly important. The principal challenge in this task stems from the very nature of current machine learning models, dependent on the data as it was at the time of training. In this study, we present the first analysis of AI “aging”: the complex, multifaceted phenomenon of AI model quality degradation as more time passes since the last model training cycle. Using datasets from four different industries (healthcare operations, transportation, finance, and weather) and four standard machine learning models, we identify and describe the main temporal degradation patterns. We also demonstrate the principal differences between temporal model degradation and related concepts that have been explored previously, such as data concept drift and continuous learning. Finally, we indicate potential causes of temporal degradation, and suggest approaches to detecting aging and reducing its impact.
Inactivity and Ca2+ signaling regulate synaptic compensation in motoneurons following hibernation in American bullfrogs
Authors: Zubov Tanya , do Amaral-Silva Lara , Santin Joseph M.
Published: July 2022

Neural networks tune synaptic and cellular properties to produce stable activity. One form of homeostatic regulation involves scaling the strength of synapses up or down in a global and multiplicative manner to oppose activity disturbances. In American bullfrogs, excitatory synapses scale up to regulate breathing motor function after inactivity in hibernation, connecting homeostatic compensation to motor behavior. In traditional models of homeostatic synaptic plasticity, inactivity is thought to increase synaptic strength via mechanisms that involve reduced Ca2+ influx through voltage-gated channels. Therefore, we tested whether pharmacological inactivity and inhibition of voltage-gated Ca2+ channels are sufficient to drive synaptic compensation in this system. For this, we chronically exposed ex vivo brainstem preparations containing the intact respiratory network to tetrodotoxin (TTX) to stop activity and nimodipine to block L-type Ca2+ channels. We show that hibernation and TTX similarly increased motoneuron synaptic strength and that hibernation occluded the response to TTX. In contrast, inhibiting L-type Ca2+ channels did not upregulate synaptic strength but disrupted the apparent multiplicative scaling of synaptic compensation typically observed in response to hibernation. Thus, inactivity drives up synaptic strength through mechanisms that do not rely on reduced L-type channel function, while Ca2+ signaling associated with the hibernation environment independently regulates the balance of synaptic weights. Altogether, these results point to multiple feedback signals for shaping synaptic compensation that gives rise to proper network function during environmental challenges in vivo.
Monolithic integration of a 10 μm cut-off wavelength InAs/GaSb type-II superlattice diode on GaAs platform
Authors: Kwan D. C. M. , Kesaria M. , Jiménez J. J. , Srivastava V. , Delmas M. , Liang B. L. , Morales F. M. , Huffaker D. L.
Published: July 2022

At room temperature, a 10 µm cut-off wavelength coincides with an infrared spectral window and the peak emission of blackbody objects. We report a 10 µm cut-off wavelength InAs/GaSb T2SL p-i-n diode on a GaAs substrate with an intentional interfacial misfit (IMF) array between the GaSb buffer layer and GaAs substrate. Transmission electron microscopy and energy-dispersive X-ray spectroscopy revealed that the heterostructure on GaSb-on-GaAs is epitaxial, single-crystalline but with a reduced material homogeneity, extended lattice defects and atomic segregation/intermixing in comparison to that on the GaSb substrate. Strain-induced degradation of the material quality is observed by temperature-dependent current–voltage measurements. The T2SL with the IMF array appears as a potentially effective route to mitigate the impact of the lattice mismatch once its fabrication is fully optimized for these systems, but additional strain compensating measures can enable a low cost, scalable manufacturing of focal plane arrays (FPA) for thermal imaging cameras for spectroscopy, dynamic scene projection, thermometry, and remote gas sensing.
A novel and non-invasive method for DNA extraction from dry bee specimens
Authors: Cilia Giovanni , Flaminio Simone , Quaranta Marino
Published: July 2022

In recent years molecular techniques have been used on museum material as integrative support for classic taxonomy. This cumulative systematics approach is especially for rare or extinct specimens, and genetic analysis may be useful to discern information that is not possible to glean from live materials or morphology. To date, the extraction of DNA required at least a partial destruction of the specimens, which is not possible for all individuals, especially the types. In this study, we described a novel method to extract mitochondrial DNA (mtDNA) from pinned museum bee individuals to avoid any external morphological damage. This method was able to amplify the mtDNA Cytochrome C oxidase subunit I (COI) gene in bee samples collected up to 27 years ago. We tested the efficacy of this method on 72 preserved be specimens belonging to nine species among four families, it could be used on many museums’ rare and/or extinct bee species because it does not provide external morphological damages. The method could be helpful for providing ecological, taxonomic, and phylogenetic information about specimens preserved in museum collections.
Presence of periodontitis may synergistically contribute to cancer progression via Treg and IL-6
Authors: Kajihara Ryo , Sakai Hironori , Han Yibing , Amari Kei , Kawamoto Makiko , Hakoyama Yusuke , Nagashio Sachiho , Yamada Shin-ichi , Sanjo Hideki , Kurita Hiroshi
Published: July 2022

A close causal relationship has been suggested to exist between cancer and periodontitis. We hypothesized that the immune surveillance system is impaired in patients with periodontitis, which contributes to cancer development and growth. Therefore, the present study investigated the relationship between immune surveillance mechanisms and periodontitis in cancer patients. The presence or absence of periodontitis was assessed and the peripheral blood (PB) concentrations of IL-6, immunosuppressive cytokines (VEGF, TGF-β1, and CCL22) and proportion of T regulatory cells (Treg, CD3 + CD4 + CD25 + Foxp3 +) were measured. Subjects were classified into the following four groups: non-cancer patients without periodontitis (C − P −), non-cancer patients with periodontitis (C − P +), cancer patients without periodontitis (C + P −), and cancer patients with periodontitis (C + P +). The results of a multivariate analysis showed that the PB concentration of IL-6 was significantly higher in C + than in C- and higher in C + P + than in C + P −. The PB proportion of Treg was significantly higher in C + P + than in C + P −, C − P + , and C − P −. The results of this study suggested that the presence of periodontitis and cancer synergistically increased Treg in PB, which may be one of the underlying causes of immunosuppression and immune evasion in cancer. It was also suggested that the presence of periodontal disease and/or cancer also increases IL-6 in PB, which would be associated with cancer progression. These results suggest the possibility that the presence of periodontitis might synergistically contribute to cancer progression.